WO2004002417A2

WO2004002417A2 - Mammalian ch1 deleted mimetibodies, compositions, methods and uses

Info

Publication number: WO2004002417A2
Application number: PCT/US2003/020347
Authority: WO
Inventors: George A. Heavner; David M. Knight; John Ghrayeb; Bernard J. Scallon; Thomas C. Nesspor; Karen A. Kutoloski
Original assignee: Centocor, Inc.
Priority date: 2002-06-28
Filing date: 2003-06-27
Publication date: 2004-01-08
Also published as: EP1545608A2; EP1545608A4; AU2003280130A1; CN1735433A; WO2004002417A3; JP2006504406A; AU2003280130B2; CA2490409A1

Abstract

The present invention relates to at least one novel human CH1-deleted mimetibody or specified portion or variant, including isolated nucleic acids that encode at least one CH1-deleted mimetibody or specified portion or variant, CH1-deleted mimetibody or specified portion or variants, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, including therapeutic compositions, methods and devices.

Description

MAMMALIAN CHI DELETED MTMETIBODIES, COMPOSITIONS, METHODS AND USES

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to mammalian CHI -deleted mimetibodies, specified portions and variants specific for bologically active proteins, fragment or ligands, CHI -deleted mimetibody encoding and complementary nucleic acids, host cells, and methods of making and using thereof, including therapeutic formulations, administration and devices.

RELATED ART

Recombinant proteins are an emerging class of therapeutic agents. Such recombinant therapeutics have engendered advances in protein formulation and chemical modification. Such modifications can potentially enhance the therapeutic utility of therapeutic proteins, such as by increaseing half lives (e.g., by blocking their exposure to proteolytic enzymes), enhancing biological activity, or reducing unwanted side effects. One such modification is the use of immunoglobulin fragments fused to receptor proteins, such as enteracept. Therapeutic proteins have also been constructed using the Fc domain to attempt to provide a longer half-life or to incorporate functions such as Fc receptor binding, protein A binding, and complement fixation.

Accordingly, there is a need to provide improved and/or modified versions of therapeutic proteins, which overcome one more of these and other problems known in the art.

SUMMARY OF THE INVENTION

The present invention provides isolated human CHI -deleted mimetibodies, including modified immunoglobulins, cleavage products and other specified portions and variants thereof, as well as CH1- deleted mimetibody compositions, encoding or complementary nucleic acids, vectors, host cells, compositions, formulations, devices, transgenic animals, transgenic plants, and methods of making and using thereof, as described and/or enabled herein, in combination with what is known in the art.

The present invention also provides at least one isolated CHI -deleted mimetibody or specified portion or variant as described herein and/or as known in the art. The CHI deleted mimetibody can optionally comprise at least one CH3 region directly linked with at least one CH2 region directly linked with at least one hinge region or fragment thereof directly linked with at least one partial V region, directly linked with an optional linker sequence, directly linked to at least one therapeutic peptide, optionally further directly linked with at least a portion of at least one variable antibody sequence. In a preferred embodiment a pair of a CH3-CH2-hinge-partial J sequence-linker-therapeutic peptide with an option N-terminal antibody sequence, the pair optionally linked by association or covalent linkage, such as, but not limited to, a Cys-Cys disulfide bond. In one embodiment, a CHI deleted mimetibody comprises formula (I):

(Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C- terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and 10, mimicing different types of immunoglobulin molecules, e.g., but not limited to IgGl, IgG2, IgG3, IgG4, IgA, IgM, IgD, IgE, and the like, or combination thereof. Thus, a CHI -deleted mimetibody of the present invention mimics at least a portion of an antibody or immnuoglobulin structure or function with its inherent properties and functions, while providing a therapeutic peptide and its inherent or acquired in vitro, in vivo or in situ properties or activities. The various portions ofthe antibody and therapeutic peptide portions of at least one CHI- deleted mimetibody ofthe present invention can vary as described herein in combinatoin with what is known in the art.

At least one CHI -deleted mimetibody or specified portion or variant ofthe invention mimics the binding ofthe Pep portion ofthe mimetibody to at least one ligand, or has at least one biological activity of, at least one protein, subunit, fragment, portion or any combination thereof.

The present invention also provides at least one isolated CHI -deleted mimetibody or specified portion or variant as described herein and/or as known in the art, wherein the CHI -deleted mimetibody or specified portion or variant has at least one activity, such as, but not limited to known biological activities of at least one bioactive peptide or polypeptide corresponding to the Pep portion of formula I. A CHI -deleted mimetibody can thus be screened for a corresponding activity according to known methods, such as at least one neutralizing activity towards a protein or fragment thereof. In one aspect, the present invention provides at least one isolated mammalian CHI -deleted mimetibody, comprising at least one Pep(n) region comprising at least a bilogically active portion of at least one of SEQ ID NOS: 1-979, or optionally with one or more substitutions, deletions or insertions as described herein and/or as known in the art.

In another aspect, the present invention provides at least one isolated mammalian CHI -deleted mimetibody, wherein the CHI-deleted mimetibody specifically binds at least one epitope comprising at least 1-3, to the entire amino acid sequence of at least one ligand or binding region which ligand binds to at least a portion of at least one of SEQ ID NOS: 1-1109, or optionally with one or more substitutions, deletions or insertions as described herein or as known in the art.

The at least one CHI -deleted mimetibody can optionally further comprise at least one characteristic selected from (i) bind at least one protein with an affinity of at least 10^"9 M, at least 10^"10 M, at least 10^"u M, or at least 10^"12 M; and/or (ii) substantially neutralize at least one activity of at least one protein or portion thereof.

The present invention provides, in one aspect, isolated nucleic acid molecules comprising, complementary, having significant identity or hybridizing to, a polynucleotide encoding specific ' mimetibodies or specified portions or variants thereof, comprising at least one specified sequence, domain, portion or variant thereof. The present invention further provides recombinant vectors comprising at least one of said isolated CHI -deleted mimetibody nucleic acid molecules, host cells containing such nucleic acids and/or recombinant vectors, as well as methods of making and/or using such CHI-deleted mimetibody nucleic acids, vectors and/or host cells. Also provided is an isolated nucleic acid encoding at least one isolated mammalian CH1- deleted mimetibody; an isolated nucleic acid vector comprising the isolated nucleic acid, and/or a prokaryotic or eukaryotic host cell comprising the isolated nucleic acid. The host cell can optionally be at least one selected from COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2, 653, SP2/0, 293, HeLa, myeloma, or lymphoma cells, or any derivative, immortalized or transformed cell thereof. Also provided is a method for producing at least one CHI -deleted mimetibody, comprising translating the CHI -deleted mimetibody encoding nucleic acid under conditions in vitro, in vivo or in situ, such that the CHI -deleted mimetibody is expressed in detectable or recoverable amounts.

The present invention also provides at least one composition comprising (a) an isolated CH1- deleted mimetibody or specified portion or variant encoding nucleic acid and/or CHI -deleted mimetibody as described herein; and (b) a suitable carrier or diluent. The carrier or diluent can optionally be pharmaceutically acceptable, according to known methods. The composition can optionally further comprise at least one further compound, protein or composition.

Also provided is a composition comprising at least one isolated mammalian CHI -deleted mimetibody and at least one pharmaceutically acceptable carrier or diluent. The composition can optionally further comprise an effective amount of at least one compound or protein selected from at least one of a detectable label or reporter, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NTHE), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.

The present invention further provides at least one anti-idiotype antibody to at least one CH1- deleted mimetibody ofthe present invention. The anti-idiotype antibody includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule, such as but not limited to at least one complimetarity determing region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into a CH1- deleted mimetibody ofthe present invention. A CHI -deleted mimetibody ofthe invention can include or be derived from any mammal, such as but not limited to a human, a mouse, a rabbit, a rat, a rodent, a primate, and the like.

The present invention further provides an anti-idiotype antibody or fragment that specifically binds at least one CHI deleted mimetibody ofthe present invention.

The present invention provides, in one aspect, isolated nucleic acid molecules comprising, complementary, or hybridizing to, a polynucleotide encoding at least one CHI -deleted mimetibody anti-idiotype antibody, comprising at least one specified sequence, domain, portion or variant thereof. The present invention further provides recombinant vectors comprising said CHI -deleted mimetibody anti-idiotype antibody encoding nucleic acid molecules, host cells containing such nucleic acids and/or recombinant vectors, as well as methods of making and/or using such anti-idiotype antiobody nucleic acids, vectors and/or host cells.

The present invention also provides at least one method for expressing at least one CH1- deleted mimetibody or specified portion or variant, or CHI -deleted mimetibody anti-idiotype antibody, in a host cell, comprising culturing a host cell as described herein and/or as known in the art under conditions wherein at least one CHI -deleted mimetibody or specified portion or variant, or anti- idiotype antibody is expressed in detectable and/or recoverable amounts.

The present invention further provides at least one CHI -deleted mimetibody, specified portion or variant in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of at least one of a bone and joint disorder, cardiovascular disoder, a dental or oral disorder, a dermatologic disorder, an ear, nose or throat disorder, an endocrine or metabolic disorder, a gastrointestinal disorder, a gynecologic disorder, a hepatic or biliary disorder, a an obstetric disorder, a hematologic disorder, an immunologic or allergic disorder, an infectious disease, a musculoskeletal disorder, a oncologic disorder, a neurologic disorder, a nutritrional disorder, an opthalmologic disorder, a pediatric disorder, a poisoning disorder, a psychiatric disorder, a renal disorder, a pulmonary disorder, or any other known disorder. (See., e.g., The Merck Manual, 17th ed. , Merck Research Laboratories, Merck and Co., Whitehouse Station, NJ (1999), entirely incoporated herein by reference), as needed in many different conditions, such as but not limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in the art.

The present invention further provides at least one CHI -deleted mimetibody, specified portion or variant in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of, at least one immune, cardiovascular, infectious, malignant, and/or neurologic disease in a cell, tissue, organ, animal or patient and/or, as needed in many different conditions, such as but not limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in the art and/or as described herein. The present invention also provides at least one composition, device and/or method of delivery of a therapeutically or prophylactically effective amount of at least one CHI -deleted mimetibody or specified portion or variant, according to the present invention.

The present invention also provides at least one composition comprising (a) an isolated CH1- deleted mimetibody encoding nucleic acid and/or CHI -deleted mimetibody as described herein; and (b) a suitable carrier or diluent. The carrier or diluent can optionally be pharmaceutically acceptable, according to known carriers or diluents. The composition can optionally further comprise at least one further compound, protein or composition.

The present invention further provides at least one CHI -deleted mimetibody method or composition, for administering a therapeutically effective amount to modulate or treat at least one protein related condition in a cell, tissue, organ, animal or patient and/or, prior to, subsequent to, or during a related condition, as known in the art and/or as described herein.

The present invention also provides at least one composition, device and/or method of delivery of a therapeutically or prophylactically effective amount of at least one CHI -deleted mimetibody, according to the present invention. The present invention further provides at least one CHI -deleted mimetibody method or composition, for diagnosing at least one protein related condition in a cell, tissue, organ, animal or patient and/or, prior to, subsequent to, or during a related condition, as known in the art and/or as described herein.

The present invention also provides at least one composition, device and/or method of delivery for diagnosing of at least one CHI -deleted mimetibody, according to the present invention. Also provided is a method for diagnosing or treating a disease condition in a cell, tissue, organ or animal, comprising

(a) contacting or administering a composition comprising an effective amount of at least one isolated mammalian CHI -deleted mimetibody ofthe invention with, or to, the cell, tissue, organ or animal. The method can optionally further comprise using an effective amount of 0.001-50 mg/kilogram ofthe cells, tissue, organ or animal. The method can optionally further comprise using the contacting or the administrating by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal. The method can optionally further comprise administering, prior, concurrently or after the (a) contacting or administering, at least one composition comprising an effective amount of at least one compound or protein selected from at least one of a detectable label or reporter, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug

(NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.

Also provided is a medical device, comprising at least one isolated mammalian CHI -deleted mimetibody ofthe invention, wherein the device is suitable to contacting or administerting the at least one CHI -deleted mimetibody by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal. Also provided is an article of manufacture for human pharmaceutical or diagnostic use, comprising packaging material and a container comprising a solution or a lyophilized form of at least one isolated mammalian CHI-deleted mimetibody ofthe present invention. The article of manufacture can optionally comprise having the container as a component of a parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery device or system. Also provided is a method for producing at least one isolated mammalian CHI -deleted mimetibody ofthe present invention, comprising providing a host cell or transgenic animal or transgenic plant or plant cell capable of expressing in recoverable amounts the CHI -deleted mimetibody. Further provided in the present invention is at least one CHI -deleted mimetibody produced by the above method. The present invention further provides any invention described herein.

DESCRD?TION OF THE INVENTION

The present invention provides isolated, recombinant and/or synthetic mimetibodies or specified portions or variants, as well as compositions and encoding nucleic acid molecules comprising at least one polynucleotide encoding at least one CHI -deleted mimetibody. Such mimetibodies or specified portions or variants ofthe present invention comprise specific CHI -deleted mimetibody sequences, domains, fragments and specified variants thereof. The present invention also provides methods of making and using said nucleic acids and mimetibodies or specified portions or variants, including therapeutic compositions, methods and devices.

The present invention also provides at least one isolated CHI -deleted mimetibody or specified portion or variant as described herein and/or as known in the art. The CHI deleted mimetibody can optionally comprise at least one CH3 region directly linked with at least one CH2 region directly linked with at least one hinge region or fragment thereof directly linked with at least one partial V region, directly linked with an optional linker sequence, directly linked to at least one therapeutic peptide, optionally further directly linked with at least a portion of at least one variable antibody sequence.

In a preferred embodiment a CHI deleted mimetibody comprises formula (I):

(Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C- terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and 10, mimicing different types of immunoglobulin molecules, e.g., but not limited to IgGl, IgG2, IgG3, IgG4, IgA, IgM, IgD, IgE, and the like, or combination thereof. The monomer where m=l can be linked to other monomers by association or covalent linkage, such as, but not limited to, a Cys-Cys disulfide bond. Thus, a CHI-deleted mimetibody ofthe present invention mimics an antibody structure with its inherent properties and functions, while providing a therapeutic peptide and its inherent or acquired in vitro, in vivo or in situ properties or activities. The various portions ofthe antibody and therapeutic peptide portions of at least one CHI -deleted mimetibody ofthe present invention can vary as described herein in combinatoin with what is known in the art. As used herein, a "CHI-deleted mimetibody," "CHI-deleted mimetibody portion," or "CHI- deleted mimetibody fragment" and/or "CHI -deleted mimetibody variant" and the like mimics, has or simulates at least one ligand binding or at least one biological activity of at least one protein, such as but not limited to at least one biologically active portion of at least one of SEQ ID NOS: 1-979, in vitro, in situ and/or preferably in vivo. For example, a suitable CHI-deleted mimetibody, specified portion or variant ofthe present invention can bind at least one protein ligand and includes at least one protein ligand, receptor, soluble receptor, and the like. A suitable CHI -deleted mimetibody, specified portion, or variant can also modulate, increase, modify, activate, at least one protein receptor signaling or other measurable or detectable activity.

Mimetibodies useful in the methods and compositions ofthe present invention are characterized by suitable affinity binding to protein ligands or receptors and optionally and preferably having low toxicity. In particular, a CHI -deleted mimetibody, where the individual components, such as the portion of variable region, constant region (without a CHI portion) and framework, or any portion thereof (e.g., a portion ofthe J, D or V rgions ofthe variable heavy or light chain; the hinge region, the constant heavy chain or light chain, and the like) individually and/or collectively optionally and preferably possess low immunogenicity, is useful in the present invention. The mimetibodies that can be used in the invention are optionally characterized by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as well as other undefined properties, may contribute to the therapeutic results achieved. "Low immunogenicity" is defined herein as raising significant HAMA, HACA or HAHA responses in less than about 75%, or preferably less than about 50, 45, 40, 35, 30, 35, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, and/or 1 % ofthe patients treated and/or raising low titres in the patient treated (less than about 300, preferably less than about 100 measured with a double antigen enzyme immunoassay) (see, e.g., Elliott et al, Lancet 344:1125-1127 (1994)).

Utility The isolated nucleic acids ofthe present invention can be used for production of at least one

CHI -deleted mimetibody, fragment or specified variant thereof, which can be used to effect in an cell, tissue, organ or animal (including mammals and humans), to modulate, treat, alleviate, help prevent the incidence of, or reduce the symptoms of, at least one protein related condition, selected from, but not limited to, at least one of an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant, and/or neurologic disorder or disease, an anemia; an immune/autoimmune; and/or an cancerous/infecteous, as well as other known or specified protein related conditions. Such a method can comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one CHI -deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention, or reduction in symptoms, effects or mechanisms. The effective amount can comprise an amount of about 0.0001 to 500 mg/kg per single or multiple administration, or to achieve a serum concentration of 0.0001-5000 μg ml serum concentration per single or multiple adminstration, or any effective range or value therein, as done and determined using known methods, as described herein or known in the relevant arts.

Citations

All publications or patents cited herein are entirely incorporated herein by reference as they show the state ofthe art at the time ofthe present invention and/or to provide description and enablement ofthe present invention. Publications refer to any scientific or patent publications, or any other information available in any media format, including all recorded, electronic or printed formats. The following references are entirely incorporated herein by reference: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2002); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2^nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); CoUigan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2002); CoUigan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2002).

Mimetibodies ofthe Present Invention

The CHI deleted mimetibody can comprise at least one CH3 region directly linked with at least one CH2 region directly linked with at least one hinge region or fragment thereof directly linked with at least one partial V region, directly linked with an optional linker sequence, directly linked to at least one therapeutic peptide, optionally further directly linked with at least a portion of at least one variable antibody sequence. In a preferred embodiment of a pair of a CH3-CH2-hinge-partial J sequence-linker-therapeutic peptide with an option N-terminal antibody sequence, the pair can be linked by association or covalent linkage, such as, but not limited to, a Cys-Cys disulfide bond. Thus, a CHI-deleted mimetibody ofthe present invention mimics an antibody structure with its inherent properties and functions, while providing a therapeutic peptide and its inherent or acquired in vitro, in vivo or in situ properties or activities. The various portions ofthe antibody and therapeutic peptide portions of at least one CHI -deleted mimetibody ofthe present invention can vary as described herein in combinatoin with what is known in the art. In particular, mimetibodies comprise at least one ligand binding region (LBR) that corresponds to at least one portion of at least one complementarity determining region (CDR, e.g., CDR1, CDR2 or CDR3 of HC or LC variable region) of at least one antibody or fragment or portion thereof where at least one ligand protein is inserted into or replaces at least a portion of at least one CDR ofthe antibody or portion thereof. Such mimetibodies ofthe present invention thus provide at least one suitable property as compared to known proteins, such as, but not limited to, at least one of increased half-life, increased activity, more specific activity, increased avidity, increased or decreased off rate, a selected or more suitable subset of activities, less immungenicity, increased quality or duration of at least one desired therapeutic effect, less side effects, and the like.

Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as described herein. For example, papain or pepsin cleavage can generate CHI -deleted mimetibody Fab or F(ab')₂ fragments, respectively. Other proteases with the requisite substrate specificity can also be used to generate Fab or F(ab')₂ fragments or portions thereof. Mimetibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream ofthe natural stop site. For example, a chimeric gene encoding a F(ab')₂ heavy chain portion can be designed to include DNA sequences encoding the

CHi domain and/or hinge region ofthe heavy chain. The various portions of mimetibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques. For example, a nucleic acid encoding the variable and constant regions of a human antibody chain can be expressed to produce a contiguous protein for use in mimetibodies ofthe present invention. See, e.g., Ladner et al, U.S. Patent No. 4,946,778 and Bird,

R.E. et al, Science, 242: 423-426 (1988), regarding single chain antibodies.

As used herein, the term "human mimetibody" refers to an antibody in which substantially every part ofthe protein (e.g., LBR, framework, C_L, C_H domains (e.g., C_H1, C_H2, C_H3), hinge, (V_L, V_H)) is expected to be substantially non-immunogenic, with only minor sequence changes or variations. Such changes or variations optionally and preferably retain or reduce the immunogenicity in humans relative to non-modified human antibodies, or mimetibodies ofthe prsent invention. Thus, a human antibody and corresponding CHI -deleted mimetibody ofthe present invention is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody and CHI -deleted mimetibody can be produced by a non-human animal or cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes, and for a CHI-deleted mimetibody, wherein at least one Ig CDR is replaced by an LBR of at least one ligand protein or fragment.

Human mimetibodies that are specific for at least one protein ligand or receptor thereof can be designed against an appropriate ligand, such as isolated and/or protein receptor or ligand, or a portion thereof (including synthetic molecules, such as synthetic peptides). Preparation of such mimetibodies are performed using known techniques to identify and characterize ligand binding regions or sequences of at least one protein or portion thereof.

In a preferred embodiment a CHI deleted mimetibody comprises formula (I): (Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C- terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and

10, mimicing different types of immunoglobulin molecules, e.g., but not limited to IgGl, IgG2, IgG3, IgG4, IgA, IgM, IgD, IgE, and the like, or combination thereof. The monomer where m=l can be linked to other monomers by association or covalent linkage, such as, but not limited to, a Cys-Cys disulfide bond. In a preferred embodiment, at least one CHI -deleted mimetibody or specified portion or variant ofthe present invention is produced by at least one cell line, mixed cell line, immortalized cell or clonal population of immortalized and/or cultured cells. Immortalized protein producing cells can be produced using suitable methods. Preferably, the at least one CHI-deleted mimetibody or specified portion or variant is generated by providing nucleic acid or vectors comprising DNA derived or having a substantially similar sequence to, at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement, and which further comprises a mimetibody structure as described herein, e.g., but not limited to Formula (I), wherein known portions of :C- and N- termiinal variable regions can be used for VI and V2, hinge regions for pHinge, CH2 for CH2 and CH3 for CH3, as known in the art. The term "functionally rearranged," as used herein refers to a segment of nucleic acid from an immunoglobulin locus that has undergone V(D)J recombination, thereby producing an immunoglobulin gene that encodes an immunoglobulin chain (e.g., heavy chain, light chain), or any portion thereof. A functionally rearranged immunoglobulin gene can be directly or indirectly identified using suitable methods, such as, for example, nucleotide sequencing, hybridization (e.g., Southern blotting, Northern blotting) using probes that can anneal to coding joints between gene segments or enzymatic amplification of immunoglobulin genes (e.g., polymerase chain reaction) with primers that can anneal to coding joints between gene segments. Whether a cell produces an CHI-deleted mimetibody or portion or variant comprising a particular variable region or a variable region comprising a particular sequence (e.g., at least one Pep sequence can also be determined using suitable methods.

Mimetibodies, specified portions and variants ofthe present invention can also be prepared using at least one CHI -deleted mimetibody or specified portion or variant encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, and the like, that produce such mimetibodies or specified portions or variants in their milk. Such animals can be provided using known methods as applied for antibody encoding sequences. See, e.g., but not limited to, US patent nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of which is entirely incorporated herein by reference.

Mimetibodies, specified portions and variants ofthe present invention can additionally be prepared using at least one CHI -deleted mimetibody or specified portion or variant encoding nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to tobacco and maize) that produce such mimetibodies, specified portions or variants in the plant parts or in cells cultured therefrom. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, e.g., using an inducible promoter. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and references cited therein. Also, transgenic maize have been used to express mammalian proteins at commercial production levels, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and references cited therein. Antibodies have also been produced in large amounts from transgenic plant seeds including antibody fragments, such as single chain mimetibodies (scFv's), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and references cited therein. Thus, mimetibodies, specified portions and variants ofthe present invention can also be produced using transgenic plants, according to know methods. See also, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., Plant Physiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994); and references cited therein. The above references are entirely incorporated herein by reference. The mimetibodies ofthe invention can bind human protein ligands with a wide range of affinities (K_D). In a preferred embodiment, at least one human CHI-deleted mimetibody ofthe present invention can optionally bind at least one protein ligand with high affinity. For example, at least one CHI -deleted mimetibody ofthe present invention can bind at least one protein ligand with a K_D equal to or less than about 10^"9 M or, more preferably, with a K_D equal to or less than about 0.1-9.9 (or any range or value therein) X 10^"10 M, 10^"11, 10^"12 , 10^"13 or any range or value therein.

The affinity or avidity of a CHI -deleted mimetibody for at least one protein ligand can be determined experimentally using any suitable method, e.g., as used for determing antibody-antigen binding affinity or avidity. (See, for example, Berzofsky, et al, "Antibody-Antigen Interactions," In Fundamental Immunology, Paul, W. E., Ed., Raven Press: New York, NY (1984); Kuby, Janis

Immunology, W. H. Freeman and Company: New York, NY (1992); and methods described herein). The measured affinity of a particular CHI -deleted mimetibody-ligand interaction can vary if measured under different conditions (e.g., salt concentration, pH). Thus, measurements of affinity and other ligand-binding parameters (e.g., K_D, K_a, K ) are preferably made with standardized solutions of CHI - deleted mimetibody and ligand, and a standardized buffer, such as the buffer described herein. Nucleic Acid Molecules

Using the information provided herein, such as the nucleotide sequences encoding at least 90- 100% ofthe contiguous amino acids of at least one of SEQID NOS:1-1009 as well as at least one portion of an antibody, wherein the above sequences are inserted as the Pep sequence of Formula (I) to provide a CHI -deleted mimetibody ofthe present invention, further comprising specified fragments, variants or consensus sequences thereof, or a deposited vector comprising at least one of these sequences, a nucleic acid molecule ofthe present invention encoding at least one CHI-deleted mimetibody or specified portion or variant can be obtained using methods described herein or as known in the art. Nucleic acid molecules ofthe present invention can be in the form of RNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA, including, but not limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, or any combination thereof. The DNA can be triple-stranded, double-stranded or single-stranded, or any combination thereof. Any portion of at least one strand ofthe DNA or RNA can be the coding strand, also known as the sense strand, or it can be the non-coding strand, also referred to as the anti-sense strand.

Isolated nucleic acid molecules ofthe present invention can include nucleic acid molecules comprising an open reading frame (ORF), optionally with one or more introns, nucleic acid molecules comprising the coding sequence for a CHI-deleted mimetibody or specified portion or variant; and nucleic acid molecules which comprise a nucleotide sequence substantially different from those described above but which, due to the degeneracy ofthe genetic code, still encode at least one CH1- deleted mimetibody as described herein and/or as known in the art. Of course, the genetic code is well known in the art. Thus, it would be routine for one skilled in the art to generate such degenerate nucleic acid variants that code for specific CHI -deleted mimetibody or specified portion or variants of the present invention. See, e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention.

As indicated herein, nucleic acid molecules ofthe present invention which comprise a nucleic acid encoding a CHI -deleted mimetibody or specified portion or variant can include, but are not limited to, those encoding the amino acid sequence of a CHI -deleted mimetibody fragment, by itself; the coding sequence for the entire CHI -deleted mimetibody or a portion thereof; the coding sequence for a CHI -deleted mimetibody, fragment or portion, as well as additional sequences, such as the coding sequence of at least one signal leader or fusion peptide, intron, non-coding 5' and 3' sequences, such as the transcribed, non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (for example - ribosome binding and stability of mRNA); an additional coding sequence that codes for additional amino acids, such as those that provide additional functionalities. Thus, the sequence encoding a CHI -deleted mimetibody or specified portion or variant can be fused to a marker sequence, such as a sequence encoding a peptide that facilitates purification ofthe fused CHI-deleted mimetibody or specified portion or variant comprising a CHI-deleted mimetibody fragment or portion.

Polynucleotides Which Selectively Hybridize to a Polynucleotide as Described Herein

The present invention provides isolated nucleic acids that hybridize under selective hybridization conditions to a polynucleotide disclosed herein, or others disclosed herein, including specified variants or portions thereof. Thus, the polynucleotides of this embodiment can be used for isolating, detecting, and/or quantifying nucleic acids comprising such polynucleotides. Low or moderate stringency hybridization conditions are typically, but not exclusively, employed with sequences having a reduced sequence identity relative to complementary sequences. Moderate and high stringency conditions can optionally be employed for sequences of greater identity. Low stringency conditions allow selective hybridization of sequences having about 40-99% sequence identity and can be employed to identify orthologous or paralogous sequences. Optionally, polynucleotides of this invention will encode at least a portion of a CHI -deleted mimetibody or specified portion or variant encoded by the polynucleotides described herein. The polynucleotides of this invention embrace nucleic acid sequences that can be employed for selective hybridization to a polynucleotide encoding a CHI-deleted mimetibody or specified portion or variant of the present invention. See, e.g., Ausubel, supra; CoUigan, supra, each entirely incorporated herein by reference. Construction of Nucleic Acids

The isolated nucleic acids ofthe present invention can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, or combinations thereof, as well-known in the art.

The nucleic acids can conveniently comprise sequences in addition to a polynucleotide ofthe present invention. For example, a multi-cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in isolation ofthe polynucleotide. Also, translatable sequences can be inserted to aid in the isolation ofthe translated polynucleotide ofthe present invention. For example, a hexa-histidine marker sequence provides a convenient means to purify the proteins ofthe present invention. The nucleic acid ofthe present invention - excluding the coding sequence - is optionally a vector, adapter, or linker for cloning and/or expression of a polynucleotide ofthe present invention.

Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation ofthe polynucleotide, or to improve the introduction ofthe polynucleotide into a cell. Use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. See, e.g., Ausubel, supra; or Sambrook, supra. Recombinant Methods for Constructing Nucleic Acids

The isolated nucleic acid compositions of this invention, such as RNA, cDNA, genomic DNA, or any combination thereof, can be obtained from biological sources using any number of cloning methodologies known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize, under suitable stringency conditions, to the polynucleotides ofthe present invention are used to identify the desired sequence in a cDNA or genomic DNA library. The isolation of RNA, and construction of cDNA and genomic libraries, is well known to those of ordinary skill in the art. (See, e.g., Ausubel, supra; or Sambrook, supra). Synthetic Methods for Constructing Nucleic Acids The isolated nucleic acids ofthe present invention can also be prepared by direct chemical synthesis by known methods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide, which can be converted into double-stranded DNA by hybridization with a complementary sequence, or by polymerization with a DNA polymerase using the single strand as a template. One of skill in the art will recognize that while chemical synthesis of DNA can be limited to sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter sequences.

Recombinant Expression Cassettes

The present invention further provides recombinant expression cassettes comprising a nucleic acid ofthe present invention. A nucleic acid sequence ofthe present invention, for example a cDNA or a genomic sequence encoding a CHI-deleted mimetibody or specified portion or variant ofthe present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired host cell. A recombinant expression cassette will typically comprise a polynucleotide ofthe present invention operably linked to transcriptional initiation regulatory sequences that will direct the transcription ofthe polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be employed to direct expression ofthe nucleic acids ofthe present invention.

In some embodiments, isolated nucleic acids that serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in intron) of a non-heterologous form of a polynucleotide ofthe present invention so as to up or down regulate expression of a polynucleotide of the present invention. For example, endogenous promoters can be altered in vivo or in vitro by mutation, deletion and/or substitution, as known in the art. A polynucleotide ofthe present invention can be expressed in either sense or anti-sense orientation as desired. It will be appreciated that control of gene expression in either sense or anti-sense orientation can have a direct impact on the observable characteristics. Another method of suppression is sense suppression. Introduction of nucleic acid configured in the sense orientation has been shown to be an effective means by which to block the transcription of target genes. Vectors And Host Cells

The present invention also relates to vectors that include isolated nucleic acid molecules ofthe present invention, host cells that are genetically engineered with the recombinant vectors, and the production of at least one CHI-deleted mimetibody or specified portion or variant by recombinant techniques, as is well known in the art. See, e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirely incorporated herein by reference.

The polynucleotides can optionally be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced into a cell using suitable known methods, such as electroporation and the like, other known methods include the use ofthe vector as a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

The DNA insert should be operatively linked to an appropriate promoter. The expression constructs will further contain sites optionally for at least one of transcription initiation, termination and, in the transcribed region, a ribosome binding site for translation. The coding portion ofthe mature transcripts expressed by the constructs will preferably include a translation initiating at the beginning and a termination codon (e.g., UAA, UGA or UAG) appropriately positioned at the end ofthe mRNA to be translated, with UAA and UAG preferred for mammalian or eukaryotic cell expression. Expression vectors will preferably but optionally include at least one selectable marker. Such markers include, e.g., but not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, US PatNos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, US PatNos. 5,122,464; 5,770,359; 5,827,739) resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for culturing in E. coli and other bacteria or prokaryotics (the above patents are entirely incorporated hereby by reference). Appropriate culture mediums and conditions for the above-described host cells are known in the art. Suitable vectors will be readily apparent to the skilled artisan. Introduction of a vector construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods are described in the art, such as Sambrook, supra, Chapters 1-4 and 16-18; Ausubel, supra, Chapters 1, 9, 13, 15, 16.

At least one CHI-deleted mimetibody or specified portion or variant ofthe present invention can be expressed in a modified form, such as a fusion protein, and can include not only secretion signals, but also additional heterologous functional regions. For instance, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of a CHI -deleted mimetibody or specified portion or variant to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, peptide moieties can be added to a CHI-deleted mimetibody or specified portion or variant ofthe present invention to facilitate purification. Such regions can be removed prior to final preparation of a CHI -deleted mimetibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18.

Those of ordinary skill in the art are knowledgeable in the numerous expression systems available for expression of a nucleic acid encoding a protein ofthe present invention. Illustrative of cell cultures useful for the production ofthe mimetibodies, specified portions or variants thereof, are mammalian cells. Mammalian cell systems often will be in the form of monolayers of cells although mammalian cell suspensions or bioreactors can also be used. A number of suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, and include the COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, hepG2 cells,

P3X63Ag8.653, SP2/0-Agl4, 293 cells, HeLa cells and the like, which are readily available from, for example, American Type Culture Collection, Manassas, Va. Preferred host cells include cells of lymphoid origin such as myeloma and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) and SP2/0-Agl4 cells (ATCC Accession Number CRL-1851). In a particularly preferred embodiment, the recombinant cell is a P3X63Ab8.653 or a SP2/0-Agl4 cell.

Expression vectors for these cells can include one or more ofthe following expression control sequences, such as, but not limited to an origin of replication; a promoter (e.g., late or early SV40 promoters, the CMV promoter (US PatNos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk

(phosphoglycerate kinase) promoter, an EF-1 alpha promoter (US Pat.No. 5,266,491), at least one human ^ήnmunoglobulin promoter; an enhancer, and/or processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences. See, e.g., Ausubel et al., supra; Sambrook, et al., supra. Other cells useful for production of nucleic acids or proteins ofthe present invention are known and/or available, for instance, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas (www.atcc.org) or other known or commercial sources.

When eukaryotic host cells are employed, polyadenlyation or transcription terminator sequences are typically incorporated into the vector. An example of a terminator sequence is the polyadenlyation sequence from the bovine growth hormone gene. Sequences for accurate splicing ofthe transcript can also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)). Additionally, gene sequences to control replication in the host cell can be incorporated into the vector, as known in the art. Purification of an CHI-deleted mimetibody or specified portion or variant Thereof A CHI -deleted mimetibody or specified portion or variant can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography ("HPLC") can also be employed for purification. See, e.g., CoUigan, Current Protocols in

Immunology, or Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2002), e.g., Chapters 1, 4, 6, 8, 9, 10, each entirely incorporated herein by reference.

Mimetibodies or specified portions or variants ofthe present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Depending upon the host employed in a recombinant production procedure, the CHI -deleted mimetibody or specified portion or variant ofthe present invention can be glycosylated or can be non- glycosylated, with glycosylated preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, CoUigan, Protein Science, supra, Chapters 12-14, all entirely incorporated herein by reference. MTMETD3ODIES, SPECTJTED FRAGMENTS AND/OR VARIANTS

The isolated mimetibodies ofthe present invention comprise a CHI-deleted mimetibody or specified portion or variant encoded by any one ofthe polynucleotides ofthe present invention as discussed more fully herein, or any isolated or prepared CHI -deleted mimetibody or specified portion or variant thereof.

Preferably, the CHI -deleted mimetibody or ligand-binding portion or variant binds at least one protein ligand or receptor, and, thereby provides at least one biological activity ofthe corresponding protein or a fragment thereof. Different therapeutically or diagnostically significant proteins are well known in the art and suitable assays or biological activities of such proteins are also well known in the art. The following is a general discussion ofthe variety of proteins, peptides and biological molecules that may be used in the in accordance with the teachings herein. These descriptions do not serve to limit the scope ofthe invention, but rather illustrate the breadth ofthe invention.

Thus, an embodiment ofthe present invention may target one or more growth factors, or, conversely, derive the target-binding moiety from one or more growth factors. Briefly, growth factors are hormones or cytokine proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type. The following Table 1 presents several factors, but is not intended to be comprehensive or complete, yet introduces some ofthe more commonly known factors and their principal activities.

Table 1: Growth Factors

Additional growth factors that may be produced in accordance with the present invention include Activin (Vale et al., 321 Nature 776 (1986); Ling et al, 321 Nature 779 (1986)), Inhibin (U.S. Patent Nos. 4,737,578; 4,740,587), and Bone Morphongenic Proteins (BMPs) (U.S. Patent No. 5,846,931; Wozney, Cellular & Molecular Biology of Bone 131-167 (1993)).

In addition to the growth factors discussed above, the present invention may target or use other cytokines. Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells. Cytokines that are secreted from lymphocytes are termed lymphokines, whereas those secreted by monocytes or macrophages are termed monokines. A large family of cytokines are produced by various cells ofthe body. Many of the lymphokines are also known as interleukins (TLs), because they are not only secreted by leukocytes, but are also able to affect the cellular responses of leukocytes. More specifically, interleukins are growth factors targeted to cells of hematopoietic origin. The list of identified interleukins grows continuously. See, e.g., U.S. Patent No. 6,174,995; U.S. Patent No. 6,143,289; Sallusto et al., 18 Annu. Rev. Immunol. 593 (2000) Kunkel et al., 59 J. Leukocyte Biol. 81 (1996).

Additional growth factor/cytokines encompassed in the present invention include pituitary hormones such as human growth hormone (HGH), follicle stimulating hormones (FSH, FSHα, and FSHβ), Human Chorionic Gonadotrophins (HCG, HCGα, HCGβ), uFSH (urofollitropin), Gonatropin releasing hormone (GRH), Growth Hormone (GH), leuteinizing hormones (LH, LHα, LHβ), somatostatin, prolactin, thyrotropin (TSH, TSHα, TSHβ), thyrotropin releasing hormone (TRH), parathyroid hormones, estrogens, progesterones, testosterones, or structural or functional analog thereof. All of these proteins and peptides are known in the art.

The cytokine family also includes tumor necrosis factors, colony stimulating factors, and interferons. See, e.g., Cosman, 7 Blood Cell (1996); Gruss et al, 85 Blood 3378 (1995); Beutler et al., 7 Annu. Rev. Immunol. 625 (1989); Aggarwal et al., 260 J. Biol. Chem. 2345 (1985); Pennica et al., 312 Nature 724 (1984); R & D Systems, Cytokine Mini-Reviews, at http://www.rndsystems.com. Several cytokines are introduced, briefly, in Table 2 below.

Table 2: Cytokines

Other cytokines of interest that may be produced by the invention described herein include adhesion molecules (R & D Systems, Adhesion Molecule I (1996), at http://www.rndsystems.com); angiogenin (U.S. Patent No. 4,721,672; Moener et al., 226 Eur. J. Biochem. 483 (1994)); annexin V (Cookson et al., 20 Genomics 463 (1994); Grundmann et al., 85 Proc. Natl. Acad. Sci. USA 3708 (1988); U.S. Patent No. 5,767,247); caspases (U.S. Patent No. 6,214,858; Thornberry et al., 281 Science 1312 (1998)); chemokines (U.S. Patent Nos. 6,174,995; 6,143,289; Sallusto et al., 18 Annu. Rev. Immunol. 593 (2000) Kunkel et al., 59 J. Leukocyte Biol. 81 (1996)); endothelin (U.S. Patent Nos. 6,242,485; 5,294,569; 5,231,166); eotaxin (U.S. Patent No. 6,271,347; Ponath et al., 97(3) J. Clin.

Invest. 604-612 (1996)); Flt-3 (U.S. Patent No. 6,190,655); heregulins (U.S. Patent Nos. 6,284,535;

6,143,740; 6,136,558; 5,859,206; 5,840,525); Leptin (Leroy et al, 271(5) J. Biol. Chem. 2365 (1996);

Maffei et al, 92 Proc. Natl. Acad. Sci. USA 6957 (1995); Zhang Y. et al. (1994) Nature 372: 425-432); Macrophage Stimulating Protein (MSP) (U.S. Patent Nos. 6,248,560; 6,030,949; 5,315,000);

Neurotrophic Factors (U.S. Patent Nos. 6,005,081; 5,288,622); Pleiotrophin/Midkine (PTN/MK)

(Pedraza et al, 117 J. Biochem. 845 (1995); Tamura et al, 3 Endocrine 21 (1995); U.S. Patent No.

5,210,026; Kadomatsu et al, 151 Biochem. Biophys. Res. Commun. 1312 (1988)); STAT proteins

(U.S. Patent Nos. 6,030808; 6,030,780; Darnell et al, 277 Science 1630-1635 (1997)); Tumor Necrosis Factor Family (Cosman, 7 Blood Cell (1996); Gruss et al, 85 Blood 3378 (1995); Beutler et al, 7

Annu. Rev. Immunol. 625 (1989); Aggarwal et al, 260 J. Biol. Chem. 2345 (1985); Pennica et al, 312

Nature 724 (1984)).

Also of interest regarding cytokines are proteins or chemical moieties that interact with cytokines, such as Matrix Metalloproteinases (MMPs) (U.S. Patent No. 6,307,089; Nagase, Matrix Metalloproteinases in Zinc Metalloproteinases in Health and Disease (1996)), and Nitric Oxide

Synthases (NOS) (Fukuto, 34 Adv. Pharm 1 (1995); U.S. Patent No. 5,268,465).

The present invention may also be used to affect blood proteins, a generic name for a vast group of proteins generally circulating in blood plasma, and important for regulating coagulation and clot dissolution. See, e.g., Haematologic Technologies, Inc., HTI CATALOG, at www.haemtech.com. Table 3 introduces, in a non-limiting fashion, some ofthe blood proteins contemplated by the present invention.

Table 3: Blood Proteins

Protein Principle Activity Reference

Fibrinogen Plasma fibrinogen, a large glycoprotein, FURLAN, Fibrinogen, IN HUMAN disulfide linked dimer made of 3 pairs PROTEIN DATA, (Haeberli, ed, VCH of non-identical chains (Aa, Bb and g), Publishers, N.Y, 1995); Doolittle, in made in liver. Aa has N-terminal peptide HAEMOSTASIS & THROMBOSIS, 491-513 (fibrinopeptide A (FPA), factor XHIa (3rd ed. Bloom et al, eds, Churchill crosslinking sites, and 2 Livingstone, 1994); HANTGAN, et al, in phosphorylation sites. Bb has HAEMOSTASIS & THROMBOSIS 269-89 fibrinopeptide B (FPB), 1 of 3 N-linked (2d ed, Forbes et al, eds, Churchill carbohydrate moieties, and an N- Livingstone, 1991). terminal pyroglutamic acid. The g chain contains the other N-linked glycos. site, and factor XHJa cross-linking sites. Two elongated subunits ((AaBbg)₂) align in an antiparallel way forming a trinodular arrangement ofthe 6 chains. Nodes formed by disulfide rings between the 3 parallel chains. Central node (n- disulfide knot, E domain) formed by N- termini of all 6 chains held together by 11 disulfide bonds, contains the 2 ϋa- sensitive sites. Release of FPA by cleavage generates Fbn I, exposing a polymerization site on Aa chain. These sites bind to regions on the D domain of Fbn to form proto-fibrils. Subsequent Ila cleavage of FPB from the Bb chain exposes additional polymerization sites, promoting lateral growth of Fbn network. Each ofthe 2 domains between the central node and the C-terminal nodes (domains D and E) has parallel a- helical regions ofthe Aa, Bb and g chains having protease- (plasmin-) sensitive sites. Another major plasmin sensitive site is in hydrophilic preturbance of a-chain from C-terminal node. Controlled plasmin degradation converts Fbg into fragments D and E.

Additional blood proteins contemplated herein include the following human serum proteins, which may also be placed in another category of protein (such as hormone or antigen): Actin, Actinin, Amyloid Serum P, Apolipoprotein E, B2-Microglobulin, C-Reactive Protein (CRP), Cholesterylester transfer protein (CETP), Complement C3B, Ceruplasmin, Creatine Kinase, Cystatin, Cytokeratin 8, Cytokeratin 14, Cytokeratin 18, Cytokeratin 19, Cytokeratin 20, Desmin, Desmocollin 3, FAS (CD95), Fatty Acid Binding Protein, Ferritin, Filamin, Glial Filament Acidic Protein, Glycogen Phosphorylase Isoenzyme BB (GPBB), Haptoglobulin, Human Myoglobin, Myelin Basic Protein, Neurofilament, Placental Lactogen, Human SHBG, Human Thyroid Peroxidase, Receptor Associated Protein, Human Cardiac Troponin C, Human Cardiac Troponin I, Human Cardiac Troponin T, Human Skeletal Troponin I, Human Skeletal Troponin T, Vimentin, Vinculin, Transferrin Receptor, Prealbumin, Albumin, Alpha-1 -Acid Glycoprotein, Alpha- 1-Antichymotrypsin, Alpha- 1-Antitrypsin, Alpha- Fetoprotein, Alpha- 1-Microglobulin, Beta-2-microglobulin, C-Reactive Protein, Haptoglobulin, Myoglobulin, Prealbumin, PSA, Prostatic Acid Phosphatase, Retinol Binding Protein, Thyroglobulin, Thyroid Microsomal Antigen, Thyroxine Binding Globulin, Transferrin , Troponin I, Troponin T, Prostatic Acid Phosphatase, Retinol Binding Globulin (RBP). All of these proteins, and sources thereof, are known in the art. Many of these proteins are available commercially from, for example, Research Diagnostics, Inc. (Flanders, N.J.).

The target in the present invention may also incorporate or target neurotransmitters, or functional portions thereof. Neurotransmitters are chemicals made by neurons and used by them to transmit signals to the other neurons or non-neuronal cells (e.g, skeletal muscle; myocardium, pineal glandular cells) that they innervate. Neurotransmitters produce their effects by being released into synapses when their neuron of origin fires (i.e., becomes depolarized) and then attaching to receptors in the membrane ofthe post-synaptic cells. This causes changes in the fluxes of particular ions across that membrane, making cells more likely to become depolarized, if the neurotransmitter happens to be excitatory, or less likely if it is inhibitory. Neurotransmitters can also produce their effects by modulating the production of other signal-transducing molecules ("second messengers") in the post- synaptic cells. See generally COOPER, BLOOM & ROTH, THE BIOCHEMICAL BASIS OF NEUROPHARMACOLOGY (7th Ed. Oxford Univ. Press, NYC, 1996); http://web.indstate.edu/thcme/mwking/nerves. Neurotransmitters contemplated in the present invention include, but are not limited to, Acetylcholine, Serotonin, γ-aminobutyrate (GABA), Glutamate, Aspartate, Glycine, Histamine, Epinephrine, Norepinephrine, Dopamine, Adenosine, ATP, Nitric oxide, and any ofthe peptide neurotransmitters such as those derived from pre-opiomelanocortin (POMC), as well as antagonists and agonists of any ofthe foregoing.

Numerous other proteins or peptides may serve as either targets, or as a source of target- binding moieties as described herein. Table 4 presents a non-limiting list and description of some pharmacologically active peptides that may serve as, or serve as a source of a functional derivative of, the target ofthe present invention.

Table 4: Pharmacologically active peptides

Peptides

Any number of peptides may be used in conjunction with the present invention. Of particular interest are peptides that mimic the activity of EPO, TPO, growth hormone, G-CSF, GM-CSF, IL-lra, leptin, CTLA4, TRAIL, TGF-α, and TGF-β. Peptide antagonists are also of interest, particularly those antagonistic to the activity of TNF, leptin, any ofthe interleukins (TL-1 - IL-23, etc.), and proteins involved in complement activation (e.g, C3b). Targeting peptides are also of interest, including tumor-homing peptides, membrane-transporting peptides, and the like. All of these classes of peptides may be discovered by methods described in the references cited in this specification and other references.

A particularly preferred group of peptides are those that bind to cytokine receptors. Cytokines have recently been classified according to their receptor code. See Inglot (1 97), Archivum Immunologiae e Therapiae Experimentalis 45: 353-7, which is hereby incorporated entirely by reference.

Non-limiting examples of suitable peptides for this invention appear in Tables 5 through 21 below. These peptides may be prepared by methods disclosed and/or known in the art. Single letter amino acid abbreviations are used in most cases. The X in these sequences (and throughout this specification, unless specified otherwise in a particular instance) means that any ofthe 20 naturally occurring amino acid residues or know derivatives thereof may be present, or any know modified amino acid thereof. Any of these peptides may be linked in tandem (i.e., sequentially), with or without linkers, and a few tandemlinked examples are provided in the table. Linkers are listed as "Δ" and may be any ofthe linkers described herein.

Tandem repeats and linkers are shown separated by dashes for clarity. Any peptide containing a cysteinyl residue may optionally be cross-linked with another Cys-containing peptide, either or both of which may be linked to a vehicle. A few crosslinked examples are provided in the table. Any peptide having more than one Cys residue may form an intrapeptide disulfide bond, as well; see, for example, EPO-mimetic peptides in Table 5. A few examples of intrapeptide disulfide-bonded peptides are specified in the table. Any of these peptides may be derivatized as described herein, and a few derivatized examples are provided in the table. For derivatives in which the carboxyl terminus may be capped with an amino group, the capping amino group is shown as -NH₂. For derivatives in which amino acid residues are substituted by moieties other than amino acid residues, the substitutions are denoted by a δ, which signifies any ofthe moieties known in the art, e.g, as described in Bhatnagar et al. (1996), J. Med. Chem. 39: 3814-9 and Cuthbertson et al. (1997), J. Med. Chem. 40:2876-82, which are entirely incorporated by reference. The J substituent and the Z substituents (Z₅, Zg, ... Z₄₀) are as defined in U.S. Pat. Nos. 5,608,035, 5,786,331, and 5,880,096, which are entirely incorporated herein by reference. For the EPO-mimetic sequences (Table 5), the substituents X₂ through Xn and the integer "n" are as defined in WO 96/40772, which is entirely incorporated by reference. The substituents "*P" "Θ," and "+" are as defined in Sparks et al. (1996), Proc. Natl. Acad. Sci. 93: 1540-4, which is entirely incorporated by reference. X4, X5, X6, and X7 are as defined in U.S. Pat. No. 5,773,569, which is hereby entirely incorporated by reference, except that: for integrin-binding peptides, XI, X2, X3, X4, X5, X6, X7, and X8 (Table 10), are as defined in PCT applications WO 95/14714, published June 1, 1995 and WO 97/08203, published March 6,1997, which are also entirely incorporated by reference; and for VIP- mimetic peptides (Table 13), Xi, Xi', Xj", X , X₃, X₄, X₅, Xβ, and Z; and the integers m and n are as defined in WO 97/40070, published October 30,1997, which is also entirely incorporated herein by reference. Xaa and Yaa below are as defined in WO 98/09985, published March 12,1998, which is entirely incorporated herein by reference. AAj, AA₂, ABi, AB₂, and AC are as defined in International application WO 98/53842, published December 3, 1998, which is entirely incorporated by reference. X¹, X², X³, and X⁴ in Table 18 only are as, defined in European application EP 0 911 393, published April 28,1999, entirely incorporated herein by reference. Residues appearing in boldface are D-amino acids, but can be optionally L-amino acids. All peptides are linked through peptide bonds unless otherwise noted. Abbreviations are listed at the end of this specification. In the "SEQ ID NO." column, "NR" means that no sequence listing is required for the given sequence.

Table 5-EPO-mimetic peptide sequences

Sequence/structure: SEQ ID NO:

YXCXXGPXTWXCXP 1

YXCXXGPXTWXCXP-YXCXXGPXTWXCXP 2

YXCXXGPXTWXCXP-A-YXCXXGPXTWXCXP 3 YXCXXGPXTWXCXP-Δ-ε-amine) 4

\ K /

YXCXXGPXTWXCXP-Δ- (α-amine) 4 GGTYSCHFGPLTWVCKPQGG 5

GGDYHCRMGPLTWVCKPLGG 6

GGVYACRMGPITWVCSPLGG 7

VGNYMCHFGPITWVCRPGGG 8

GGLYLCRFGPVTWDCGYKGG 9 GGTYSCHFGPLTWVCKPQGG- 10

GGTYSCHFGPLTWNCKPQGG -Δ-GGTYSCHFGPLTWVCKPQGG 11

GGTYSCHFGPLTWVCKPQGGSSK 12

GGTYSCHFGPLTWVCKPQGGSSK 13 GGTYSCHFGPLTWVCKPQGGSSK 14 GGTYSCHFGPLTWVCKPQGGSSK-Δ-GGTYSCHFGPLTWVCKPQGGSSK GGTYSCHFGPLTWVCKPQGGSS -Δ-ε-amine)

\ K /

GGTYSCHFGPLTWNCKPQGGSS-Δ- (α-amine) 15

GGTYSCHFGPLT NCKPQGGSSK(-Δ-biotin) 16

GGTYSCHGPLTWVCKPQGG 18 VGΝYMAHMGPITWVCRPGG 19

GGPHHVYACRMGPLTWIC 20

GGTYSCHFGPLTWNCKPQ 21

GGLYACHMGPMTWVCQPLRG 22

TIAQYICYMGPETWECRPSPKA 23 YSCHFGPLTWVCK 24

YCHFGPLTWVC 25

X₃X₄X₅GPX₆TWX₇X₈ 26

YX2X3X4X5GP 6TWX7X8 27

XιYX2X₃X4X5GPX6X7X₈ 9XιoXιι 28 X₁YX₂CX4X₅GPX₆TWX7CX₉XιoXιι 29

GGLYLCRFGPVTWDCGYKGG 30

GGTYSCHFGPLTWNCKPQGG 31

GGDYHCRMGPLTWVCKPLGG 32

VGΝYMCHFGPITWNCRPGGG 33 GGVYACRMGPITWVCSPLGG 34

VGΝYMAHMGPITWVCRPGG 35

GGTYSCHFGPLTWVCKPQ 36

GGLYACHMGPMTWVCQPLRG 37

TIAQYICYMGPETWECRPSPKA 38 YSCHFGPLTWVCK 39

YCHFGPLTWVC 40

SCHFGPLTWVCK 41

(AX₂)_nX₃X₄X5GPX₆TWX₇X₈ 42

Table 6-IL-l antagonist peptide sequences

SEQUENCE/STRUCTURE SEQ ID NO:

XXQZ₅YZ₆XX 44 Z₇XQZ₅YZ₆XX 45

Zι₂Zi₃Zi₄Zi₅Zi₆Zi₇Zι₈Zi₉Z_{2θ 2l}Z₂₂ZπZ₇Z₈QZ₅YZ₆Z₉ZιoL 48

Z₂₃NZ₂₄Z₃₉Z₂5Z₂₆Z₂₇Z₂₈Z₂₉Z3θZ₄o 49 TANVSSFEWTPYYWQPYALPL 50

SWTDYGYWQPYALPISGL 51

ETPFTWEESNAYYWQPYALPL 52

ENTYSPNWADSMYWQPYALPL 53

SVGEDHNFWTSEYWQPYALPL 54 DGYDRWRQSGERYWQPYALPL 55

FEWTPGYWQPY 56

FEWTPGYWQHY 57

FEWTPGWYQJY 58

AcFEWTPGWYQJY 59 FEVffPGWpYQJY 60

FAWTPGYWQJY 61

FEWAPGYWQJY 62

FEWVPGYWQJY 63

FEWTPGYWQJY 64 AcFEWTPGYWQJY 65

FEWTPaWYQJY 66

FEWTPSarWYQJY 67

FEWTPGYYQPY 68

FEWTPGWWQPY 69 FEWTPNYWQPY 70 FEVffPvYWQJY 71 FEWTPecGYWQJY 72 FEWTPAibYWQJY 73 FEVffSarGYWQJY 74 FEWTPGYWQPY 75 FEWTPGYWQHY 76 FEWTPGWYQJY 77 AcFEWTPGWYQJY 78 FEWTPGW-pY-QJY 79 FAWTPGYWQJY 80 FEWAPGYWQJY 81 FEWVPGYWQJY 82 FEWTPGYWQJY 83 AcFEWTPGYWQJY 84 FEWTPAWYQJY 85 FEWTPSarWYQJY 86 FEWTPGYYQPY 87 FEWTPGWWQPY FEWTPNYWQPY 89 FEWTPVYWQJY 90 FEWTPecGYWQJY 91 FEWTPAibYWQJY 92 FEWTSarGYWQJY 93 FEWTPGYWQPYALPL 94

NapEWTPGYYQJY 95

YEWTPGYYQJY 96

FEWVPGYYQJY 97

FEWTPSYYQJY 99

FEWTPNYYQJY "

TKPR 100 RKSSK 101 RKQDK 102 NRKQDK 103 RKQDKR 104 — .^^{i iv}w 105

VTKFYF ₁06

VTKFY ₁07

VTDFY ₁08

5

SHLYWQPYSVQ 109

TLVYWQPYSLQT 110

RGDYWQPYSVQS 111

VHVYWQPYSVQT 112

RLVYWQPYSVQT 113 0 SRVWFQPYSLQS 114

NM WQPYSIQT 115

SWFWQPYSVQT 116

TFVYWQPYALPL 117

TLVYWQPYSIQR 118 5 RLVYWQPYSVQR 119

SPVFWQPYSIQI 120

WIEWWQPYSVQS 121

SLIYWQPYSLQM 122

TRLYWQPYSVQR 123 RCDYWQPYSVQT 124

MRVFWQPYSVQN 125

KΓVΎWQPYSVQT 126

RHLYWQPYSVQR 127

ALVWWQPYSEQI 128 SRVWFQPYSLQS 129

WEQPYALPLE 130

QLVWWQPYSVQR 131

DLRYWQPYSVQV 132

ELVWWQPYSLQL 133 DLVWWQPYSVQW 134

NGNYWQPYSFQV 135

ELVYWQPYSIQR 136

ELMY)AIQPYSVQE 137

NLLYWQPYSMQD 138 GYEWYQPYSVQR 139

CEN0302 -PCT O 2004/002417 ,„„..,,«!. ,„..lf ,rf IC U Ji "*/

LSEQYQPYSVQR 141

GGGWWQPYSVQR 142

VGRWYQPYSVQR 143 VHVYWQPYSVQR 144

QARWYQPYSVQR 145

VHVYWQPYSVQT 146

RSVYWQPYSVQR 147

TRVWFQPYSVQR 148 GRIWFQPYSVQR 149

GRVWFQPYSVQR 150

ARTWYQPYSVQR 151

ARVWWQPYSVQM 152

RLMFYQPYSVQR 153 ESMWYQPYSVQR 154

HFGWWQPYSVHM 155

ARFWWQPYSVQR 156

RLVYWQPYAPIY 157

RLVYWQPYSYQT 158 RLVYWQPYSLPI 159

RLVYWQPYSVQA 160

SRVWYQPYAKGL 161

SRVWYQPYAQGL 162

SRVWYQPYAMPL 163 SRVWYQPYSVQA 164

SRVWYQPYSLGL 165

SRVWYQPYAREL 166

SRVWYQPYSRQP 167

SRVWYQPYFVQP 168 EYEWYQPYALPL 169

IPEYWQPYALPL 170

SRIWWQPYALPL 171

DPLFWQPYALPL 172

SRQWVQPYALPL 173 ΓRSWWQPYALPL 174

CEN0302-PCT RGYWQPYALPL 175

RLLWVQPYALPL 176

EYRWFQPYALPL 177

DAYWVQPYALPL 178 WSGYFQPYALPL 179

NIEFWQPYALPL 180

TRDWVQPYALPL 181

DSSWYQPYALPL 182

IGNWYQPYALPL 183 NLRWDQPYALPL 184

LPEFWQPYALPL 185

DSYWWQPYALPL 186

RSQYYQPYALPL 187

ARFWLQPYALPL 188 NSYFWQPYALPL 189

RFMYWQPYSVQR 190

AHLFWQPYSVQR 191

WWQPYALPL 192

YYQPYALPL 193 YFQPYALGL 194

YWYQPYALPL 195

RWWQPYATPL 196

GWYQPYALGF 197

YWYQPYALGL 198 IWYQPYAMPL 199

SNMQPYQRLS 200

TFVYWQPYAVGLPAAETACN 201

TFVYWQPYSVQMTITGKVTM 202

TFVYWQPYSSHXXVPXGFPL 203 TFVYWQPYYGNPQWAIHVRH 204

TFVYWQPYVLLELPEGAVRA 205

TFVYWQPYVDYVWPΓPIAQV 206

GWYQPYVDGWR 207

RWEQPYVKDGWS 208 EWYQPYALGWAR 209 GWWQPYARGL 210

LFEQPYAKALGL 211

GWEQPYARGLAG 212

AWVQPYATPLDE 213 MWYQPYSSQPAE 214

GWTQPYSQQGEV 215

DWFQPYSIQSDE 216

PWIQPYARGFG 217

RPLYWQPYSVQV 218 TLΓYWQPYSVQI 219

RFDYWQPYSDQT 220

WHQFVQPYALPL 221

EWDSVYWQPYSVQTLLR 223

WEQNVYWQPYSVQSFAD 224 SDVVYWQPYSVQSLEM 225

YYDGVYWQPYSVQVMPA 226

SDIWYQPYALPL 227

QRIWWQPYALPL 228

SRIWWQPYALPL 229 RSLYWQPYALPL 230

TΠWEQPYALPL 231

WETWYQPYALPL 232

SYDWEQPYALPL 233

SRIWCQPYALPL 234 EIMFWQPYALPL 235

DYVWQQPYALPL _N 236

MDLLVQWYQPYALPL 237

GSKVILWYQPYALPL 238

RQGANIWYQPYALPL 239 GGGDEPWYQPYALPL 240

SQLERTWYQPYALPL 241

ETWVREWYQPYALPL 242

KKGSTQWYQPYALPL 243

LQARMNWYQPYALPL 244 EPRSQKWYQPYALPL 245 VKQKWRWYQPYALPL 246

LRRHDVWYQPYALPL 247

RSTASIWYQPYALPL 248

ESKEDQWYQPYALPL 249 EGLTMKWYQPYALPL 250

EGSREGWYQPYALPL 251

VΓEWWQPYALPL 252

VWYWEQPYALPL 253

ASEWWQPYALPL 254 FYEWWQPYALPL 255

EGWWVQPYALPL 256

WGEWLQPYALPL 257

DYVWEQPYALPL 258

AHTWWQPYALPL 259 FIEWFQPYALPL 260

WLAWEQPYALPL 261

VMEWWQPYALPL 262

ERMWQPYALPL 263

NXXWXXPYALPL 264 WGNWYQPYALPL 265

TLYWEQPYALPL 266

VWRWEQPYALPL 267

LLWTQPYALPL 268

SRIWXX PYALPL 269 SDIWYQPYALPL 270

WGYYXX PYALPL 271

TSGWYQPYALPL 272

VHPYXXPYALPL 273

EHSYFQPYALPL 274 XXIWYQPYALPL 275

AQLHSQPYALPL 276

WANWFQPYALPL 277

SRLYSQPYALPL 278

GVTFSQPYALPL 279 SrVWSQPYALPL 280 SRDLVQPYALPL 281

HWGHVYWQPYSVQDDLG 282

SWHSVYWQPYSVQSVPE 283

WRDSVYWQPYSVQPESA 284 TWDAVYWQPYSVQKWLD 285

TPPWVYWQPYSVQSLDP 286

YWSSVYWQPYSVQSVHS 287

YWYQPYALGL 288

YWYQPYALPL 289 EWIQPYATGL 290

NWEQPYAKPL 291

AFYQPYALPL 292

FLYQPYALPL 293

VCKQPYLEWC 294 ETPFTWEESNAYYWQPYALPL 295

QGWLTWQDSVDMYWQPYALPL 296

FSEAGYTWPENTYWQPYALPL 297

TESPGGLDWAKTYWQPYALPL 298

DGYDRWRQSGERYWQPYALPL 299 TANVSSFEWTPGYWQPYALPL 300

SVGEDHNFWTSE YWQPYALPL 301

MNDQTSEVSTFPYWQPYALPL 302

SWSEAFEQPRNLYWQPYALPL 303

QYAEPSALNDWGYWQPYALPL 304 NGDWATADWSNYYWQPYALPL 305

THDEHΓYWQPYALPL 306

MLEKTYTTWTPG YWQPYALPL 307

WSDPLTRDADLYWQPYALPL 308

SDAFTTQDSQAMYWQPYALPL 309 GDDAAWRTDSLTYWQPYALPL 310

AΠRQLYRWSEMYWQPYALPL 311

ENTYSPNWADSMYWQPYALPL 312

MNDQTSEVSTFPYWQPYALPL 313

S VGEDHNF WTSEY WQPYALPL 314 QTPFTWEESNAYYWQPYALPL 315 ENPFTWQESNAYYWQPYALPL 316

VTPFTWEDSNVF YWQPYALPL 317

QIPFTWEQSNAYYWQPYALPL 318

QAPLTWQESAAYYWQPYALPL 319 EPTFTWEESKAT YWQPYALPL 320

TTTLTWEESNAYYWQPYALPL 321

ESPLTWEESSALYWQPYALPL 322

ETPLTWEESNAYYWQPYALPL 323

EATFTWAESNAYYWQPYALPL 324 EALFTWKESTAYYWQPYALPL 325

STP-TWEESNAYYWQPYALPL 326

ETPFTWEESNAYYWQPYALPL 327

KAPFTWEESQAYYWQPYALPL 328

STSFTWEESNAYYWQPYALPL 329 DSTFTWEESNAYYWQPYALPL 330

YIPFTWEESNAYYWQPYALPL 331

QTAFTWEESNAYYWQPYALPL 332

ETLFTWEESNAT YWQPYALPL 333

VSSFTWEESNAYYWQPYALPL 334 QPYALPL 335

Py-1-NapPYQJYALPL 336

TANVSSFEWTPG YWQPYALPL 337

FEWTPGYWQPYALPL 338

FEWTPGYWQJYALPL 339 FEWTPGYYQJYALPL 340

ETPFTWEESNAYYWQPYALPL 341

FTWEESNAYYWQJYALPL 342

ADVLYWQPYAPVTLWV 343

GDVAEYWQPYALPLTSL 344 SWTDYGYWQPYALPISGL 345

FEWTPGYWQPYALPL 346

FEWTPGYWQJYALPL 347

FEWTPGWYQPYALPL 348

FEWTPGWYQJYALPL 349 FEWTPGYYQPYALPL 350 FEWTPGYYQJYALPL 351

TANVSSFEWTPGYWQPYALPL 352

SWTDYGYWQPYALPISGL 353

ETPFTWEESNAWAIQPYALPL 354 ENTYSPNWADSMYWQPYALPL 355

SVGEDHNFWTSEYWQPYALPL 356

DGYDRWRQSGERYWQPYALPL 357

FEWTPGYWQPYALPL 358

FEWTPGYWQPY 359 FEWTPGYWQJY 360

EWTPGYWQPY 361

FEWTPGWYQJY 362

AEWTPGYWQJY 363

FAWTPGYWQJY 364 FEATPGYWQJY 365

FEWAPGYWQJY 366

FEWTAGYWQJY 367

FEWTPAYWQJY 368

FEWTPGAWQJY 369 FEWTPGYAQJY 370

FEWTPGYWQJA 371

FEWTGGYWQJY 372

FEWTPGYWQJY 373

FEWTJGYWQJY 374 FEVffPecGYWQJY 375

FEWTPAibYWQJY 376

FEWTPSarWYQJY 377

FEWTSarGYWQJY 378

FEWTPNYWQJY 379 FEWTPVYWQJY 380 FEWTVPYWQJY 381

AcFEWTPGVVYQJY 382

AcFEVffPGYWQJY 383

INap-EVffPGYYQJY 384 YEWTPGYYQJY 385 FEWVPGYYQJY 386

FEVffPGYYQJY 387

FEVffPsYYQJY 388

FEWTPnYYQJY 389 SHLY-Nap-QPYSVQM 390

TLVY-Nap-LDPYSLQT 391

RGDY-Nap-QPYSVQS 392

NMVY-Nap-QPYSIQT 393

VYWQPYSVQ 394 VY-Nap-QPYSVQ 395

TFVYWQJYALPL 396

FEWTPGYYQJ-Bpa 397

XaaFEWTPGYYQJ-Bpa 398

FEWTPGY-Bpa-QJY 399 AeFEWTPGY-Bpa-QJY 400

FEWTPG-Bpa-YQJY 401

AcFEWTPG-Bpa-YQJY 402

AcFE-Bpa-TPGYYQJY 403

AcFE-Bpa-TPGYYQJY 404 Bpa-EWTPGYYQJY 405

AcBpa-EWTPGYYQJY 406

VYWQPYSVQ 407

RLVYWQPYSVQR 408

RLVY-Nap-QPYSVQR 409 RLDYWQPYSVQR 410

RLVWFQPYSVQR 411

RLVYWQPYSIQR 412

DNSSWYDSFLL 413

DNTAWYESFLA 414 DNTAWYENFLL 415

PAREDNTAWYDSFLIWC 416

TSEYDNTTWYEKFLASQ 417

SQIPDNTAWYQSFLLHG 418

SPFΓDNTAWYENFLLTY 419 EQIYDNTAWYDHFLLSY 420 TPFΓDNTAWYENFLLTY 421

TYTYDNTAWYERFLMSY 422

TMTQDNTAWYENFLLSY 423

TΓDNTAWYANLVQTYPQ 424 TIDNTAWYERFLAQYPD 425

HTDNTAWYENFLLTYTP 426

SQDNTAWYENFLLSYKA 427

QIDNTAWYERFLLQYNA 428

NQDNTAWYESFLLQYNT 429 TΓDNTAWYENFLLNHNL 430

HYDNTAWYERFLQQGWH 431

ETPFTWEESNAYYWQPYALPL 432

YIPFTWEESNAYYWQPYALPL 433

DGYDRWRQSGERYWQPYALPL 434 pY-INap-pY-QJYALPL 435

TANVSSFEWTPGYWQPYALPL 436

FEWTPGYWQJYALPL 437

FEWTPGYWQPYALPLSD 438

FEWTPGYYQJYALPL 439 FEWTPGYWQJY 440

AcFEWTPGYWQJY 441

AcFEWTPGWYQJY 442

AcFEWTPGYYQJY 443

AcFEWTPaYWQJY 444 AcFEWTPaWYQJY 445

AcFEWTPaYYQJY 446

FEWTPGYYQJYALPL 447

FEWTPGYWQJYALPL 448

FEWTPGWYQJYALPL 449 TANVSSFEWTPGYWQPYALPL 450

AcFEWTPGYWQJY 451

AcFEWTPGWYQJY 452

AcFEWTPGYYQJY 453

AcFEWTPAYWQJY 454 AcFEWTPAWYQJY 455 f AcFEWTPAYYQJY 456 Table 7-TPO-mimetic peptide sequences

Table 8-G-CSF-mimetic peptide sequences

Sequence/structure SEQ ID NO:

EEDCK 519 EEDαK 520 pGluEDαK 521

PicSDαK 522

EEDCK-Δ-EEDCK 523

EEDXK-Δ-EEDXK 524

Table 9-TNF-antagonist peptide sequences

Sequence/structure SEQ ID NO:

YCFTASENHCY 525 YCFTNSENHCY 526

YCFTRSENHCY 527

FCASENHCY 528

YCASENHCY 529

FCNSENHCY 530 FCNSENRCY 531

FCNSVENRCY 532

YCSQSVSNDCF 533

FCVSNDRCY 534

YCRKELGQVCY 535 YCKEPGQCY 536

YCRKEMGCY 537

FCRKEMGCY 538

YCWSQNLCY 539

YCELSQYLCY 540 YCWSQNYCY 541

YCWSQYLCY 542

DFLPHYKNTSLGHRP 543

Table 10-Integrin-binding peptide sequences Sequence/structure SEQ ID NO:

RXιETX2WX₃ 544

RGDGX 546

CRGDGXC 547

CXιX₂RLDX₃X₄C 548

CARRLDAPC 549

CPSRLDSPC 550

CX₂CRGDCX5C 552

CDCRGDCFC 553

CDCRGDCLC 554

CLCRGDCIC 555

X,X2X₃DDX4X5X6X7X₈ 557

CWDDGWL 558

CWDDLWWLC 559

CWDDGLMC 560 CWDDGWMC 561

CSWDDGWLC 562

CPDDLWWLC 563

NGR NR

GSL NR RGD NR

CGRECPRLCQSSC 564

CNGRCVSGCAGRC 565

CLSGSLSC 566

RGD NR NGR NR

GSL NR

NGRAHA 567

CNGRC 568

CDCRGDCFC 569 CGSLVRC 570 DLXXL 571

RTDLDSLRTYTL 572

RTDLDSLRTY 573

RTDLDSLRT 574 RTDLDSLR 575

GDLDLLKLRLTL 576

GDLHSLRQLLSR 577

RDDLHMLRLQLW 578

SSDLHALKKRYG 579 RGDLKQLSELTW 580

RGDLAALSAPPV 581

Table 11-Selectin antagonist peptide sequences

Sequence/structure SEQ ID NO:

DITWDQLWDLMK 582

DITWDELWKIMN 583

DYTWFELWDMMQ 584

QITWAQLWNMMK 585 DMTWHDLWTLMS 586

DYSWHDLWEMMS 587

EITWDQLWEVMN 588

HVSWEQLWDIMN 589

HITWDQLWRIMT 590 RNMSWLELWEHMK 591

AEWTWDQLWHVMNPAESQ 592

HRAEWLALWEQMSP 593

KKEDWLALWRIMSV 594

ITWDQLWDLMK 595 DITWDQLWDLMK 596

DITWDQLWDLMK 597

DITWDQLWDLMK 598

CQNRYTDLVAIQNKNE 599

AENWADNEPNNKRNNED 600 RKNNKTWTWVGTKKALTNE 601 KKALTNEAENWAD 602

CQXRYTDLVAIQNKXE 603

RKXNXXWTWVGTXKXLTEE 604

AENWADGEPNNKXNXED 605 CXXXYTXLVAIQNKXE 606

RKXXXXWXWVGTXKXLTXE 607

AXNWXXXEPNNXXXED 608

XKXKTXEAXNWXX 609

Table 12-Antipathogenic peptide sequences

Sequence/structure SEQ ID NO:

GFFALΓPKΠSSPLFKTLLSAVGSALSSSGGQQ 61 o

GFFALIPKΠSSPLFKTLLSAVGSALSSSGGQE 611 GFFALΓPKΠSSPLFKTLLSAV 612

GFFALPKHSSPLFKTLLSAV 613

KGFFALΓPKΠSSPLFKTLLSAV βu

KKGFFALΓPKΠSSPLFKTLLSAV βis

KKGFFALΓPKΠSSPLFKTLLSAV 6i6 GFFALIPKΠS 6\1

GIGAVLKVLTTGLPALISWΓKRKRQQ 618

GIGAVLKVLTTGLPALISWΓKRKRQQ 619

GIGAVLKVLTTGLPALISWIKRKRQQ 620

GIGAVLKVLTTGLPALISWIKR 621 AVLKVLTTGLPALISWTKR 622

KLLLLLKLLLLK 623

KLLLKLLLKLLK 624

KLLLKLKLKLLK 625

KKLLKLKLKLKK 626 KLLLKLLLKLLK 627

KLLLKLKLKLLK 628

KLLLLK 629

KLLLKLLK 630

KLLLKLKLKLLK 631 KLLLKLKLKLLK 632 KLLLKLKLKLLK 633

KAAAKAAAKAAK 634

KWVKVWKVVK 635

KWVKVKVKWK 636

KVWKVKVKVK 637

KWVKVKVKWK 638

KLILKL 639

KVLHLL 640

LKLRLL ⁶⁴¹

KPLHLL ⁶⁴²

KLILKLVR ⁶⁴³

KVFHLLHL ⁶⁴⁴

HKFRILKL ⁶⁴⁵

KPFHILHL ⁶⁴⁶ κiirκικικπκ ⁶⁴⁷ κmκικrκιικ ⁶⁴⁸

KIIIKIKIKiIK 649

KΓPΓKΓKIKIPK ⁶⁵⁰

KIPIKIKΓKΓVK ⁶⁵¹ RIJIRΓRIRIIR ⁶⁵²

RπiRIRIRπR ⁶⁵³

W[IRIRΓRΠR ⁶⁵⁴

RΓVIRIRIRLΓR 655

RIΓVRIRLRΠR 656 MGΓRLRVRΠR 657

KINIRIRIRLIR 658

RIAVKWRLRFΓK 659

KIGWKLRVRJJR 660

KKIGWLΠRVRR 661 RWIRIRΓRLΓRIR 662

RΠVRΓRLRΠRVR 663

RIGIRLRVRΠRRV 664

KINIRIRARLiRIRIR 665

RIIVKIRLRIΓKKTRL 666 KIGIKARVRΠRVKΠ 667 RIWHIRLRriHHIRL 668 fflGIKAHVRπRVHπ 669

RIWKIHLRYIKKIRL 670

KIGHKARVHΠRYKΠ 67 I RIYVKPHPRYIKKIRL 672

KPGHKARPHΠRYKΠ 673

KWIRIRIRLIRIRΓRKΓV 674

RTIVKIRLRIIKKIRLIKK 675

KIGWKLRVRΠRVKIGRLR 676 KINIRIRIRLrRIRmKIVKVKRIR 677

RFAVKIRLRIIKKMLKKIRKRVIK 678

KAGWKLRVRIIRVKIGRLRKIGWKKRVRIK 679

RΓYVKPHPRYIKKΓRL 68O

KPGHKARPHΠRYKΠ 68 I KIVIRIRIRLrWRIRKlV 682

RIIVKIRLRIIKKIRLIKK 683

RIYVSKISIYIKiαRL 684

KIVIFTRIRLTSΓRΠISΓV 685

KPfflKARPTHRYKMI 686 cyclicCKGFFALIPKHSSPLFKTLLSAVC 687

CKKGFFALIPKIISSPLFKTLLSAVC 688

CKKKGFFALIPKπSSPLFKTLLSAVC 689

CyclicCRWIRTRIRLIRIRC 690

CyclicCKPGHKARPHπRYKIIC 691 CyclicCRFAVKIRLRIIJKJ RLKXαRKRVrKC 692

KLLLKLLL KLLKC 693

KLLLKLLLKLLK 694

KLLLKLKLKLLKC 695

KLLLKLLLKLLK 696

Table 13-VJP-mimetic peptide sequences

Sequence/structure SEQ ID NO:

HSDAVFYDNYTR LRKQMAVKKYLN SILN 697

Me HSDAVFYDNYTR LRKQMAVKKYLN SILN 698 X_l X X_l" X₂ 699

KKYL 701

NSΓLN 702

KKYL 703 KKYA 704

AVKKYL 705

NSILN 706

KKYV 707

SILauN 708 KKYLNIe 709

NSYLN 710

NSJYN 711

KKYLPPNSILN 712

LauKKYL 713 CapKKYL 714

KYL NR

KKYNIe 715

VKKYL 716

LNSπ-N 717 YLNSILN 718

KKYLN 719

KKYLNS 720

KKYLNSI 721

KKYLNSIL 722 KKYL 723

KKYDA 724

AVKKYL 725

NSILN 726

KKYV 727 SILauN 728

NSYLN 729 SIYN 730

KKYLNIe 731

KKYLPPNSILN 732 KKYL 733 KKYDA 734

AVKKYL 735

NSILN 736

IKKYV 737 SILauN 738

LauKKYL 739

CapKKYL 740

KYL NR

KYL NR KKYNIe 741

VKKYL 742

LNSILN 743

YLNSILN 744

KKYLNIe 745 KKYLN 746

KKYLNS 747

KKYLNSI 748

KKYLNSIL 749

KKKYLD 750 cyclicCKKYLC 751

CKKYLK 752

KKYA 753

WWTDTGLW 754

WWTDDGLW 755 WWDTRGLWVWTI 756

FWGNDGIWLESG 757

DWDQFGLWRGAA 758

RWDDNGLWVWL 759

SGMWSHYGIWMG 760 GGRWDQAGLWVA 761

KLWSEQGIWMGE 762

CWSMHGLWLC 763

GCWDNTGIWVPC 764

DWDTRGLWVY 765 SLWDENGAWI 766

f KWDDRGLWMH 767

QAWNERGLWT 768

QWDTRGLWVA 769

WNVHGIWQE 770 SWDTRGLWVE 771

DWDTRGLWVA 772

SWGRDGLWTE 773

EWTDNGLWAL 774

SWDEKGLWSA 775 SWDSSGLWMD 776

Table 14-Mdm/hdm antagonist peptide sequences

Sequence/structure SEQ ID NO:

TFSDLW 777 QETFSDLWKLLP 778

QPTFSDLWKLLP 779

QETFSDYWKLLP 780

QPTFSDYWKLLP 781

MPRFMDYWEGLN 782 VQNFIDYWTQQF 783

TGPAFTHYWATF 784

IDRAPTFRDHWFALV 785

PRPALVFADYWETLY 786

PAFSRFWSDLSAGAH 787 PAFSRFWSKLSAGAH 788

PXFXDYWXXL 789

QETFSDLWKLLP 790

QPTFSDLWKLLP 791

QETFSDYWKLLP 792 QPTFSDYWKLLP 793

Table 15-Calmodulin antagonist peptide sequences

Sequence/structure SEQ ID NO: SCVKWGKKEFCGS 794 SCWKYWGKECGS 795

SCYEWGKLRWCGS 796

SCLRWGKWSNCGS 797

SCWRWGKYQICGS 798 SCVSWGALKLCGS 799

SCIRWGQNTFCGS 800

SCWQWGNLKICGS 801

SCVRWGQLSICGS 802

LKKFNARRKLKGAILTTMLAK 803 RRWKKNFIAVSAANRFKK 804

RKWQKTGHAVRAIGRLSS 805

ΓNLKALAALAKKΓL 806

KIWSILAPLGTTLVKLVA _, 807

LKKLLKLLKKLLKL 808 LKWKKLLKLLKKLLKKLL 809

AEWPSLTEΓKTLSHFSV βio

AEWPSPTRVISTTYFGS 811

AELAHWPPVKTVLRSFT 812

AEGSWLQLLNLMKQMNN 813 AEWPSLTEIK 814

Table 16-Mast cell antagonists/Mast cell protease inhibitor peptide sequences

Sequence/structure SEQ ID NO: SGSGVLKRPLPILPVTR 815

RWLSSRPLPPLPLPPRT 816

GSGSYDTLALPSLPLHPMSS 817

GSGSYDTRALPSLPLHPMSS 818

GSGSSGVTMYPKLPPHWSMA 819 GSGSSGVRMYPKLPPHWSMA 820

GSGSSSMRMVPTΓPGSAKHG 821

RNR NR

QT NR

RQK NR NRQ NR RQK NR

RNRQKT 822

RNRQ 823

RNRQK 824 NRQKT 825

RQKT 826

Table 17-SH3 antagonist peptide sequences

Sequence/structure SEQ ID NO:

RPLPPLP 827

RELPPLP 828

SPLPPLP 829

GPLPPLP 830 RPLPIPP 831

RPLPrPP 832

RRLPPTP 834

RQLPPTP 835

RPLPSRP 836 RPLPTRP 837

SRLPPLP 838

RALPSPP 839

RRLPRTP 840

RPVPPIT 841 ILAPPVP 842

RPLPMLP 843

RPLPILP 844

RPLPSLP 845

RPLPSLP 846 RPLPMIP 847

RPLPLIP 848

RPLPPTP 849

RSLPPLP 850

RPQPPPP 851 RQLPIPP 852 XXXRPLPPLPXP 853

XXXRPLPPIPXX 854

XXXRPLPPLPXX 855

RXXRPLPPLPXP 856 RXXRPLPPLPPP 857

PPPYPPPPIPXX 858

PPPYPPPPVPXX 859

LXXRPLPXTP 860

ΨXXRPLPXLP 861 PPXΘXPPPΨP 862

+PPΨPXKPXWL 863

RPXΨPΨR+SXP 864

PPVPPRPXXTL 865

ΨPΨLPΨK 866 +ΘDXPLPXLP 867

Table 18-Somatostatin or cortistatin mimetic peptide sequences

Sequence/structure SEQID NO: X^ -Asn-Phe-Phe-Trp-Lys-Thr-Phe-X^Ser-X⁴ 868

Asp Arg Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys Lys 869

Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys Lys 870

Cys Arg Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys Lys 871

Asp Arg Met Pro_Cys Arg Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 872 Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 873

Cys Arg Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 874

Asp Arg Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 875

Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys Lys 876

Cys Lys Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys Lys 877 Asp Arg Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 878

Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 879

Cys Lys Asn Phe Phe Trp Lys Thr Phe Ser Ser Cys 880

Asp Arg Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Lys 881

Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Lys 882 Cys Arg Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Lys 883

Asp Arg Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 884

Met Pro Cys Arg Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 885

Cys Arg Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 886

Asp Arg Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Lys 887

Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Lys 889

Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Lys 890

Asp Arg Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 891

Met Pro Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 892

Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 893

Table 19-UKR antagonist peptide sequences

Sequence/structure SEQID O: AEPMPHSLNFSQYLWYT 894 AEHTYSSLWDTYSPLAF 895 AELDLWMRHYPLSFSNR 896 AESSLWTRYAWPSMPSY 897 AEWHPGLSFGSYLWSKT 898 AEPALLNWSFFFNPGLH 899 AEWSFYNLHLPEPQTTF 900 AEPLDLWSLYSLPPLAM 901 AEPTLWQLYQFPLRLSG 902 AEISFSELMWLRSTPAF 903 AELSEADLWTTWFGMGS 904 AESSLWPJFSPSALMMS 905 AESLPTLTSILWGKESV 906 AETLFMDLWHDKHTLLT 907 AEILNFPLWHEPLWSTE 908 AESQTGTLNTLFWNTLR 909 AEPVYQYELDSYLRSYY 910 AELDLSTFYDIQYLLRT 911 AEFFKLGPNGYVYLHSA 912 FKLXXXGYVYL 913 AESTYHHLSLGYMYTLN 914 YHXLXXGYMYT 915

Table 20-Macrophage and/or T-cell inhibiting peptide sequences

Sequence/structure SEQ ID NO:

Xaa-Yaa-Arg NR Arg-Yaa-Xaa NR

Xaa-Arg-Yaa NR

Yaa-Arg-Xaa NR

Ala-Arg NR

Arg-Arg NR Asn-Arg NR

Asp-Arg NR

Cys-Arg NR

GIn-Arg NR

Glu-Arg NR Gly-Arg NR

His-Arg NR

Ile-Arg NR

Leu-Arg NR

Lys-Arg NR Met-Arg NR

Phe-Arg NR

Ser-Arg NR

Thr-Arg NR

Trp-Arg NR Tyr-Arg NR

Val-Arg NR

Ala-Glu-Arg NR

Arg-Glu-Arg NR

Asn-Glu-Arg NR Asp-Glu-Arg NR

Cys-Glu-Arg NR

Gln-Glu-Arg NR

Glu-Glu-Arg NR

Gly-Glu-Arg NR His-Glu-Arg NR Ile-Glu-Arg NR

Leu-Glu-Arg NR

Lys-Glu-Arg NR

Met-Glu-Arg NR Phe-Glu-Arg NR

Pro-Glu-Arg NR

Ser-Glu-Arg NR

Thr-GIu-Arg NR

Trp-Glu-Arg NR Tyr-Glu-Arg NR

Val-Glu-Arg NR

Arg-Ala NR

Arg-Asp NR

Arg-Cys NR Arg-Gln NR

Arg-Glu NR

Arg-Gly NR

Arg-His NR

Arg-Ile NR Arg-Leu NR

Arg-Lys NR

Arg-Met NR

Arg-Phe NR

Arg-Pro NR Arg-Ser NR

Arg-Thr NR

Arg-Trp NR

Arg-Tyr NR

Arg-Val NR Arg-Glu-Ala NR

Arg-Glu-Asn NR

Arg-Glu-Asp NR

Arg-Glu-Cys NR

Arg-Glu-Gln NR Arg-Glu-Glu NR Arg-Glu-Gly NR

Arg-Glu-His NR

Arg-Glu-Ile NR

Arg-Glu-Leu NR Arg-Glu-Lys NR

Arg-Glu-Met NR

Arg-Glu-Phe NR

Arg-Glu-Pro NR

Arg-Glu-Ser NR Arg-Glu-Thr NR

Arg-Glu-Trp NR

Arg-Glu-Tyr NR

Arg-Glu-Val NR

Ala-Arg-Glu NR Arg-Arg-Glu NR

Asn-Arg-Glu NR

Asp-Arg-Glu NR

Cys-Arg-Glu NR

Gln-Arg-Glu NR Glu-Arg-Glu NR

Gly-Arg-Glu NR

His-Arg-Glu NR

Ile-Arg-Glu NR

Leu-Arg-Glu NR Lys-Arg-Glu NR

Met-Arg-Glu NR

Phe-Arg-Glu NR

Pro-Arg-Glu NR

Ser-Arg-Glu NR Thr-Arg-Glu NR

Trp-Arg-Glu NR

Tyr-Arg-Glu NR

Val-Arg-Glu NR

Glu-Arg-Ala NR Glu-Arg-Arg NR Glu-Arg-Asn NR

Glu-Arg-Asp NR

Glu-Arg-Cys NR

Glu-Arg-Gln NR

Glu-Arg-Gly NR

Glu-Arg-His NR

Glu-Arg-Ile NR

Glu-Arg-Leu NR

Glu-Arg-Lys NR

Glu-Arg-Met NR

Glu-Arg-Phe NR

Glu-Arg-Pro NR

Glu-Arg-Ser NR

Glu-Arg-Thr NR

Glu-Arg-Trp NR

Glu-Arg-Tyr NR

Glu-Arg-Val NR

Table 21-Additional Exemplary Pharmacologically Active Peptides

Sequence/Structure SEQ ID NO: Activity

VEPNCDΠΓVMWΈWECFERL 916 VEGF-antagonist

GERWCFDGPLTWVCGEES 917 VEGF-antagonist

RGWVEICVADDNGMCVTEAQ 918 VEGF-antagonist

GWDECDVARMWEWECFAGV 919 VEGF- antagonist

GERWCFDGPRAWVCGWEI 920 VEGF- antagonist

EELWCFDGPRAWVCGYVK 921 VEGF- antagonist

RGWVEICAADDYGRCLTEAQ 922 VEGF- antagonist

RGWVEICESDVWGRCL 923 VEGF- antagonist

RGWVEICESDVWGRCL 924 VEGF- antagonist

GGNECDIARMWEWECFERL 925 VEGF- antagonist

RGWVEICAADDYGRCL 926 VEGF-antagonist

CTTHWGFTLC 927 MMP inhibitor

CLRSGXGC 928 MMP inhibitor CXXHWGFXXC 929 MMP inhibitor CXPXC 930 MMP inhibitor

CRRHWGFEFC 931 MMP inhibitor

STTHWGFTLS 932 MMP inhibitor

CSLHWGFWWC 933 CTLA4-mimetic

GFVCSGΓFAVGVGRC 934 CTLA4-mimetic

APGVRLGCAVLGRYC 935 CTLA4-mimetic

LLGRMK 936 Antiviral (HBV)

ICWQDWGHHRCTAGHMANLTSHA ASSAAII : 993377 C3b antagonist ICWQDWGHHRCT 938 C3b antagonist CWQDWGHHAC 939 C3b antagonist

STGGFDDVYDWARGVSSALTTTLV 'AATTRR . 994400 Vinculin-binding STGGFDDVYDWARRVSSALTTTLV ΆATTRR 9 94411 Vinculin-binding SRGVNFSEWLYDMSAAMKEASNVFPSRRSR 942 Vinculin-binding SSQNWDMEAGVEDLTAAMLGLLSTIHSSSR 943 Vinculin-binding SSPSLYTQFLVNYESAATRIQDLLIASRPSR 944 Vinculin-binding SUGMroiLLGAILQRAADATRTSIPIPSLQNSIR 945 Vinculin-binding DVYTKKELIECARRVSEK 946 Vinculin-binding

EKGSYYPGSGIAQFHIDYNNVS 947 C4BP-binding

SGIAQFHTOYNNVSSAEGWHVN 948 C41BP-binding

LVTVEKGSYYPGSGIAQFEODYNNVSSAEGWHVN 949 4BP-binding

SGIAQFHTOYNNVS 950 C4BP-binding

LLGRMK 951 anti-HBV

ALLGRMKG 952 anti-HBV

LDPAFIR 953 anti-HBV

CXXRGDC 954 Inhibition of platelet aggrepation

RPLPPLP 955 Src antagonist

PPVPPR 956 Src antagonist

XFXDXWXXLXX 957 Anti-cancer

KACRRLFGPVDSEQLSRDCD 958 pi 6-mimetic

RERWNFDFVTETPLEGDFAW 959 pi 6-mimetic

KRRQTSMTDFYHSKRRLIFS 960 pi 6-mimetic

TSMTDFYHSKRRLΓFSKRKP 961 pi 6-mimetic

RRLIF 962 pi 6-mimetic KRRQTSATDFYHSKRRLIFSRQIKIWFQNRRMKWKK 963 pi 6-mimetic KRRLIFSKRQIKIWFQNRRMKWKK 964 pi 6-mimetic

Asn Gin Gly Arg His Phe Cys Gly Gly Ala Leu He His Ala Arq Phe Val Met Thr Ala Ala Ser Cys Phe Gin 965 CAP37 mimetic/LPs bindin

Arg His Phe Cys Gly Gly Ala Leu He His Ala Arg Phe Val Met Thr Ala Ala Ser Cys 499 CAP37 mimetic/LPS binding Gly Thr Arg Cys Gin Val Ala Gly Trp Gly Ser Gin Arg Ser Gly Gly Arg Leu Ser Arg Phe Pro

Arg Phe Val Asn Val 966 CAP37 mimetic/LPS binding

WΉWRHRΓPLQLAAGR 967 carbohydrate (GID1 alpha) mimetic

LKTPRV 968 I32GPI Ab binding

NTLKTPRV 969 I32GPI Ab binding

NTLKTPRVGGC 970 02GPI Ab binding

KDKATF 971 02GPI Ab binding

KDKATFGCHD 972 P2GP1 Ab binding

KDKATFGCHDGC 973 02GPI Ab bindinq

TLRVYK 974 02GPI Ab binding

ATLRVYKG 975 02GPI Ab binding

CATLRVYKGG 976 132GPI Ab binding

INLKALAALAKKIL 977 Membrane transporting

GWT NR Membrane transporting

GWTLNSAGYLLG 978 Membrane transporting

GWTLNSAGYLLGKINLKALAALAKKIL 979 Membrane transporting

The present invention is also particularly useful with peptides having activity in treatment of: a VEGF related condition, e.g., but not limited to, cancer, wherein the peptide is a VEGF-mimetic or a VEGF receptor antagonist, a HER2 agonist or antagonist, a CD20 antagonist and the like; asthma, wherein the protein of interest is a CKR3 antagonist, an IL-5 receptor antagonist, and the like; thrombosis, wherein the protein of interest is a GPΩb antagonist, a GPHIa antagonist, and the like; autoimmune diseases and other conditions involving immune modulation, wherein the protein of interest is an IL-2 receptor antagonist, a CD40 agonist or antagonist, a CD40L agonist or antagonist, a thymopoietin mimetic and the like.

For example, EPO biological activities are well known in the art. See, e.g., Anagnostou A et al Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proceedings ofthe National Academy of Science (USA) 87: 5978-82 (1990); Fandrey J and Jelkman WE Interleukin 1 and tumor necrosis factor-alpha inhibit erythropoietin production in vitro. Annals ofthe New York Academy of Science 628: 250-5 (1991); Geissler K et al Recombinant human erythropoietin: A multipotential hemopoietic growth factor in vivo and in vitro. Contrib. Nephrol. 87: 1-10 (1990); Gregory CJ Erythropoietin sensitivity as a differentiation marker in the hemopoietic system. Studies of three erythropoietic colony responses in culture. Journal of Cellular Physiology 89: 289-301 (1976); Jelkman W et al Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci. 50: 301-8 (1992); Kimata H et al Human recombinant erythropoietin directly stimulates B cell immunoglobulin production and proliferation in serum-free medium. Clinical and Experimental Immunology 85: 151-6 (1991); Kimata H et al Erythropoietin enhances immunoglobulin production and proliferation by human plasma cells in a serum-free medium. Clin. Immunology Immunopathol. 59: 495-501 (1991); Kimata H et al Effect of recombinant human erythropoietin on human IgE production in vitro Clinical and Experimental Immunology 83: 483-7 (1991); Koury MJ and Bondurant MC Erythropoietin retards DNA breakdown and prevents programmed cell death in erythroid progenitor cells. Science 248: 378-81 (1990); Lim VS et al Effect of recombinant human erythropoietin on renal function in humans. Kidney International 37: 131-6 (1990); Mitjavila MT et al Autocrine stimulation by erythropoietin and autonomous growth of human erythroid leukemic cells in vitro. Journal of Clinical Investigation 88: 789-97 (1991); Andre M et al Performance of an immunoradiometric assay of erythropoietin and results for specimens from anemic and polycythemic patients. Clinical Chemistry 38: 758-63 (1992); Hankins WD et al Erythropoietin-dependent and erythropoietin-producing cell lines. Implications for research and for leukemia therapy. Annals ofthe New York Academy of Science 554: 21-8 (1989); Kendall RGT et al Storage and preparation of samples for erythropoietin radioimmunoassay. Clin. Lab. Haematology 13: 189-96 (1991); Krumvieh D et al Comparison of relevant biological assays for the determination of biological active erythropoietin. Dev. Biol. Stand. 69: 15-22 (1988); Ma DD et al Assessment of an EIA for measuring human serum erythropoietin as compared with RIA and an in-vitro bioassay. British Journal of Haematology 80: 431-6 (1992); Noe G et al A sensitive sandwich ELISA for measuring erythropoietin in human serum British Journal of Haematology 80: 285-92 (1992); Pauly JU et al Highly specific and highly sensitive enzyme immunoassays for antibodies to human interleukin 3 (IL3) and human erythropoietin (EPO) in serum. Behring Institut Mitteilungen 90: 112-25 (1991); Sakata S and Enoki Y Improved microbioassay for plasma erythropoietin based on CFU-E colony formation. Ann. Hematology 64: 224-30 (1992); Sanengen T et al Immunoreactive erythropoietin and erythropoiesis stimulating factor(s) in plasma from hypertransfused neonatal and adult mice. Studies with a radioimmunoassay and a cell culture assay for erythropoietin. Acta Physiol. Scand. 135: 11-6 (1989); Widness JA et al A sensitive and specific erythropoietin immunoprecipitation assay: application to pharmacokinetic studies. Journal of Lab. Clin. Med. 119: 285-94 (1992); for further information see also individual cell lines used in individual bioassays. Each ofthe above references are entirely incorporated herein by reference. EPO can be assayed by employing cell lines such as HCD57 , NFS-60 , TF-1 and UT-7 , which respond to the factor . EPO activity can be assessed also in a Colony formation assay by determining the number of CFU-E from bone marrow cells. An alternative and entirely different detection method is RT-PCR quantitation of cytokines.

A CHI -deleted mimetibody, or specified portion or variant thereof, that partially or preferably substantially provides at least one biological activity of at least one protein or fragment, can bind the protein or fragment ligand and thereby provide at least one activity that is otherwise mediated through the binding of protein to at least one protein ligand or receptor or through other protein-dependent or mediated mechanisms. As used herein, the term "CHI-deleted mimetibody activity" refers to a CHI- deleted mimetibody that can modulate or cause at least one protein-dependent activity by about 20- 10,000%, preferably by at least about 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 % or more depending on the assay.

The capacity of a CHI -deleted mimetibody or specified portion or variant to provide at least one protein-dependent activity is preferably assessed by at least one suitable protein biological assay, as described herein and/or as known in the art. A human CHI-deleted mimetibody or specified portion or variant ofthe invention can be similar to any class (IgG, IgA, IgM, etc.) or isotype and can comprise at least a portion of a kappa or lambda light chain, wherein at least one ofthe LBRs is replaced by at least one LBR as described herein. In one embodiment, the human CHI -deleted mimetibody or specified portion or variant comprises an IgG heavy chain or defined fragment, for example, at least one of isotypes, IgGl, IgG2, IgG3 or IgG4. In another embodiment, the human protein human CHI- deleted mimetibody or specified portion or variant thereof comprises an IgGl heavy chain and an IgGl light chain.

At least one CHI -deleted mimetibody or specified portion or variant ofthe invention binds at least one specified ligand specific to at least one protein, subunit, fragment, portion or any combination thereof. The at least one LBR of at least one CHI -deleted mimetibody, specified portion or variant ofthe present invention can optionally bind at least one specified ligand epitope ofthe ligand. The binding epitope can comprise any combination of at least one amino acid sequence of at least 1-3 amino acids to the entire specified portion of contiguous amino acids ofthe sequences selected from the group consisting of a protein ligand, such as a receptor or portion thereof. Generally, the CHI -deleted mimetibody or ligand-binding fragment ofthe present invention can comprise a ligand binding region (LBR) (e.g., LBR1, LBR2 and LBR3) or variant provided in at least one heavy chain variable region and at least one ligand binding region (LBR1, LBR2 and LBR3) or variant provided in at least one light chain variable region. As a non-limiting example, the CH1- deleted mimetibody or ligand-binding portion or variant can comprise at least one ofthe heavy chain LBR3, and/or a light chain LBR3. In a particular embodiment, the CHI -deleted mimetibody or ligand- binding fragment can have an ligand-binding region that comprises at least a portion of at least one heavy chain LBR (i.e., LBR1, LBR2 and/or LBR3) having the amino acid sequence ofthe corresponding LBRs 1, 2 and/or 3. In another particular embodiment, the CHI -deleted mimetibody or ligand-binding portion or variant can have an ligand-binding region that comprises at least a portion of at least one light chain LBR (i.e., LBR1, LBR2 and/or LBR3) having the amino acid sequence ofthe corresponding LBRs 1, 2 and/or 3. Such mimetibodies can be prepared by joining together the various portions (e.g., LBRs, framework) ofthe CHI-deleted mimetibody using known techniques, by preparing and expressing at least one (i.e., one or more) nucleic acid molecules that encode the CH1- deleted mimetibody, using known techniques of recombinant DNA technology or by using any other suitable method, such as chemical synthesis.

The CHI -deleted mimetibody can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. Mimetibodies that bind to human protein ligands or receptors and that comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as phage display (Katsube, Y., et al, Int J Mol. Med, l(5):863-868 (1998)) or methods that employ transgenic animals, as known in the art and/or as described herein. The CHI- deleted mimetibody, specified portion or variant can be expressed using the encoding nucleic acid or portion thereof in a suitable host cell.

The invention also relates to mimetibodies, ligand-binding fragments, immunoglobulin chains and LBRs comprising amino acids in a sequence that is substantially the same as an amino acid sequence described herein. Preferably, such mimetibodies or ligand-binding fragments and mimetibodies comprising such chains or LBRs can bind human protein ligands with high affinity (e.g., K_D less than or equal to about 10^"9 M). Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and/or insertions. A conservative amino acid substitution refers to the replacement of a first amino acid by a second amino acid that has chemical and/or physical properties (e.g., charge, structure, polarity, hydrophobicity/ hydrophilicity) that are similar to those ofthe first amino acid. Conservative substitutions include replacement of one amino acid by another within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W and Y; C, S and T.

Amino Acid Codes

The amino acids that make up mimetibodies or specified portions or variants ofthe present invention are often abbreviated. The amino acid designations can be indicated by designating the amino acid by its single letter code, its three letter code, name, or three nucleotide codon(s) as is well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994):

A CHI -deleted mimetibody or specified portion or variant ofthe present invention can include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation, as specified herein. Of course, the number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions or deletions for at least one of a CHI -deleted mimetibody LBR, variable, constant, light or heavy chain, or Ig will not be more than 40, 30, 20,19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 amino acids, such as 1-30 or any range or value therein, as specified herein. Amino acids in a CHI -deleted mimetibody or specified portion or variant ofthe present invention that are essential for function can be identified by methods known in the art, such as site- directed mutagenesis or alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity, such as, but not limited to at least one protein related activity, as specified herein or as known in the art. Sites that are critical for CHI -deleted mimetibody or specified portion or variant binding can also be identified by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)).

Mimetibodies or specified portions or variants ofthe present invention can comprise as the Pep portion of Formula (I), but are not limited to, at least one portion, sequence or combination selected from 3 to all the of at least one of SEQ ID NOS: 1-979. Non-limiting variants that can enhance or maintain at least one ofthe listed activities include, but are not limited to, any ofthe above polypeptides, further comprising at least one mutation corresponding to at least one substitution, insertion or deletion that does not significantly affect the suitable biological activtities or functions of said CHI -deleted mimetibody. A CHI -deleted mimetibody or specified portion or variant can further optionally comprise at least one functional portion of at least one polypeptide as Pep portion of Formula (I), at least one of 90- 100% of SEQID NOS:l-l 109. A CHI-deleted mimetibody can further optionally comprise an amino acid sequence for the Pep portion of Formula (I), selected from one or more of SEQID NOS:l-l 109. In one embodiment, the Pep amino acid sequence of an immunoglobulin chain, or portion thereof (e.g., comprising at least one specified variable region, LBR) has about 90-100% identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the corresponding amino acid sequence ofthe corresponding portion of at least one of SEQ ID NOS: 1-979. Preferably, 90- 100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) is determined using a suitable computer algorithm, as known in the art. Mimetibodies or specified portions or variants ofthe present invention can comprise any number of contiguous amino acid residues from a CHI-deleted mimetibody or specified portion or variant ofthe present invention, wherein that number is selected from the group of integers consisting of from 10-100% ofthe number of contiguous residues in a CHI-deleted mimetibody. Optionally, this subsequence of contiguous amino acids is at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,

200, 210, 220, 230, 240, 250 or more amino acids in length, or any range or value therein. Further, the number of such subsequences can be any integer selected from the group consisting of from 1 to 20, such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more. As those of skill will appreciate, the present invention includes at least one biologically active CHI-deleted mimetibody or specified portion or variant ofthe present invention. Biologically active mimetibodies or specified portions or variants have a specific activity at least 20%, 30%, or 40%, and preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95%-1000% of that of the native (non-synthetic), endogenous or related and known inserted or fused protein or specified portion or variant. Methods of assaying and quantifying measures of enzymatic activity and substrate specificity are well known to those of skill in the art.

In another aspect, the invention relates to human mimetibodies and ligand-binding fragments, as described herein, which are modified by the covalent attachment of an organic moiety. Such modification can produce a CHI -deleted mimetibody or ligand-binding fragment with improved pharmacokinetic properties (e.g., increased in vivo serum half-life). The organic moiety can be a linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group. In particular embodiments, the hydrophilic polymeric group can have a molecular weight of about 800 to about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, and the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms.

The modified mimetibodies and ligand-binding fragments ofthe invention can comprise one or more organic moieties that are covalently bonded, directly or indirectly, to the CHI -deleted mimetibody or specified portion or variant. Each organic moiety that is bonded to a CHI-deleted mimetibody or ligand-binding fragment ofthe invention can independently be a hydrophilic polymeric group, a fatty acid group or a fatty acid ester group. As used herein, the term "fatty acid" encompasses mono-carboxylic acids and di-carboxylic acids. A "hydrophilic polymeric group," as the term is used herein, refers to an organic polymer that is more soluble in water than in octane. For example, polylysine is more soluble in water than in octane. Thus, a CHI -deleted mimetibody modified by the covalent attachment of polylysine is encompassed by the invention. Hydrophilic polymers suitable for modifying mimetibodies ofthe invention can be linear or branched and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone. Preferably, the hydrophilic polymer that modifies the CHI -deleted mimetibody ofthe invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecular entity. For example, PEG2₅oo_> PEG₅₀oo, PEG₇₅oo, PEGgooo, PEG] oooo, PEGι₂₅oo, PEGι₅₀₀o, and PEG₂o,ooo, wherein the subscript is the average molecular weight ofthe polymer in Daltons, can be used. The hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or fatty acid ester groups. Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods. For example, a polymer comprising an amine group can be coupled to a carboxylate ofthe fatty acid or fatty acid ester, and an activated carboxylate (e.g., activated with N,N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a hydroxyl group on a polymer.

Fatty acids and fatty acid esters suitable for modifying mimetibodies ofthe invention can be saturated or can contain one or more units of unsaturation. Fatty acids that are suitable for modifying mimetibodies ofthe invention include, for example, n-dodecanoate (Cn, laurate), n-tetradecanoate (Cj₄, myristate), n-octadecanoate (Cι₈, stearate), n-eicosanoate (C₂o, arachidate), n-docosanoate (C₂₂, behenate), n-triacontanoate (C₃0), n-tetracontanoate (C₄₀), cw-Δ9-octadecanoate (C₁₈, oleate), all cis- 5,8,11,14-eicosatetraenoate (C₂0, arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid esters include mono-esters of dicarboxylic acids that comprise a linear or branched lower alkyl group. The lower alkyl group can comprise from one to about twelve, preferably one to about six, carbon atoms. The modified human mimetibodies and ligand-binding fragments can be prepared using suitable methods, such as by reaction with one or more modifying agents. A "modifying agent" as the term is used herein, refers to a suitable organic group (e.g., hydrophilic polymer, a fatty acid, a fatty acid ester) that comprises an activating group. An "activating group" is a chemical moiety or functional group that can, under appropriate conditions, react with a second chemical group thereby forming a covalent bond between the modifying agent and the second chemical group. For example, amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like. Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, 5-thiol-2- nitrobenzoic acid thiol (TNB-thiol), and the like. An aldehyde functional group can be coupled to amine- or hydrazide-containing molecules, and an azide group can react with a trivalent phosphorous group to form phosphoramidate or phosphorimide linkages. Suitable methods to introduce activating groups into molecules are known in the art (see for example, Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). An activating group can be bonded directly to the organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester), or through a linker moiety, for example a divalent C₁-C₁₂ group wherein one or more carbon atoms can be replaced by a heteroatom such as oxygen, nitrogen or sulfur. Suitable linker moieties include, for example, tetraethylene glycol, -(CH₂) -, -NH-(CH₂)₆-NH-, -(CH₂)₂-NH- and -CH₂-O-CH₂-CH₂-O-CH₂-CH2-O-CH-NH-. Modifying agents that comprise a linker moiety can be produced, for example, by reacting a mono-Boc- alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimido derivative ofthe fatty acid. (See, for example, Thompson, et al, WO 92/16221 the entire teachings of which are incorporated herein by reference.)

The modified mimetibodies ofthe invention can be produced by reacting an human CH1- deleted mimetibody or ligand-binding fragment with a modifying agent. For example, the organic moieties can be bonded to the CHI -deleted mimetibody in a non-site specific manner by employing an amine-reactive modifying agent, for example, an NHS ester of PEG. Modified human mimetibodies or ligand-binding fragments can also be prepared by reducing disulfide bonds (e.g., intra-chain disulfide bonds) of a CHI -deleted mimetibody or ligand-binding fragment. The reduced CHI -deleted mimetibody or ligand-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified CHI -deleted mimetibody ofthe invention. Modified human mimetibodies and ligand-binding fragments comprising an organic moiety that is bonded to specific sites of a CH1- deleted mimetibody or specified portion or variant ofthe present invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al, Bioconjugate Chem., 3:147-153 (1992); Werlen et al, Bioconjugate Chem., 5:411-417 (1994); Kumaran et al, Protein Sci. 6(10):2233-2241 (1997); Itoh et al, Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al, iotechnol. Bioeng, 56(4):456- 463 (1997)), and the methods described in Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996). CHI-DELETED MIMETD3ODY COMPOSITIONS

The present invention also provides at least one CHI -deleted mimetibody or specified portion or variant composition comprising at least one, at least two, at least three, at least four, at least five, at least six or more mimetibodies or specified portions or variants thereof, as described herein and/or as known in the art that are provided in a non-naturally occurring composition, mixture or form. Such composition percentages are by weight, volume, concentration, molarity, or molality as liquid or dry solutions, mixtures, suspension, emulsions or colloids, as known in the art or as described herein. Such compositions can comprise 0.00001-99.9999 percent by weight, volume, concentration, molarity, or molality as liquid, gas, or dry solutions, mixtures, suspension, emulsions or colloids, as known in the art or as described herein, on any range or value therein, such as but not limited to 0.00001, 0.00003, 0.00005, 0.00009, 0.0001, 0.0003, 0.0005, 0.0009, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.1, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.1, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.1, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 %. Such compositions ofthe present invention thus include but are not limited to 0.00001-100 mg/ml and/or 0.00001-100 mg/g.

The composition can optionally further comprise an effective amount of at least one compound or protein selected from at least one of an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug or the like. Such drugs are well known in the art, including formulations, indications, dosing and administration for each presented herein (see, e.g., Nursing 2001 Handbook of Drugs, 21^st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ; Pharmcotherapy Handbook, Wells et al., ed., Appleton & Lange, Stamford, CT, each entirely incorporated herein by reference). The anti-infective drug can be at least one selected from amebicides or at least one antiprotozoals, anthelmintics, antifungals, antimalarials, antituberculotics or at least one antileprotics, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolide anti-infectives, miscellaneous anti-infectives. The CV drug can be at least one selected from inotropics, antiarrhythmics, antianginals, antihypertensives, antilipemics, and miscellaneous cardiovascular drugs. The CNS drug can be at least one selected from nonnarcotic analgesics or at least one selected from antipyretics, nonsteroidal anti-inflammatory drugs, narcotic or at least one opiod analgesics, sedative-hypnotics, anticonvulsants, antidepressants, antianxiety drugs, antipsychotics, central nervous system stimulants, antiparkinsonians, miscellaneous central nervous system drugs. The ANS drug can be at least one selected from cholinergics (parasympathomimetics), anticholinergics, adrenergics (sympathomimetics), adrenergic blockers (sympatholytics), skeletal muscle relaxants, neuromuscular blockers. The respiratory tract drug can be at least one selected from antihistamines, bronchodilators, expectorants or at least one antitussives, miscellaneous respiratory drugs. The GI tract drug can be at least one selected from antacids or at least one adsorbents or at least one antiflatulents, digestive enzymes or at least one gallstone solubilizers, antidiarrheals, laxatives, antiemetics, antiulcer drugs. The hormonal drug can be at least one selected from corticosteroids, androgens or at least one anabolic steroids, estrogens or at least one progestins, gonadotropins, antidiabetic drugs or at least one glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones, parathyroid-like drugs. The drug for fluid and electrolyte balance can be at least one selected from diuretics, electrolytes or at least one replacement solutions, acidifiers or at least one alkalinizers. The hematologic drug can be at least one selected from hematinics, anticoagulants, blood derivatives, thrombolytic enzymes. The antineoplastics can be at least one selected from alkylating drugs, antimetabolites, antibiotic antineoplastics, antineoplastics that alter hormone balance, miscellaneous antineoplastics. The immunomodulation drug can be at least one selected from immunosuppressants, vaccines or at least one toxoids, antitoxins or at least one antivenins, immune serums, biological response modifiers. The ophthalmic, otic, and nasal drugs can be at least one selected from ophthalmic anti-infectives, ophthalmic anti-inflammatories, miotics, mydriatics, ophthalmic vasoconstrictors, miscellaneous ophthalmics, otics, nasal drugs. The topical drug can be at least one selected from local anti-infectives, scabicides or at least one pediculicides, topical corticosteroids. The nutritional drug can be at least one selected from vitamins, minerals, or calorics. See, e.g., contents of Nursing 2001 Drug Handbook, supra.

The at least one amebicide or antiprotozoal can be at least one selected from atovaquone, chloroquine hydrochloride, chloroquine phosphate, metronidazole, metronidazole hydrochloride, pentamidine isethionate. The at least one anthelmintic can be at least one selected from mebendazole, pyrantel pamoate, thiabendazole. The at least one antifungal can be at least one selected from amphotericin B, amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposomal, fluconazole, flucytosine, griseofulvin microsize, griseofulvin ultramicrosize, itraconazole, ketoconazole, nystatin, terbinafine hydrochloride. The at least one antimalarial can be at least one selected from chloroquine hydrochloride, chloroquine phosphate, doxycycline, hydroxychloroquine sulfate, mefloquine hydrochloride, primaquine phosphate, pyrimethamine, pyrimethamine with sulfadoxine. The at least one antituberculotic or antileprotic can be at least one selected from clofazimine, cycloserine, dapsone, ethambutol hydrochloride, isoniazid, pyrazinamide, rifabutin, rifampin, rifapentine, streptomycin sulfate. The at least one aminoglycoside can be at least one selected from amikacin sulfate, gentamicin sulfate, neomycin sulfate, streptomycin sulfate, tobramycin sulfate. The at least one penicillin can be at least one selected from amoxcillin/clavulanate potassium, amoxicillin trihydrate, ampicillin, ampicillin sodium, ampicillin trihydrate, ampicillin sodium/sulbactam sodium, cloxacillin sodium, dicloxacillin sodium, mezlocillin sodium, nafcillin sodium, oxacillin sodium, penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V potassium, piperacillin sodium, piperacillin sodium/tazobactam sodium, ticarcillin disodium, ticarcillin disodium/clavulanate potassium. The at least one cephalosporin can be at least one selected from at least one of cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, loracarbef. The at least one tetracycline can be at least one selected from demeclocycline hydrochloride, doxycycline calcium, doxycycline hyclate, doxycycline hydrochloride, doxycycline monohydrate, minocycline hydrochloride, tetracycline hydrochloride. The at least one sulfonamide can be at least one selected from co-trimoxazole, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfisoxazole acetyl. The at least one fluoroquinolone can be at least one selected from alatrofloxacin mesylate, ciprofloxacin, enoxacin, levofloxacin, lomefloxacin hydrochloride, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin mesylate. The at least one fluoroquinolone can be at least one selected from alatrofloxacin mesylate, ciprofloxacin, enoxacin, levofloxacin, lomefloxacin hydrochloride, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin mesylate. The at least one antiviral can be at least one selected from abacavir sulfate, acyclovir sodium, amantadine hydrochloride, amprenavir, cidofovir, delavirdine mesylate, didanosine, efavirenz, famciclovir, fomivirsen sodium, foscarnet sodium, ganciclovir, indinavir sulfate, lamivudine, lamivudine/zidovudine, nelfinavir mesylate, nevirapine, oseltamivir phosphate, ribavirin, rimantadine hydrochloride, ritonavir, saquinavir, saquinavir mesylate, stavudine, valacyclovir hydrochloride, zalcitabine, zanamivir, zidovudine. The at least one macroline anti-infective can be at least one selected from azithromycin, clarithromycin, dirithromycin, erythromycin base, erythromycin estolate, erythromycin ethylsuccinate, erythromycin lactobionate, erythromycin stearate. The at least one miscellaneous anti-infective can be at least one selected from aztreonam, bacitracin, chloramphenicol sodium sucinate, clindamycin hydrochloride, clindamycin palmitate hydrochloride, clindamycin phosphate, imipenem and cilastatin sodium, meropenem, nitrofurantoin macrocrystals, nitrofurantoin microcrystals, quinupristin/dalfopristin, spectinomycin hydrochloride, trimethoprim, vancomycin hydrochloride. (See, e.g., pp. 24-214 of Nursing 2001 Drug Handbook

The at least one inotropic can be at least one selected from amrinone lactate, digoxin, milrinone lactate. The at least one antiarrhythmic can be at least one selected from adenosine, amiodarone hydrochloride, atropine sulfate, bretylium tosylate, diltiazem hydrochloride, disopyramide, disopyramide phosphate, esmolol hydrochloride, flecainide acetate, ibutilide fumarate, lidocaine hydrochloride, mexiletine hydrochloride, moricizine hydrochloride, phenytoin, phenytoin sodium, procainamide hydrochloride, propafenone hydrochloride, propranolol hydrochloride, quinidine bisulfate, quinidine gluconate, quinidine polygalacturonate, quinidine sulfate, sotalol, tocainide hydrochloride, verapamil hydrochloride. The at least one antianginal can be at least one selected from amlodipidine besylate, amyl nitrite, bepridil hydrochloride, diltiazem hydrochloride, isosorbide dinitrate, isosorbide mononitrate, nadolol, nicardipine hydrochloride, nifedipine, nitroglycerin, propranolol hydrochloride, verapamil, verapamil hydrochloride. The at least one antihypertensive can be at least one selected from acebutolol hydrochloride, amlodipine besylate, atenolol, benazepril hydrochloride, betaxolol hydrochloride, bisoprolol fumarate, candesartan cilexetil, captopril, carteolol hydrochloride, carvedilol, clonidine, clonidine hydrochloride, diazoxide, diltiazem hydrochloride, doxazosin mesylate, enalaprilat, enalapril maleate, eprosartan mesylate, felodipine, fenoldopam mesylate, fosinopril sodium, guanabenz acetate, guanadrel sulfate, guanfacine hydrochloride, hydralazine hydrochloride, irbesartan, isradipine, labetalol hydrchloride, lisinopril, losartan potassium, methyldopa, methyldopate hydrochloride, metoprolol succinate, metoprolol tartrate, minoxidil, moexipril hydrochloride, nadolol, nicardipine hydrochloride, nifedipine, nisoldipine, nitroprusside sodium, penbutolol sulfate, perindopril erbumine, phentolamine mesylate, pindolol, prazosin hydrochloride, propranolol hydrochloride, quinapril hydrochloride, ramipril, telmisartan, terazosin hydrochloride, timolol maleate, trandolapril, valsartan, verapamil hydrochloride The at least one antilipemic can be at least one selected from atorvastatin calcium, cerivastatin sodium, cholestyramine, colestipol hydrochloride, fenofibrate (micronized), fluvastatin sodium, gemfibrozil, lovastatin, niacin, pravastatin sodium, simvastatin. The at least one miscellaneous CV drug can be at least one selected from abciximab, alprostadil, arbutamine hydrochloride, cilostazol, clopidogrel bisulfate, dipyridamole, eptifibatide, midodrine hydrochloride, pentoxifylline, ticlopidine hydrochloride, tirofiban hydrochloride. (See, e.g., pp.215-336 of Nursing 2001 Drug Handbook The at least one nonnarcotic analgesic or antipyretic can be at least one selected from acetaminophen, aspirin, choline magnesium trisalicylate, diflunisal, magnesium salicylate. The at least one nonsteroidal anti-inflammatory drug can be at least one selected from celecoxib, diclofenac potassium, diclofenac sodium, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, indomethacin sodium trihydrate, ketoprofen, ketorolac tromethamine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, sulindac. The at least one narcotic or opiod analgesic can be at least one selected from alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, codeine phosphate, codeine sulfate, fentanyl citrate, fentanyl transdermal system, fentanyl transmucosal, hydromorphone hydrochloride, meperidine hydrochloride, methadone hydrochloride, morphine hydrochloride, morphine sulfate, morphine tartrate, nalbuphine hydrochloride, oxycodone hydrochloride, oxycodone pectinate, oxymorphone hydrochloride, pentazocine hydrochloride, pentazocine hydrochloride and naloxone hydrochloride, pentazocine lactate, propoxyphene hydrochloride, propoxyphene napsylate, remifentanil hydrochloride, sufentanil citrate, tramadol hydrochloride. The at least one sedative-hypnotic can be at least one selected from chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, temazepam, triazolam, zaleplon, zolpidem tartrate. The at least one anticonvulsant can be at least one selected from acetazolamide sodium, carbamazepine, clonazepam, clorazepate dipotassium, diazepam, divalproex sodium, ethosuximde, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, phenobarbital sodium, phenytoin, phenytoin sodium, phenytoin sodium (extended), primidone, tiagabine hydrochloride, topiramate, valproate sodium, valproic acid. The at least one antidepressant can be at least one selected from amitriptyline hydrochloride, amitriptyline pamoate, amoxapine, bupropion hydrochloride, citalopram hydrobromide, clomipramine hydrochloride, desipramine hydrochloride, doxepin hydrochloride, fluoxetine hydrochloride, imipramine hydrochloride, imipramine pamoate, mirtazapine, nefazodone hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, phenelzine sulfate, sertraline hydrochloride, tranylcypromine sulfate, trimipramine maleate, venlafaxine hydrochloride. The at least one antianxiety drug can be at least one selected from alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam, mephrobamate, midazolam hydrochloride, oxazepam. The at least one antipsychotic drug can be at least one selected from chlorpromazine hydrochloride, clozapine, fluphenazine decanoate, fluephenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanoate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine fumarate, risperidone, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, trifluoperazine hydrochloride. The at least one central nervous system stimulant can be at least one selected from amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, modafinil, pemoline, phentermine hydrochloride. The at least one antiparkinsonian can be at least one selected from amantadine hydrochloride, benztropine mesylate, biperiden hydrochloride, biperiden lactate, bromocriptine mesylate, carbidopa-levodopa, entacapone, levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, trihexyphenidyl hydrochloride. The at least one miscellaneous central nervous system drug can be at least one selected from bupropion hydrochloride, donepezil hydrochloride, droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine polacrilex, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, zolmitriptan.

(See, e.g., pp. 337-530 of Nursing 2001 Drug Handbook.)

The at least one cholinergic (e.g., parasymathomimetic) can be at least one selected from bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine salicylate, pyridostigmine bromide. The at least one anticholinergics can be at least one selected from atropine sulfate, dicyclomine hydrochloride, glycopyrrolate, hyoscyamine, hyoscyamine sulfate, propantheline bromide, scopolamine, scopolamine butylbromide, scopolamine hydrobromide. The at least one adrenergics (sympathomimetics) can be at least one selected from dobutamine hydrochloride, dopamine hydrochloride, metaraminol bitartrate, norepinephrine bitartrate, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate. The at least one adrenergic blocker (sympatholytic) can be at least one selected from dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, propranolol hydrochloride. The at least one skeletal muscle relaxant can be at least one selected from baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine hydrochloride, dantrolene sodium, methocarbamol, tizanidine hydrochloride. The at least one neuromuscular blockers can be at least one selected from atracurium besylate, cisatracurium besylate, doxacurium chloride, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, vecuronium bromide. (See, e.g., pp. 531-84 of Nursing 2001 Drug Handbook.)

The at least one antihistamine can be at least one selected from brompheniramine maleate, cetirizine hydrochloride, chlorpheniramine maleate, clemastine fumarate, cyproheptadine hydrochloride, diphenhydramine hydrochloride, fexofenadine hydrochloride, loratadine, promethazine hydrochloride, promethazine theoclate, triprolidine hydrochloride. The at least one bronchodilators can be at least one selected from albuterol, albuterol sulfate, aminophylline, atropine sulfate, ephedrine sulfate, epinephrine, epinephrine bitartrate, epinephrine hydrochloride, ipratropium bromide, isoproterenol, isoproterenol hydrochloride, isoproterenol sulfate, levalbuterol hydrochloride, metaproterenol sulfate, oxtriphylline, pirbuterol acetate, salmeterol xinafoate, terbutaline sulfate, theophylline. The at least one expectorants or antitussives can be at least one selected from benzonatate, codeine phosphate, codeine sulfate, dextramethorphan hydrobromide, diphenhydramine hydrochloride, guaifenesin, hydromorphone hydrochloride. The at least one miscellaneous respiratory drug can be at least one selected from acetylcysteine, beclomethasone dipropionate, beractant, budesonide, calfactant, cromolyn sodium, dornase alfa, epoprostenol sodium, flunisolide, fluticasone propionate, montelukast sodium, nedocromil sodium, palivizumab, triamcinolone acetonide, zafirlukast, zileuton. (See, e.g., pp. 585-642 of Nursing 2001 Drug Handbook

The at least one antacid, adsorbents, or antiflatulents can be at least one selected from aluminum carbonate, aluminum hydroxide, calcium carbonate, magaldrate, magnesium hydroxide, magnesium oxide, simethicone, sodium bicarbonate. The at least one digestive enymes or gallstone solubilizers can be at least one selected from pancreatin, pancrelipase, ursodiol. The at least one antidiarrheal can be at least one selected from attapulgite, bismuth subsalicylate, calcium polycarbophil, diphenoxylate hydrochloride or atropine sulfate, loperamide, octreotide acetate, opium tincture, opium tincure (camphorated). The at least one laxative can be at least one selected from bisocodyl, calcium polycarbophil, cascara sagrada, cascara sagrada aromatic fluidextract, cascara sagrada fluidextract, castor oil, docusate calcium, docusate sodium, glycerin, lactulose, magnesium citrate, magnesium hydroxide, magnesium sulfate, methylcellulose, mineral oil, polyethylene glycol or electrolyte solution, psyllium, senna, sodium phosphates. The at least one antiemetic can be at least one selected from chlorpromazine hydrochloride, dimenhydrinate, dolasetron mesylate, dronabinol, granisetron hydrochloride, meclizine hydrochloride, metocloproamide hydrochloride, ondansetron hydrochloride, perphenazine, prochlorperazine, prochlorperazine edisylate, prochlorperazine maleate, promethazine hydrochloride, scopolamine, thiethylperazine maleate, trimethobenzamide hydrochloride. The at least one antiulcer drug can be at least one selected from cimetidine, cimetidine hydrochloride, famotidine, lansoprazole, misoprostol, nizatidine, omeprazole, rabeprozole sodium, rantidine bismuth citrate, ranitidine hydrochloride, sucralfate. (See, e.g., pp. 643-95 of Nursing 2001 Drug Handbook.) The at least one coricosteroids can be at least one selected from betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate. The at least one androgen or anabolic steroids can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, testosterone transdermal system. The at least one estrogen or progestin can be at least one selected from esterified estrogens, estradiol, estradiol cypionate, estradiol/norethindrone acetate transdermal system, estradiol valerate, estrogens (conjugated), estropipate, ethinyl estradiol, ethinyl estradiol and desogestrel, ethinyl estradiol and ethynodiol diacetate, ethinyl estradiol and desogestrel, ethinyl estradiol and ethynodiol diacetate, ethinyl estradiol and levonorgestrel, ethinyl estradiol and norethindrone, ethinyl estradiol and norethindrone acetate, ethinyl estradiol and norgestimate, ethinyl estradiol and norgestrel, ethinyl estradiol and norethindrone and acetate and ferrous fumarate, levonorgestrel, medroxyprogesterone acetate, mestranol and norethindron, norethindrone, norethindrone acetate, norgestrel, progesterone. The at least one gonadroptropin can be at least one selected from ganirelix acetate, gonadoreline acetate, histrelin acetate, menotropins. The at least one antidiabetic or glucaon can be at least one selected from acarbose, chlorpropamide, glimepiride, glipizide, glucagon, glyburide, insulins, metformin hydrochloride, miglitol, pioglitazone hydrochloride, repaglinide, rosiglitazone maleate, troglitazone. The at least one thyroid hormone can be at least one selected from levothyroxine sodium, liothyronine sodium, liotrix, thyroid. The at least one thyroid hormone antagonist can be at least one selected from methimazole, potassium iodide, potassium iodide (saturated solution), propylthiouracil, radioactive iodine (sodium iodide ¹³¹I ), strong iodine solution. The at least one pituitary hormone can be at least one selected from corticotropin, cosyntropin, desmophressin acetate, leuprolide acetate, repository corticotropin, somatrem, somatropin, vasopressin. The at least one parathyroid-like drug can be at least one selected from calcifediol, calcitonin (human), calcitonin (salmon), calcitriol, dihydrotachysterol, etidronate disodium. (See, e.g., pp. 696-796 of Nursing 2001 Drug Handbook.) The at least one diuretic can be at least one selected from acetazolamide, acetazolamide sodium, amiloride hydrochloride, bumetanide, chlorthalidone, ethacrynate sodium, ethacrynic acid, furosemide, hydrochlorothiazide, indapamide, mannitol, metolazone, spironolactone, torsemide, triamterene, urea. The at least one electrolyte or replacement solution can be at least one selected from calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, calcium lactate, calcium phosphate (dibasic), calcium phosphate (tribasic), dextran (high-molecular-weight), dextran (low-molecular-weight), hetastarch, magnesium chloride, magnesium sulfate, potassium acetate, potassium bicarbonate, potassium chloride, potassium gluconate, Ringer's injection, Ringer's injection (lactated), sodium chloride. The at least one acidifier or alkalinizer can be at least one selected from sodium bicarbonate, sodium lactate, tromethamine. (See, e.g., pp. 797-833 of Nursing 2001 Drug Handbook)

The at least one hematinic can be at least one selected from ferrous fumarate, ferrous gluconate, ferrous sulfate, ferrous sulfate (dried), iron dextran, iron sorbitol, polysaccharide-iron complex, sodium ferric gluconate complex. The at least one anticoagulant can be at least one selected from ardeparin sodium, dalteparin sodium, danaparoid sodium, enoxaparin sodium, heparin calcium, heparin sodium, warfarin sodium. The at least one blood derivative can be at least one selected from albumin 5%, albumin 25%, antihemophilic factor, anti-inhibitor coagulant complex, antithrombin HI (human), factor IX (human), factor IX complex, plasma protein fractions. The at least one thrombolytic enzyme can be at least one selected from alteplase, anistreplase, reteplase (recombinant), streptokinase, urokinase. (See, e.g., pp. 834-66 of Nursing 2001 Drug Handbook.)

The at least one alkylating drug can be at least one selected from busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, ifosfamide, lomustine, mechlorethamine hydrochloride, melphalan, melphalan hydrochloride, streptozocin, temozolomide, thiotepa. The at least one antimetabolite can be at least one selected from capecitabine, cladribine, cytarabine, floxuridine, fludarabine phosphate, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, methotrexate sodium, thioguanine. The at least one antibiotic antineoplastic can be at least one selected from bleomycin sulfate, dactinomycin, daunorubicin citrate liposomal, daunorubicin hydrochloride, doxorubicin hydrochloride, doxorubicin hydrochloride liposomal, epirubicin hydrochloride, idarubicin hydrochloride, mitomycin, pentostatin, plicamycin, valrubicin. The at least one antineoplastics that alter hormone balance can be at least one selected from anastrozole, bicalutamide, estramustine phosphate sodium, exemestane, flutamide, goserelin acetate, letrozole, leuprolide acetate, megestrol acetate, nilutamide, tamoxifen citrate, testolactone, toremifene citrate. The at least one miscellaneous antineoplastic can be at least one selected from asparaginase, bacillus Calmette-Guerin (BCG) (live intravesical), dacarbazine, docetaxel, etoposide, etoposide phosphate, gemcitabine hydrochloride, irinotecan hydrochloride, mitotane, mitoxantrone hydrochloride, paclitaxel, pegaspargase, porfimer sodium, procarbazine hydrochloride, rituximab, teniposide, topotecan hydrochloride, trastuzumab, tretinoin, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate. (See, e.g., pp. 867-963 of Nursing 2001 Drug Handbook)

The at least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immune globulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, tacrolimus. The at least one vaccine or toxoid can be at least one selected from BCG vaccine, cholera vaccine, diphtheria and tetanus toxoids (adsorbed), diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed, diphtheria and tetanus toxoids and whole-cell pertussis vaccine, Haemophilius b conjugate vaccines, hepatitis A vaccine (inactivated), hepatisis B vaccine (recombinant), influenza virus vaccine 1999-2000 trivalent types A & B (purified surface antigen), influenza virus vaccine 1999-2000 trivalent types A & B (subvirion or purified subvirion), influenza virus vaccine 1999-2000 trivalent types A & B (whole virion), Japanese encephalitis virus vaccine (inactivated), Lyme disease vaccine (recombinant OspA), measles and mumps and rubella virus vaccine (live), measles and mumps and rubella virus vaccine (live attenuated), measles virus vaccine (live attenuated), meningococcal polysaccharide vaccine, mumps virus vaccine (live), plague vaccine, pneumococcal vaccine (polyvalent), poliovirus vaccine (inactivated), poliovirus vaccine (live, oral, trivalent), rabies vaccine (adsorbed), rabies vaccine (human diploid cell), rubella and mumps virus vaccine (live), rubella virus vaccine (live, attenuated), tetanus toxoid (adsorbed), tetanus toxoid (fluid), typhoid vaccine (oral), typhoid vaccine (parenteral), typhoid Vi polysaccharide vaccine, varicella virus vaccine, yellow fever vaccine. The at least one antitoxin or antivenin can be at least one selected from black widow spider antivenin, Crotalidae antivenom (polyvalent), diphtheria antitoxin (equine), Micrurus fulvius antivenin). The at least one immune serum can be at least one selected from cytomegalovirus immune globulin (intraveneous), hepatitis B immune globulin (human), immune globulin intramuscular, immune globulin intravenous, rabies immune globulin (human), respiratory syncytial virus immune globulin intravenous (human), Rho(D) immune globulin (human), Rho(D) immune globulin intravenous (human), tetanus immune globulin (human), varicella-zoster immune globulin. The at least one biological response modifiers can be at least one selected from aldesleukin, epoetin alfa, filgrastim, glatiramer acetate for injection, interferon alfacon-l, interferon alfa-2a (recombinant), interferon alfa-2b (recombinant), interferon beta- la, interferon beta- lb (recombinant), interferon gamma- lb, levamisole hydrochloride, oprelvekin, sargramostim. (See, e.g., pp. 964-1040 of Nursing 2001 Drug Handbook)

The at least one ophthalmic anti-infectives can be selected form bacitracin, chloramphenicol, ciprofloxacin hydrochloride, erythromycin, gentamicin sulfate, ofloxacin 0.3%, polymyxin B sulfate, sulfacetamide sodium 10%, sulfacetamide sodium 15%, sulfacetamide sodium 30%, tobramycin, vidarabine. The at least one ophthalmic anti-inflammatories can be at least one selected from dexamethasone, dexamethasone sodium phosphate, diclofenac sodium 0.1%, fluorometholone, flurbiprofen sodium, ketorolac tromethamine, prednisolone acetate (suspension) prednisolone sodium phosphate (solution). The at least one miotic can be at least one selected from acetylocholine chloride, carbachol (intraocular), carbachol (topical), echothiophate iodide, pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate. The at least one mydriatic can be at least one selected from atropine sulfate, cyclopentolate hydrochloride, epinephrine hydrochloride, epinephryl borate, homatropine hydrobromide, phenylephrine hydrochloride, scopolamine hydrobromide, tropicamide. The at least one ophthalmic vasoconstrictors can be at least one selected from naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride. The at least one miscellaneous ophthalmics can be at least one selected from apraclonidine hydrochloride, betaxolol hydrochloride, brimonidine tartrate, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, emedastine difumarate, fluorescein sodium, ketotifen fumarate, latanoprost, levobunolol hydrochloride, metipranolol hydrochloride, sodium chloride (hypertonic), timolol maleate. The at least one otic can be at least one selected from boric acid, carbamide peroxide, chloramphenicol, triethanolamine polypeptide oleate-condensate. The at least one nasal drug can be at least one selected from beclomethasone dipropionate, budesonide, ephedrine sulfate, epinephrine hydrochloride, flunisolide, fluticasone propionate, naphazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride, triamcinolone acetonide, xylometazoline hydrochloride. (See, e.g., pp. 1041-97 of Nursing 2001 Drug Handbook) The at least one local anti-infectives can be at least one selected from acyclovir, amphotericin

B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, tolnaftate. The at least one scabicide or pediculicide can be at least one selected from crotamiton, lindane, permethrin, pyrethrins. The at least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcionide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocorisone valerate, mometasone furoate, triamcinolone acetonide.

(See, e.g., pp. 1098-1136 of ursing 2001 Drug Handbook.)

The at least one vitamin or mineral can be at least one selected from vitamin A, vitamin B complex, cyanocobalamin, folic acid, hydroxocobalamin, leucovorin calcium, niacin, niacinamide, pyridoxine hydrochloride, riboflavin, thiamine hydrochloride, vitamin C, vitamin D, cholecalciferol, ergocalciferol, vitamin D analogue, doxercalciferol, paricalcitol, vitamin E, vitamin K analogue, phytonadione, sodium fluoride, sodium fluoride (topical), trace elements, chromium, copper, iodine, manganese, selenium, zinc. The at least one calorics can be at least one selected from amino acid infusions (crystalline), amino acid infusions in dextrose, amino acid infusions with electrolytes, amino acid infusions with electrolytes in dextrose, amino acid infusions for hepatic failure, amino acid infusions for high metabolic stress, amino acid infusions for renal failure, dextrose, fat emulsions, medium-chain triglycerides. (See, e.g., pp. 1137-63 of Nursing 2001 Drug Handbook.)

CHI deleted mimetibody antibody or polypeptide compositions ofthe present invention can further comprise at least one of any suitable and/or effective amount of a composition or pharmaceutical composition comprising at least one CHI deleted mimetibody protein or antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy, optionally further comprising at least one selected from at least one TNF antagonist (e.g., but not limited to a TNF chemical or protein antagonist, TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or H (TBP-1 or TBP-π), nerelimonmab, infliximab, enteracept, CDP-571, CDP-870, afelimomab, lenercept, and the like), an antirheumatic (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropieitin (e.g., epoetin alpha), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Non-limiting examples of such cytokines include, but are not limted to, any of IL- 1 to JL-23. Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2^nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which references are entirely incorporated herein by reference. Such compositions can also include toxin molecules that are associated, bound, co-formulated or co-administered with at least one antibody or polypeptide ofthe present invention. The toxin can optionally act to selectively kill the pathologic cell or tissue. The pathologic cell can be a cancer or other cell. Such toxins can be, but are not limited to, purified or recombinant toxin or toxin fragment comprising at least one functional cytotoxic domain of toxin, e.g., selected from at least one of ricin, diphtheria toxin, a venom toxin, or a bacterial toxin. The term toxin also includes both endotoxins and exotoxins produced by any naturally occurring, mutant or recombinant bacteria or viruses which may cause any pathological condition in humans and other mammals, including toxin shock, which can result in death. Such toxins may include, but are not limited to, enterotoxigenic E. coli heat-labile enterotoxin (LT), heat-stable enterotoxin (ST), Shigella cytotoxin, Aeromonas enterotoxins, toxic shock syndrome toxin-1 (TSST-1), Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcal enterotoxins and the like. Such bacteria include, but are not limited to, strains of a species of enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli (e.g., strains of serotype 0157:H7), Staphylococcus species (e.g., Staphylococcus aureus, Staphylococcus pyogenes), Shigella species (e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei), Salmonella species (e.g., Salmonella typhi, Salmonella cholera-suis, Salmonella enteritidis), Clostridium species (e.g., Clostridium perfringens, Clostridium dificile, Clostridium botulinum), Camphlobacter species (e.g., Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species, (e.g., Heliobacter pylori), Aeromonas species (e.g., Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae), Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (e.g., Vibrios cholerae, Vibrios parahemolyticus), Klebsiella species, Pseudomonas aeruginosa, and Streptococci. See, e.g., Stein, ed., INTERNAL MEDICINE, 3rd ed., pp 1-13, Little, Brown and Co., Boston, (1990); Evans et al., eds., Bacterial Infections of Humans: Epidemiology and Control, 2d. Ed., pp 239-254, Plenum Medical Book Co., New York (1991); Mandell et al, Principles and Practice of Infectious Diseases, 3d. Ed., Churchill Livingstone, New York (1990); Berkow et al, eds., The Merck Manual, 16th edition, Merck and Co.,

Rahway, N.J., 1992; Wood et al, FEMS Microbiology Immunology, 76:121-134 (1991); Marrack et al, Science, 248:705-711 (1990), the contents of which references are incorporated entirely herein by reference.

CHI -deleted mimetibody or specified portion or variant compositions ofthe present invention can further comprise at least one of any suitable auxiliary, such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Pharmaceutically acceptable auxiliaries are preferred. Non-limiting examples of, and methods of preparing such sterile solutions are well known in the art, such as, but limited to, Gennaro, Ed., Remington 's Pharmaceutical Sciences, 18^th Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the CHI-deleted mimetibody composition as well known in the art or as described herein.

Pharmaceutical excipients and additives useful in the present composition include but are not limited to proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, terra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/CHl- deleted mimetibody or specified portion or variant components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine.

Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol and the like. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose.

CHI-deleted mimetibody compositions can also include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present compositions are organic acid salts such as citrate.

Additionally, the CHI -deleted mimetibody or specified portion or variant compositions ofthe invention can include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phosphohpids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA). These and additional known pharmaceutical excipients and/or additives suitable for use in the

CHI-deleted mimetibody compositions according to the invention are known in the art, e.g., as listed in "Remington: The Science & Practice of Pharmacy", 19^th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52^nd ed., Medical Economics, Montvale, NJ (1998), the disclosures of which are entirely incorporated herein by reference. Preferrred carrier or excipient materials are carbohydrates (e.g., saccharides and alditols) and buffers (e.g., citrate) or polymeric agents. Formulations

As noted above, the invention provides for stable formulations, which can preferably include a suitable buffer with saline or a chosen salt, as well as optional preserved solutions and formulations containing a preservative as well as multi-use preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one CHI -deleted mimetibody or specified portion or variant in a pharmaceutically acceptable formulation. Preserved formulations contain at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent. Any suitable concentration or mixture can be used as known in the art, such as 0.001-5%, or any range or value therein, such as, but not limited to 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.1, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range or value therein. Non-limiting examples include, no preservative, 0.1-2% m-cresol (e.g., 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1., 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005-1.0% alkylparaben(s) (e.g, 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

As noted above, the invention provides an article of manufacture, comprising packaging material and at least one vial comprising a solution of at least one CHI -deleted mimetibody or specified portion or variant with the prescribed buffers and/or preservatives, optionally in an aqueous diluent, wherein said packaging material comprises a label that indicates that such solution can be held over a period of 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or greater. The invention further comprises an article of manufacture, comprising packaging material, a first vial comprising lyophilized at least one CHI -deleted mimetibody or specified portion or variant, and a second vial comprising an aqueous diluent of prescribed buffer or preservative, wherein said packaging material comprises a label that instructs a patient to reconstitute the at least one CHI -deleted mimetibody or specified portion or variant in the aqueous diluent to form a solution that can be held over a period of twenty-four hours or greater.

The at least one CHI -deleted mimetibody or specified portion or variant used in accordance with the present invention can be produced by recombinant means, including from mammalian cell or transgenic preparations, or can be purified from other biological sources, as described herein or as known in the art. The range of amounts of at least one CHI -deleted mimetibody or specified portion or variant in the product ofthe present invention includes amounts yielding upon reconstitution, if in a wet/dry system, concentrations from about 1.0 μg ml to about 1000 mg/ml, although lower and higher concentrations are operable and are dependent on the intended delivery vehicle, e.g, solution formulations will differ from transdermal patch, pulmonary, transmucosal, or osmotic or micro pump methods.

Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m- cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof. The concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect. Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan.

Other excipients, e.g. isotonicity agents, buffers, antioxidants, preservative enhancers, can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH control. The formulations can cover a wide range of pHs, such as from about pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred range of about 6.0 to about 8.0. Preferably the formulations ofthe present invention have pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably sodium phosphate, particularly phosphate buffered saline (PBS).

Other additives, such as a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block copolymers, and chelators such as EDTA and EGTA can optionally be added to the formulations or compositions to reduce aggregation. These additives are particularly useful if a pump or plastic container is used to administer the formulation. The presence of pharmaceutically acceptable surfactant mitigates the propensity for the protein to aggregate.

The formulations ofthe present invention can be prepared by a process which comprises mixing at least one CHI-deleted mimetibody or specified portion or variant and a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof in an aqueous diluent. Mixing the at least one CHI -deleted mimetibody or specified portion or variant and preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one CHI -deleted mimetibody or specified portion or variant in buffered solution is combined with the desired preservative in a buffered solution in quantities sufficient to provide the protein and preservative at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that may be optimized for the concentration and means of administration used.

The claimed formulations can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized at least one CHI -deleted mimetibody or specified portion or variant that is reconstituted with a second vial containing water, a preservative and/or excipients, preferably a phosphate buffer and/or saline and a chosen salt, in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus can provide a more convenient treatment regimen than currently available.

The present claimed articles of manufacture are useful for administration over a period of immediately to twenty-four hours or greater. Accordingly, the presently claimed articles of manufacture offer significant advantages to the patient. Formulations ofthe invention can optionally be safely stored at temperatures of from about 2 to about 40°C and retain the biologically activity ofthe protein for extended periods of time, thus, allowing a package label indicating that the solution can be held and/or used over a period of 6, 12, 18, 24, 36, 48, 72, or 96 hours or greater. If preserved diluent is used, such label can include use up to at least one of 1-12 months, one-half, one and a half, and/or two years.

The solutions of at least one CHI -deleted mimetibody or specified portion or variant in the invention can be prepared by a process that comprises mixing at least one CHI -deleted mimetibody or specified portion or variant in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a measured amount of at least one CHI -deleted mimetibody or specified portion or variant in water or buffer is combined in quantities sufficient to provide the protein and optionally a preservative or buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that may be optimized for the concentration and means of administration used.

The claimed products can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized at least one CHI -deleted mimetibody or specified portion or variant that is reconstituted with a second vial containing the aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available.

The claimed products can be provided indirectly to patients by providing to pharmacies, clinics, or other such institutions and facilities, clear solutions or dual vials comprising a vial of lyophilized at least one CHI -deleted mimetibody or specified portion or variant that is reconstituted with a second vial containing the aqueous diluent. The clear solution in this case can be up to one liter or even larger in size, providing a large reservoir from which smaller portions ofthe at least one CHI -deleted mimetibody or specified portion or variant solution can be retrieved one or multiple times for transfer into smaller vials and provided by the pharmacy or clinic to their customers and/or patients.

Recognized devices comprising these single vial systems include those pen-injector devices for delivery of a solution such as Humaject^®'NovoPen^®, B-D^®Pen, AutoPen^®, and OptiPen^®. Recognized devices comprising a dual vial system include those pen-injector systems for reconstituting a lyophilized drug in a cartridge for delivery ofthe reconstituted solution such as the HumatroPen^®. The products presently claimed include packaging material. The packaging material provides, in addition to the information required by the regulatory agencies, the conditions under which the product can be used. The packaging material ofthe present invention provides instructions to the patient to reconstitute the at least one CHI -deleted mimetibody or specified portion or variant in the aqueous diluent to form a solution and to use the solution over a period of 2-24 hours or greater for the two vial, wet/dry, product. For the single vial, solution product, the label indicates that such solution can be used over a period of 2-24 hours or greater. The presently claimed products are useful for human pharmaceutical product use.

The formulations ofthe present invention can be prepared by a process that comprises mixing at least one CHI -deleted mimetibody or specified portion or variant and a selected buffer, preferably a phosphate buffer containing saline or a chosen salt. Mixing the at least one CHI -deleted mimetibody or specified portion or variant and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one CHI -deleted mimetibody or specified portion or variant in water or buffer is combined with the desired buffering agent in water in quantities sufficient to provide the protein and buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and means of administration used. The claimed stable or preserved formulations can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized at least one CHI-deleted mimetibody or specified portion or variant that is reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available.

At least one CHI -deleted mimetibody or specified portion or variant in either the stable or preserved formulations or solutions described herein, can be administered to a patient in accordance with the present invention via a variety of delivery methods including SC or IM injection; transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micro pump, or other means appreciated by the skilled artisan, as well-known in the art.

Therapeutic Applications

The present invention for mimetibodies also provides a method for modulating or treating anemia, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of any anemia, cancer treatment related anemia, radiotherapy or chemotherapy related anemia, viral or bacterial infection treatment related anemia, renal anemia, anemia of prematurity, pediatric and/or adult cancer-associated anemia, anemia associated with lymphoma, myeloma, multple myeloma, ATDS-associated anemia, concomitant treatment for patients with or without autologous blood donation awaiting elective surgery, preoperatve and post operative for surgery, autologous blood donation or transfusion, perioperative management, cyclic neutropenia or Kostmann syndrome (congenital agranulocytosis), end-stage renal disease, anemia associated with dialysis, chronic renal insufficiency, primary hemopoietic diseases, such as congenital hypoplastic anemia, thalassemia major, or sickle cell disease, vaso-occlusive complications of sickle cell disease. Furman et al. Pediatrics 1992; 90: 716- 728, Goldberg Science. 1988;242:1412-1415; Paul et al, Exp Hematol. 1984;12:825-830; Erslev et al.

Arch Intern Med. 1968;122:230-235; Ersley et al, Ann Clin Lab Sci. 1980;10:250-257; Jacobs et al. Nature. 1985;313:806-810; Lin et al, Proc Natl Acad Sci USA. 1985;82:7580-7584; Law et al, Proc Natl Acad Sci USA. 1986;83:6920-6924; Goldwasser et al, JBiol Chem. 1974;249:4202-4206; Eaves et a. Blood. 1978;52:1196-1210; Sawyer et al. Blood. 1989;74:103-109; Winearls et al. Lancet. 1986;2:1175-1178; Eschbach et al, N Engl J Med. 1987;316:73-78; Eschbach et al, Ann Intern Med. 1989; 111 :992-l 000, each reference entirely incoporated herein by reference. Mimetibodies ofthe present invention can also be used for non-renal forms of anemia induced, for example, by chronic infections, inflammatory processes, radiation therapy, and cytostatic drug treatment, and encouraging results in patients with non-renal anemia have been reported. See, e.g, Abels RI and Rudnick SA Erythropoietin: evolving clinical applications. Experimental Hematology 19: 842-50 (1991); Graber SE and Krantz SB Erythropoietin: biology and clinical use. Hematology/Oncol. Clin. North Amer. 3: 369-400 (1989); Jelkman W and Gross AJ (eds) Erythropoietin. Springer, Berlin 1989; Koury MJ and Bondurant MC The molecular mechanism of erythropoietin action. European Journal of Biochemistry 210: 649-63 (1992); Krantz SB Erythropoietin. Blood 77: 419-34 (1991); Tabbara IA. Erythropoietin. Biology and clinical applications. Archives of Internal Medicine 153: 298- 304 (1993), each entirely incorporated herein by reference .

The present invention also provides a method for modulating or treating an anemia or blood cell related condition, in a cell, tissue, organ, animal, or patient, wherein said anemia or blood cell related condition is associated with at least one including, but not limited to, at least one of immune related disease, cardiovascular disease, infectious, malignant and/or neurologic disease. Such a method can optionally comprise administering an effective amount of at least one composition or pharmaceutical composition comprising at least one CHI -deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. The present invention also provides a method for modulating or treating cancer/infecteous disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, FflV infection/HTv neuropathy, meningitis, hepatitis, septic arthritis, peritonitis, pneumonia , epiglottitis, e. coli 0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, vital-associated hemaphagocytic syndrome, vital encephalitis/aseptic meningitis, and the like; (ii) leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignamt lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy, solid tumors, adenocarcinomas, sarcomas, malignant melanoma, and the like; or (iii) neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders' such as lesions ofthe corticospinal system; disorders ofthe basal ganglia or cerebellar disorders; hyperkinetic movement disorders such as Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supranucleo Palsy; structural lesions ofthe cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado- Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi.system disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders ofthe motor unit' such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; Wernicke- Korsakoff syndrome; chronic alcoholism; Creutzfeldt- Jakob disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica, and the like. Such a method can optionally comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one TNF antibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. See, e.g, the Merck Manual, 16^th Edition, Merck & Company, Rahway, NJ (1992)

Such a method can optionally comprise administering an effective amount of at least one composition or pharmaceutical composition comprising at least one CHI -deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.

The present invention also provides a method for modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal, or patient, including, but not limited to, at least one of cardiac stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, diabetic ateriosclerotic disease, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis ofthe cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrythmias, ventricular fibrillation, His bundle arrythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, coronary artery disease, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart diseases, endocarditis, pericardial disease, cardiac tumors, aordic and peripheral aneuryisms, aortic dissection, inflammation ofthe aorta, occulsion ofthe abdominal aorta and its branches, peripheral vascular disorders, occulsive arterial disorders, peripheral atherlosclerotic disease, thromboangitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury, and the like. Such a method can optionally comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CHI-deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.

Any method ofthe present invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CHI -deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such a method can optionally further comprise co-administration or combination therapy for treating such immune diseases, wherein the administering of said at least one CHI -deleted mimetibody, specified portion or variant thereof, further comprises administering, before concurrently, and/or after, at least one selected from at least one TNF antagonist (e.g, but not limited to a TNF antibody or fragment, a soluble TNF receptor or fragment, fusion proteins thereof, or a small molecule TNF antagonist), an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial (e.g, aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropieitin (e.g, epoetin alpha), a filgrastim (e.g, G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g, basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Suitable dosages are well known in the art. See, e.g. Wells et al, eds, Pharmacotherapy Handbook, 2^nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which references are entirely incorporated herein by reference. Mimetibodies can also be used ex vivo, such as in autologous marrow culture. Briefly, bone marrow is removed from a patient prior to chemotherapy and treated with TPO and/or EPO, optionally in combination with mimetibodies, optionally in combination with one or more additional cytokines. The treated marrow is then returned to the patient after chemotherapy to speed the recovery ofthe marrow, hi addition, TPO, alone and in combination with EPO mimetibodies and/or EPO, can also be used for the ex vivo expansion of marrow or peripheral blood progenitor (PBPC) cells. Prior to chemotherapy treatment, marrow can be stimulated with stem cell factor (SCF) or G-CSF to release early progenitor cells into peripheral circulation. These progenitors are optionally collected and concentrated from peripheral blood and then treated in culture with TPO and mimetibodies, optionally in combination with one or more other cytokines, including but not limited to SCF, G-CSF, IL-3, GMCSF, IL-6 or IL-11, to differentiate and proliferate into high-density megakaryocyte cultures, which are optionally then be returned to the patient following high-dose chemotherapy. Doses of TPO for ex vivo treatment of bone marrow will be in the range of 100 pg/ml to 10 ng/ml, preferably 500 pg/ml to 3 ng/ml. Doses of mimetibodies will be equivalent in activity to EPO which can be used from 0.1 units/ml to 20 units/ml, preferably from 0.5 units/ml to 2 units/ml, or any range or value therein.

TNF antagonists suitable for compositions, combination therapy, co-administration, devices and/or methods ofthe present invention (further comprising at least one anti body, specified portion and variant thereof, ofthe present invention), include, but are not limited to, anti-TNF antibodies, ligand-binding fragments thereof, and receptor molecules which bind specifically to TNF; compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g, pentoxifylline and rolipram), A2b adenosine receptor agonists and A2b adenosine receptor enhancers; compounds which prevent and/or inhibit TNF receptor signalling, such as mitogen activated protein (MAP) kinase inhibitors; compounds which block and/or inhibit membrane TNF cleavage, such as metalloproteinase inhibitors; compounds which block and/or inhibit TNF activity, such as angiotensin converting enzyme (ACE) inhibitors (e.g, captopril); and compounds which block and/or inhibit TNF production and/or synthesis, such as MAP kinase inhibitors.

As used herein, a "tumor necrosis factor antibody," "TNF antibody," "TNFα antibody," or fragment and the like decreases, blocks, inhibits, abrogates or interferes with TNFα activity in vitro, in situ and/or preferably in vivo. For example, a suitable TNF human antibody ofthe present invention can bind TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and specified mutants or domains thereof that bind specifically to TNFα. A suitable TNF antibody or fragment can also decrease block, abrogate, interfere, prevent and/or inhibit TNF RNA, DNA or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and/or synthesis.

Chimeric antibody cA2 consists ofthe antigen binding variable region ofthe high-affinity neutralizing mouse anti-human TNFα IgGl antibody, designated A2, and the constant regions of a human IgGl, kappa immunoglobulin. The human IgGl Fc region improves allogeneic antibody effector function, increases the circulating serum half-life and decreases the immunogenicity ofthe antibody. The avidity and epitope specificity ofthe chimeric antibody cA2 is derived from the variable region ofthe murine antibody A2. In a particular embodiment, a preferred source for nucleic acids encoding the variable region ofthe murine antibody A2 is the A2 hybridoma cell line.

Chimeric A2 (cA2) neutralizes the cytotoxic effect of both natural and recombinant human TNFα in a dose dependent manner. From binding assays of chimeric antibody cA2 and recombinant human TNFα, the affinity constant of chimeric antibody cA2 was calculated to be 1.04xl0¹⁰M^"1. Preferred methods for determining monoclonal antibody specificity and affinity by competitive inhibition can be found in Harlow, et al, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988; CoUigan et al, eds. Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, New York, (1992-2002); Kozbor et al, Immunol. Today, 4:12-19 (1983); Ausubel et al, eds. Current Protocols in Molecular Biology, Wiley Interscience, New York (1987-2002); and Muller, Meth. Enzymol, 92:589-601 (1983), which references are entirely incorporated herein by reference.

In a particular embodiment, murine monoclonal antibody A2 is produced by a cell line designated cl34A. Chimeric antibody cA2 is produced by a cell line designated cl68A.

Additional examples of monoclonal anti-TNF antibodies that can be used in the present invention are described in the art (see, e.g, U.S. Patent No. 5,231,024; Mδller, A. et al, Cytokine 2(3):162-169 (1990); U.S. Application No. 07/943,852 (filed September 11, 1992); Rathjen et al, International Publication No. WO 91/02078 (published February 21, 1991); Rubin et al, EPO Patent Publication No. 0 218 868 (published April 22, 1987); Yone et al, EPO Patent Publication No. 0 288

088 (October 26, 1988); Liang, et al, Biochem. Biophys. Res. Comm. 737:847-854 (1986); Meager, et al, Hybridoma (5:305-311 (1987); Fendly et al, Hybridoma 6:359-369 (1987); Bringman, et al, Hybridoma 6:489-507 (1987); and Hirai, et al, J. Immunol. Meth. 96:51-62 (1987), which references are entirely incorporated herein by reference). TNF Receptor Molecules

Preferred TNF receptor molecules useful in the present invention are those that bind TNFα with high affinity (see, e.g, Feldmann et al, International Publication No. WO 92/07076 (published April 30, 1992); Schall et al, Cell 61:361-310 (1990); and Loetscher et al, Cell 67:351-359 (1990), which references are entirely incorporated herein by reference) and optionally possess low immunogenicity. In particular, the 55 kDa (p55 TNF-R) and the 75 kDa (p75 TNF-R) TNF cell surface receptors are useful in the present invention. Truncated forms of these receptors, comprising the extracellular domains (ECD) ofthe receptors or functional portions thereof (see, e.g, Corcoran et al, Eur. J. Biochem. 223:831-840 (1994)), are also useful in the present invention. Truncated forms ofthe TNF receptors, comprising the ECD, have been detected in urine and serum as 30 kDa and 40 kDa TNFα inhibitory binding proteins (Engelmann, H. et al, J. Biol. Chem. 265: 1531-1536 (1990)). TNF receptor multimeric molecules and TNF immunoreceptor fusion molecules, and derivatives and fragments or portions thereof, are additional examples of TNF receptor molecules which are useful in the methods and compositions ofthe present invention. The TNF receptor molecules which can be used in the invention are characterized by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as well as other undefined properties, may contribute to the therapeutic results achieved.

TNF receptor multimeric molecules useful in the present invention comprise all or a functional portion ofthe ECD of two or more TNF receptors linked via one or more polypeptide linkers or other nonpeptide linkers, such as polyethylene glycol (PEG). The multimeric molecules can further comprise a signal peptide of a secreted protein to direct expression ofthe multimeric molecule. These multimeric molecules and methods for their production have been described in U.S. Application No. 08/437,533 (filed May 9, 1995), the content of which is entirely incorporated herein by reference.

TNF immunoreceptor fusion molecules useful in the methods and compositions ofthe present invention comprise at least one portion of one or more immunoglobulin molecules and all or a functional portion of one or more TNF receptors. These immunoreceptor fusion molecules can be assembled as monomers, or hetero- or homo-multimers. The immunoreceptor fusion molecules can also be monovalent or multivalent. An example of such a TNF immunoreceptor fusion molecule is TNF receptor/IgG fusion protein. TNF immunoreceptor fusion molecules and methods for their production have been described in the art (Lesslauer et al, Eur. J. Immunol 27:2883-2886 (1991);

Ashkenazi et al, Proc. Natl. Acad. Sci. USA <°<°:10535-10539 (1991); Peppel et al, J. Exp. Med. 774:1483-1489 (1991); Kolls et al, Proc. Natl Acad. Sci. USA 97:215-219 (1994); Butler et al, Cytokine 6(6):616-623 (1994); Baker et al, Eur. J. Immunol 24:2040-2048 (1994); Beutler et al, U.S. Patent No. 5,447,851; and U.S. Application No. 08/442,133 (filed May 16, 1995), each of which references are entirely incorporated herein by reference). Methods for producing immunoreceptor fusion molecules can also be found in Capon et al, U.S. Patent No. 5,116,964; Capon et al, U.S. Patent No. 5,225,538; and Capon et al, Nature 337:525-531 (1989), which references are entirely incorporated herein by reference.

A functional equivalent, derivative, fragment or region of TNF receptor molecule refers to the portion o the TNF receptor molecule, or the portion ofthe TNF receptor molecule sequence which encodes TNF receptor molecule, that is of sufficient size and sequences to functionally resemble TNF receptor molecules that can be used in the present invention (e.g, bind TNFα with high affinity and possess low immunogenicity). A functional equivalent of TNF receptor molecule also includes modified TNF receptor molecules that functionally resemble TNF receptor molecules that can be used in the present invention (e.g, bind TNFα with high affinity and possess low immunogenicity). For example, a functional equivalent of TNF receptor molecule can contain a "SILENT" codon or one or more amino acid substitutions, deletions or additions (e.g, substitution of one acidic amino acid for another acidic amino acid; or substitution of one codon encoding the same or different hydrophobic amino acid for another codon encoding a hydrophobic amino acid). See Ausubel et al, Current

Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley-Inierscience, New York (1987- 2002).

Cytokines include, but are not limited to all known cytokines. See, e.g, CopewithCytokines.com. Cytokine antagonists include, but are not limited to, any antibody, fragment or mimetic, any soluble receptor, fragment or mimetic, any small molecule antagonist, or any combination thereof.

Any method ofthe present invention can comprise a method for treating a protein mediated disorder, comprising administering an effective amount of a composition or pharmaceutical composition comprising at least one CHI -deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such a method can optionally further comprise co-administration or combination therapy for treating such immune diseases, wherein the administering of said at least one CHI -deleted mimetibody, specified portion or variant thereof, further comprises administering, before concurrently, and/or after, at least one selected from at least one other cytokines such as IL-3, IL -6 and IL -11; stem cell factor; G-CSF and GM-CSF. Combination therapy with GM-CSF, for example, is indicated in patients with low neutrophil levels.

Typically, treatment of pathologic conditions is effected by administering an effective amount or dosage of at least one CHI-deleted mimetibody composition that total, on average, a range from at least about 0.01 to 500 milligrams of at least one CHI-deleted mimetibody or specified portion or variant /kilogram of patient per dose, and preferably from at least about 0.1 to 100 milligrams CHI-deleted mimetibody or specified portion or variant /kilogram of patient per single or multiple administration, depending upon the specific activity of contained in the composition. Alternatively, the effective serum concentration can comprise 0.1-5000 μg ml serum concentration per single or multiple adminstration. Suitable dosages are known to medical practitioners and will, of course, depend upon the particular disease state, specific activity ofthe composition being administered, and the particular patient undergoing treatment. In some instances, to achieve the desired therapeutic amount, it can be necessary to provide for repeated administration, i.e., repeated individual administrations of a particular monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved. Preferred doses can optionally include 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 009, 0.1, 0.2,

0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and/or 30 mg/kg/administration, or any range, value or fraction thereof, or to achieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and/or 5000 μg/ml serum concentration per single or multiple administration, or any range, value or fraction thereof.

Alternatively, the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics ofthe particular agent, and its mode and route of administration; age, health, and weight ofthe recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight. Ordinarily 0.1 to 50, and preferably 0.1 to 10 milligrams per kilogram per administration or in sustained release form is effective to obtain desired results.

As a non-limiting example, treatment of humans or animals can be provided as a one-time or periodic dosage of at least one CHI -deleted mimetibody or specified portion or variant ofthe present invention 0.01 to 100 mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or any combination thereof, using single, infusion or repeated doses.

Dosage forms (composition) suitable for internal administration generally contain from about 0.0001 milligram to about 500 milligrams of active ingredient per unit or container. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95%) by weight based on the total weight ofthe composition. For parenteral administration, the CHI -deleted mimetibody or specified portion or variant can be formulated as a solution, suspension, emulsion or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used. The vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g, sodium chloride, mannitol) and chemical stability (e.g, buffers and preservatives). The formulation is sterilized by known or suitable techniques.

Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Therapeutic Administration

Many known and developed modes of can be used according to the present invention for administering pharmaceutically effective amounts of at least one CHI -deleted mimetibody or specified portion or variant according to the present invention. While pulmonary administration is used in the following description, other modes of administration can be used according to the present invention with suitable results.

A CHI -deleted mimetibody ofthe present invention can be delivered in a carrier, as a solution, emulsion, colloid, or suspension, or as a powder, using any of a variety of devices and methods suitable for administration by inhalation or other modes described here within or known in the art.

Parenteral Formulations and Administration

Formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Aqueous or oily suspensions for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known methods. Agents for injection can be a non-toxic, non-orally administrable diluting agent such as aquous solution or a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer's solution, isotonic saline, etc. are allowed; as an ordinary solvent, or suspending solvent, sterile involatile oil can be used. For these purposes, any kind of involatile oil and fatty acid can be used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthtetic mono- or di- or tri-glycerides. Parental administration is known in the art and includes, but is not limited to, conventional means of injections, a gas pressured needle-less injection device as described in U.S. Pat. No. 5,851,198, and a laser perforator device as described in U.S. Pat. No. 5,839,446 entirely incorporated herein by reference. Alternative Delivery

The invention further relates to the administration of at least one CHI -deleted mimetibody or specified portion or variant by parenteral, subcutaneous, intramuscular, intravenous, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal means. Protein, CHI -deleted mimetibody or specified portion or variant compositions can be prepared for use for parenteral (subcutaneous, intramuscular or intravenous) administration particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration particularly in semisolid forms such as creams and suppositories; for buccal, or sublingual administration particularly in the form of tablets or capsules; or intranasally particularly in the form of powders, nasal drops or aerosols or certain agents; or transdermally particularly in the form of a gel, ointment, lotion, suspension or patch delivery system with chemical enhancers such as dimethyl sulfoxide to either modify the skin structure or to increase the drug concentration in the transdermal patch (Junginger, et al. In "Drug Permeation Enhancement"; Hsieh, D. S, Eds, pp. 59-90 (Marcel Dekker, Inc. New York 1994, entirely incorporated herein by reference), or with oxidizing agents that enable the application of formulations containing proteins and peptides onto the skin (WO 98/53847), or applications of electric fields to create transient transport pathways such as electroporation, or to increase the mobility of charged drugs through the skin such as iontophoresis, or application of ultrasound such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents being entirely incorporated herein by reference).

Pulmonary Nasal Administration

For pulmonary administration, preferably at least one CHI -deleted mimetibody or specified portion or variant composition is delivered in a particle size effective for reaching the lower airways of the lung or sinuses. According to the invention, at least one CHI -deleted mimetibody or specified portion or variant can be delivered by any of a variety of inhalation or nasal devices known in the art for administration of a therapeutic agent by inhalation. These devices capable of depositing aerosolized formulations in the sinus cavity or alveoli of a patient include metered dose inhalers, nebulizers, dry powder generators, sprayers, and the like. Other devices suitable for directing the pulmonary or nasal administration of CHI -deleted mimetibody or specified portion or variants are also known in the art. All such devices can use of formulations suitable for the administration for the dispensing of CHI-deleted mimetibody or specified portion or variant in an aerosol. Such aerosols can be comprised of either solutions (both aqueous and non aqueous) or solid particles. Metered dose inhalers like the Ventolin^® metered dose inhaler, typically use a propellent gas and require actuation during inspiration (See, e.g, WO 94/16970, WO 98/35888). Dry powder inhalers like Turbuhaler™ (Astra), Rotahaler^® (Glaxo), Diskus^® (Glaxo), Spiros™ inhaler (Dura), devices marketed by Inhale Therapeutics, and the Spinhaler^® powder inhaler (Fisons), use breath-actuation of a mixed powder (US 4668218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, US 5458135 Inhale, WO 94/06498 Fisons, entirely incorporated herein by reference). Nebulizers like AERx™ Aradigm, the Ulfravent^® nebulizer (Mallinckrodt), and the Acorn π^® nebulizer (Marquest Medical Products) (US 5404871 Aradigm, WO 97/22376), the above references entirely incorporated herein by reference, produce aerosols from solutions, while metered dose inhalers, dry powder inhalers, etc. generate small particle aerosols. These specific examples of commercially available inhalation devices are intended to be a representative of specific devices suitable for the practice of this invention, and are not intended as limiting the scope ofthe invention. Preferably, a composition comprising at least one CHI-deleted mimetibody or specified portion or variant is delivered by a dry powder inhaler or a sprayer. There are a several desirable features of an inhalation device for administering at least one CHI -deleted mimetibody or specified portion or variant ofthe present invention. For example, delivery by the inhalation device is advantageously reliable, reproducible, and accurate. The inhalation device can optionally deliver small dry particles, e.g. less than about 10 μm, preferably about 1-5 μm, for good respirability.

Administration of CHI-deleted mimetibody or specified portion or variant Compositions as a Spray

A spray including CHI -deleted mimetibody or specified portion or variant composition protein can be produced by forcing a suspension or solution of at least one CHI -deleted mimetibody or specified portion or variant through a nozzle under pressure. The nozzle size and configuration, the applied pressure, and the liquid feed rate can be chosen to achieve the desired output and particle size. An electrospray can be produced, for example, by an electric field in connection with a capillary or nozzle feed. Advantageously, particles of at least one CHI-deleted mimetibody or specified portion or variant composition protein delivered by a sprayer have a particle size less than about 10 μm, preferably in the range of about 1 μm to about 5 μm, and most preferably about 2 μm to about 3 μm.

Formulations of at least one CHI -deleted mimetibody or specified portion or variant composition protein suitable for use with a sprayer typically include CHI -deleted mimetibody or specified portion or variant composition protein in an aqueous solution at a concentration of about 1 mg to about 20 mg of at least one CHI -deleted mimetibody or specified portion or variant composition protein per ml of solution. The formulation can include agents such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and, preferably, zinc. The formulation can also include an excipient or agent for stabilization ofthe CHI -deleted mimetibody or specified portion or variant composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate. Bulk proteins useful in formulating CHI -deleted mimetibody or specified portion or variant composition proteins include albumin, protamine, or the like. Typical carbohydrates useful in formulating CHI- deleted mimetibody or specified portion or variant composition proteins include sucrose, mannitol, lactose, trehalose, glucose, or the like. The CHI-deleted mimetibody or specified portion or variant composition protein formulation can also include a surfactant, which can reduce or prevent surface- induced aggregation ofthe CHI-deleted mimetibody or specified portion or variant composition protein caused by atomization ofthe solution in forming an aerosol. Various conventional surfactants can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. Amounts will generally range between 0.001 and 14% by weight ofthe formulation. Especially preferred surfactants for purposes of this invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art for formulation of a protein such as mimetibodies, or specified portions or variants, can also be included in the formulation.

Administration of CHI-deleted mimetibody or specified portion or variant compositions by a Nebulizer

CHI -deleted mimetibody or specified portion or variant composition protein can be administered by a nebulizer, such as jet nebulizer or an ultrasonic nebulizer. Typically, in a jet nebulizer, a compressed air source is used to create a high-velocity air jet through an orifice. As the gas expands beyond the nozzle, a low-pressure region is created, which draws a solution of CHI - deleted mimetibody or specified portion or variant composition protein through a capillary tube connected to a liquid reservoir. The liquid stream from the capillary tube is sheared into unstable filaments and droplets as it exits the tube, creating the aerosol. A range of configurations, flow rates, and baffle types can be employed to achieve the desired performance characteristics from a given jet nebulizer. In an ultrasonic nebulizer, high-frequency electrical energy is used to create vibrational, mechanical energy, typically employing a piezoelectric transducer. This energy is transmitted to the formulation of CHI -deleted mimetibody or specified portion or variant composition protein either directly or through a coupling fluid, creating an aerosol including the CHI -deleted mimetibody or specified portion or variant composition protein. Advantageously, particles of CHI -deleted mimetibody or specified portion or variant composition protein delivered by a nebulizer have a particle size less than about 10 μm, preferably in the range of about 1 μm to about 5 μm, and most preferably about 2 μm to about 3 μm.

Formulations of at least one CHI -deleted mimetibody or specified portion or variant suitable for use with a nebulizer, either jet or ultrasonic, typically include CHI -deleted mimetibody or specified portion or variant composition protein in an aqueous solution at a concentration of about 1 mg to about 20 mg of at least one CHI -deleted mimetibody or specified portion or variant protein per ml of solution. The formulation can include agents such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and, preferably, zinc. The formulation can also include an excipient or agent for stabilization ofthe at least one CHI -deleted mimetibody or specified portion or variant composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate. Bulk proteins useful in formulating at least one CHI -deleted mimetibody or specified portion or variant composition proteins include albumin, protamine, or the like. Typical carbohydrates useful in formulating at least one CHI- deleted mimetibody or specified portion or variant include sucrose, mannitol, lactose, trehalose, glucose, or the like. The at least one CHI -deleted mimetibody or specified portion or variant formulation can also include a surfactant, which can reduce or prevent surface-induced aggregation of the at least one CHI -deleted mimetibody or specified portion or variant caused by atomization ofthe solution in forming an aerosol. Various conventional surfactants can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbital fatty acid esters. Amounts will generally range between 0.001 and 4% by weight ofthe formulation. Especially preferred surfactants for purposes of this invention are polyoxyethylene sorbitan mono-oleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art for formulation of a protein such as CHI -deleted mimetibody or specified portion or variant protein can also be included in the formulation.

Administration of CHI-deleted mimetibody or specified portion or variant compositions By A

Metered Dose Inhaler

In a metered dose inhaler (MDI), a propellant, at least one CHI -deleted mimetibody or specified portion or variant, and any excipients or other additives are contained in a canister as a mixture including a liquefied compressed gas. Actuation ofthe metering valve releases the mixture as an aerosol, preferably containing particles in the size range of less than about 10 μm, preferably about 1 μm to about 5 μm, and most preferably about 2 μm to about 3 μm. The desired aerosol particle size can be obtained by employing a formulation of CHI -deleted mimetibody or specified portion or variant composition protein produced by various methods known to those of skill in the art, including jet- milling, spray drying, critical point condensation, or the like. Preferred metered dose inhalers include those manufactured by 3M or Glaxo and employing a hydrofluorocarbon propellant.

Formulations of at least one CHI -deleted mimetibody or specified portion or variant for use with a metered-dose inhaler device will generally include a finely divided powder containing at least one CHI -deleted mimetibody or specified portion or variant as a suspension in a non-aqueous medium, for example, suspended in a propellant with the aid of a surfactant. The propellant can be any conventional material employed for this purpose, such as chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like. Preferably the propellant is a hydrofluorocarbon. The surfactant can be chosen to stabilize the at least one CHI -deleted mimetibody or specified portion or variant as a suspension in the propellant, to protect the active agent against chemical degradation, and the like. Suitable surfactants include sorbitan trioleate, soya lecithin, oleic acid, or the like. In some cases solution aerosols are preferred using solvents such as ethanol. Additional agents known in the art for formulation of a protein such as protein can also be included in the formulation.

One of ordinary skill in the art will recognize that the methods ofthe current invention can be achieved by pulmonary administration of at least one CHI -deleted mimetibody or specified portion or variant compositions via devices not described herein. Mucosal Formulations and Administration For absorption through mucosal surfaces, compositions and methods of administering at least one CHI -deleted mimetibody or specified portion or variant include an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, a bioactive peptide, and an aqueous continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion of the emulsion particles (U.S. Pat. Nos. 5,514,670). Mucous surfaces suitable for application ofthe emulsions ofthe present invention can include corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, stomachic, intestinal, and rectal routes of administration. Formulations for vaginal or rectal administration, e.g. suppositories, can contain as excipients, for example, polyalkyleneglycols, vaseline, cocoa butter, and the like. Formulations for intranasal administration can be solid and contain as excipients, for example, lactose or can be aqueous or oily solutions of nasal drops. For buccal administration excipients include sugars, calcium stearate, magnesium stearate, pregelinatined starch, and the like (U.S. Pat. No. 5,849,695). Oral Formulations and Administration

Formulations for oral rely on the co-administration of adjuvants (e.g, resorcinols and nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability ofthe intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g, pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. The active constituent compound ofthe solid-type dosage form for oral administration can be mixed with at least one additive, including sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, and glyceride. These dosage forms can also contain other type(s) of additives, e.g, inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidant such as cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent, perfuming agent, etc. Tablets and pills can be further processed into enteric-coated preparations. The liquid preparations for oral administration include emulsion, syrup, elixir, suspension and solution preparations allowable for medical use. These preparations may contain inactive diluting agents ordinarily used in said field, e.g, water. Liposomes have also been described as drug delivery systems " for insulin and heparin (U.S. Pat. No. 4,239,754). More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals (U.S. Pat. No.

4,925,673). Furthermore, carrier compounds described in U.S. Pat. No. 5,879,681 and U.S. Pat. No. 5,5,871,753 are used to deliver biologically active agents orally are known in the art. Transdermal Formulations and Administration

For transdermal administration, the at least one CHI -deleted mimetibody or specified portion or variant is encapsulated in a delivery device such as a liposome or polymeric nanoparticles, microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless otherwise stated). A number of suitable devices are known, including microparticles made of synthetic polymers such as polyhydroxy acids such as polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyanhydrides, and polyphosphazenes, and natural polymers such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides, and combinations thereof (U.S. Pat. No. 5,814,599). Prolonged Administration and Formulations

It can be sometimes desirable to deliver the compounds ofthe present invention to the subject over prolonged periods of time, for example, for periods of one week to one year from a single administration. Various slow release, depot or implant dosage forms can be utilized. For example, a dosage form can contain a pharmaceutically acceptable non-toxic salt ofthe compounds that has a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acids, polygalacturonic acid, and the like; (b) a salt with a polyvalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g, N,N- dibenzyl-ethylenediamine or ethylenediamine; or (c) combinations of (a) and (b) e.g. a zinc tannate salt. Additionally, the compounds ofthe present invention or, preferably, a relatively insoluble salt such as those just described, can be formulated in a gel, for example, an aluminum monostearate gel with, e.g. sesame oil, suitable for injection. Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts, and the like. Another type of slow release depot formulation for injection would contain the compound or salt dispersed for encapsulated in a slow degrading, non-toxic, non-antigenic polymer such as a polylactic acid/polyglycolic acid polymer for example as described in U.S. Pat. No. 3,773,919. The compounds or, preferably, relatively insoluble salts such as those described above can also be formulated in cholesterol matrix silastic pellets, particularly for use in animals. Additional slow release, depot or implant formulations, e.g. gas or liquid liposomes are known in the literature (U.S. Pat. No. 5,770,222 and "Sustained and Controlled Release Drug Delivery Systems", J. R. Robinson ed. Marcel Dekker, Inc., N.Y, 1978).

Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.

Example 1: Cloning and Expression of CHI-deleted mimetibody in Mammalian Cells

A typical mammalian expression vector contains at least one promoter element, which mediates the initiation of transcription of mRNA, the CHI -deleted mimetibody or specified portion or variant coding sequence, and signals required for the termination of transcription and polyadenylation ofthe transcript. Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription can be achieved with the early and late promoters from SV40, the long terminal repeats (LTRS) from Retroviruses, e.g, RSV, HTLVI, HTVI and the early promoter ofthe cytomegalovirus (CMV). However, cellular elements can also be used (e.g, the human actin promoter). Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pIRESlneo, pRetro-Off, pRetro-On, PLXSN, or pLNCX (Clonetech Labs, Palo Alto, CA), pcDNA3.1 (+/-), pcDNA/Zeo (+/-) or pcDNA3.1/Hygro (+/- ) (Invitrogen), PSVL and PMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146) and pBC12MI (ATCC 67109). Mammalian host cells that could be used include human Hela 293, H9 and Jurkat cells, mouse NTH3T3 and C 127 cells, Cos 1, Cos 7 and CV 1, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells.

Alternatively, the gene can be expressed in stable cell lines that contain the gene integrated into a chromosome. The co-transfection with a selectable marker such as dhfr, gpt, neomycin, or hygromycin allows the identification and isolation ofthe transfected cells. The transfected gene can also be amplified to express large amounts ofthe encoded CHI- deleted mimetibody or specified portion or variant. The DHFR (dihydrofolate reductase) marker is useful to develop cell lines that carry several hundred or even several thousand copies ofthe gene of interest. Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy, et al, Biochem. J. 227:277-279 (1991); Bebbington, et al, Bio/Technology 10:169-175 (1992)). Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of CHI -deleted mimetibody or specified portion or variants.

The expression vectors pCl and pC4 contain the strong promoter (LTR) ofthe Rous Sarcoma Virus (Cullen, et al, Molec. Cell. Biol. 5:438-447 (1985)) plus a fragment ofthe CMV-enhancer

(Boshart, et al. Cell 41:521-530 (1985)). Multiple cloning sites, e.g, with the restriction enzyme cleavage sites BamHI, Xbal and Asp718, facilitate the cloning ofthe gene of interest. The vectors contain in addition the 3' intron, the polyadenylation and termination signal ofthe rat preproinsulin gene. Cloning and Expression in CHO Cells

The vector pC4 is used for the expression of CHI -deleted mimetibody or specified portion or variant. Plasmid pC4 is a derivative ofthe plasmid pSV2-dhfr (ATCC Accession No. 37146). The plasmid contains the mouse DHFR gene under control ofthe SV40 early promoter. Chinese hamster ovary- or other cells lacking dihydrofolate activity that are transfected with these plasmids can be selected by growing the cells in a selective medium (e.g, alpha minus MEM, Life Technologies, Gaithersburg, MD) supplemented with the chemotherapeutic agent methotrexate. The amplification of the DHFR genes in cells resistant to methotrexate (MTX) has been well documented (see, e.g, F. W. Alt, et al, J. Biol. Chem.253:1357-1370 (1978); J. L. Hamlin and C. Ma, Biochem. et Biophys. Acta 1097:107-143 (1990); and M. J. Page and M. A. Sydenham, Biotechnology 9:64-68 (1991)). Cells grown in increasing concentrations of MTX develop resistance to the drug by overproducing the target enzyme, DHFR, as a result of amplification ofthe DHFR gene. If a second gene is linked to the DHFR gene, it is usually co-amplified and over-expressed. It is known in the art that this approach can be used to develop cell lines carrying more than 1,000 copies ofthe amplified gene(s). Subsequently, when the methotrexate is withdrawn, cell lines are obtained that contain the amplified gene integrated into one or more chromosome(s) ofthe host cell.

Plasmid pC4 contains for expressing the gene of interest the strong promoter ofthe long terminal repeat (LTR) ofthe Rous Sarcoma Virus (Cullen, et al, Molec. Cell. Biol. 5:438-447 (1985)) plus a fragment isolated from the enhancer ofthe immediate early gene of human cytomegalovirus (CMV) (Boshart, et al. Cell 41:521-530 (1985)). Downstream ofthe promoter are BamHI, Xbal, and Asp718 restriction enzyme cleavage sites that allow integration ofthe genes. Behind these cloning sites the plasmid contains the 3' intron and polyadenylation site ofthe rat preproinsulin gene. Other high efficiency promoters can also be used for the expression, e.g, the human b-actin promoter, the SV40 early or late promoters or the long terminal repeats from other retroviruses, e.g, HTV and HTLVI. Clontech's Tet-Off and Tet-On gene expression systems and similar systems can be used to express the EPO in a regulated way in mammalian cells (M. Gossen, and H. Bujard, Proc. Natl. Acad. Sci. USA 89: 5547-5551 (1992)). For the polyadenylation ofthe mRNA other signals, e.g, from the human growth hormone or globin genes can be used as well. Stable cell lines carrying a gene of interest integrated into the chromosomes can also be selected upon co-transfection with a selectable marker such as gpt, G418 or hygromycin. It is advantageous to use more than one selectable marker in the beginning, e.g, G418 plus methotrexate.

The plasmid pC4 is digested with restriction enzymes and then dephosphorylated using calf intestinal phosphatase by procedures known in the art. The vector is then isolated from a 1% agarose gel. The DNA sequence encoding the complete CHI -deleted mimetibody or specified portion or variant is used, e.g, as presented in SEQID NOS: 13, 14, 15, 16, 17, 18, corresponding to HC and LC variable regions of a CHI -deleted mimetibody ofthe present invention, according to known method steps. Isolated nucleic acid encoding a suitable human constant region (i.e., HC and LC regions) is also used in this construct (e.g, as provided in vector pl351).

The isolated variable and constant region encoding DNA and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC4 using, for instance, restriction enzyme analysis. Chinese hamster ovary (CHO) cells lacking an active DHFR gene are used for transfection. 5 μg ofthe expression plasmid pC4 is cotransfected with 0.5 μg ofthe plasmid pSV2-neo using lipofectin. The plasmid pSV2neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 μg /ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of methotrexate plus 1 μg /ml G418. After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 mM, 2 mM, 5 mM, 10 mM, 20 mM). The same procedure is repeated until clones are obtained that grow at a concentration of 100 - 200 mM. Expression ofthe desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reverse phase HPLC analysis.

Additional constructs can be expressed with single or multiple amino acid changes in order to avoid undesirable activities. These changes may be expressed alone or multiple changes combined in a single construct. The cysteine normally involved in a disulfide bridge between the HC and LC will be mutated to an alanine. While this cysteine may be involved in stabilizing the construct by forming a third disulfide bridge, it is possible that it may aberrantly form a disulfide bond with other cyseines within the construct, or it could form a disulfide linkage between two constructs. By removing the cysteine, proper folding and assembly could be enhanced and the possibility of self-association diminished.

It has been shown that mutation of two lysine (L) residues, L234 & L235, in the IgGl lower hinge region to alanine (A) will abrogate the ability ofthe immunoglobulin to mediate complement dependent cytotoxicity (CDC) and antibody dependant cellular cytotoxicity (ADCC) (Hezereh et al, 2001, J. Virol, vol. 75 (24), 12161-68).

Another modification that would result in a decrease in mediation of immune effector functions is the removal ofthe glycosylation attachment site. This can be accomplished by mutation ofthe asparagine to glutamine (Q). Aglycosylated versions ofthe IgGl subclass are known to be poor mediators of immune effector function (Jefferis et al. 1998, Immol. Rev, vol. 163, 50-76).

An additional modification that is currently being pursued is the replacement ofthe IgGl CH2 and CH3 regions with the same regions ofthe IgG4 subtype while retaining the GI hinge region. As discussed previously, the ability ofthe IgG4 subclass to mediate immune effector functions is much lower than that ofthe GI subclass. So this construct is expected to retain activity of NfusCGl without the concerns of potential immune effector functions.

Other envisioned modifications are those that would decrease the potential immunogenicity ofthe constructs. One important determinant of immunogenicity is the ability of peptides derived from a protein to be efficiently bound and presented by MHC molecules to T cells and to elicit a cell based immune response or T cell help for an antibody response. Using publicly available web based algorithms for MHC binding (SYFPETHI, Ramensee et al, 1999, Immunogenetics, vol. 50, 213-19 and BIMAS) potential MHC binding epitopes within the NfusCGl were analyzed. Mutations that would decrease the predicted immunogenicity of one or more peptides are evaluated for in vivo effect on immunogenicity. Advantages: The novel construct, NfusCGl described above offers an alternative way of displaying bioactive peptides. In addition, proposed modifications are expected to, in combination and in addition to the novel features of mimetibodies ofthe present invention, enhance their utility.

It will be clear that the invention can be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations ofthe present invention are possible in light ofthe above teachings and, therefore, are within the scope ofthe present invention

Claims

WHAT IS CLAIMED IS:

1 . At least one CHI deleted mimetibody nucleic acid, comprising at least one polynucleotide encoding a polypeptide according to Formula (I):

(Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C- terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and 10.

2 . At least one CHI deleted mimetibody polypeptide, comprising a polypeptide according to Formula (I):

(Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide selected from SEQ ID NOS:43-518, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C-terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and 10.

3 . At least one CHI deleted mimetibody polypeptide, comprising a polypeptide according to Formula (I):

(Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide selected from SEQ ID NOS:519-l 110, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C-terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and 10.

4 . A(n) CHI deleted mimetibody nucleic acid or CHI deleted mimetibody polypeptide according to any of claims 1-3, wherein said polypeptide has at least one activity of at least one Pep polypeptide.

5 . A CHI deleted mimetibody antibody, comprising a monoclonal or polyclonal antibody, fusion protein, or fragment thereof, that specifically binds at least one CHI deleted mimetibody polypeptide according to any of claims 1-3.

6 . A CHI deleted mimetibody nucleic acid encoding at least one CHI deleted mimetibody polypeptide or CHI deleted mimetibody antibody according to any of claim 1-5.

7 . A CHI deleted mimetibody vector comprising at least one isolated nucleic acid according to claim 6.

8 . A CHI deleted mimetibody host cell comprising an isolated nucleic acid according to claim 7.

9 . A CHI deleted mimetibody host cell according to claim 8, wherein said host cell is at least one selected from COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2,

653, SP2/0, 293, NSO, DG44 CHO, CHO KI, HeLa, myeloma, or lymphoma cells, or any derivative, immortalized or transformed cell thereof.

10 . A method for producing at least one CHI deleted mimetibody polypeptide or CHI deleted mimetibody antibody, comprising translating a nucleic acid according to claim 6 under conditions in vitro, in vivo or in situ, such that the CHI deleted mimetibody or antibody is expressed in detectable or recoverable amounts.

11 . A composition comprising at least one CHI deleted mimetibody nucleic acid, CHI deleted mimetibody polypeptide, or CHI deleted mimetibody antibody according to any of claims 1-5.

12 . A composition according to claim 11, wherein said composition further comprises at least one pharmaceutically acceptable carrier or diluent.

13 . A composition according to claim 11, further comprising at least one composition comprising an therapeutically effective amount of at least one compound, composition or polypeptide selected from at least one of a detectable label or reporter, a TNF antagonist, an anti- infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an opthalmic, otic or nasal drug, a topical drug, a nutritional drug, a cytokine, or a cytokine antagonist.

14 . A composition according to claim 11, in a form of at least one selected from a liquid, gas, or dry, solution, mixture, suspension, emulsion or colloid, a lyophilized preparation, or a powder.

15 . A method for diagnosing or treating a CHI deleted mimetibody ligand related condition in a cell, tissue, organ or animal, comprising (a) contacting or administering a composition comprising an effective amount of at least one CHI deleted mimetibody nucleic acid, polypeptide or antibody according to any of claims 1-5, with, or to, said cell, tissue, organ or animal.

16 . A method according to claim 15, wherein said effective amount is 0.001-50 mg of CHI deleted mimetibody antibody; 0.000001-500 mg of said CHI deleted mimetibody; or 0.0001-100μg of said CHI deleted mimetibody nucleic acid per kilogram of said cells, tissue, organ or animal.

17 . A method according to claim 15, wherein said contacting or said administrating is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.

18 . A method according to claim 15, further comprising administering, prior, concurrently or after said (a) contacting or administering, at least one composition comprising an effective amount of at least one compound or polypeptide selected from at least one of a detectable label or reporter, a TNF antagonist, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an opthalmic, otic or nasal drug, a topical drug, a nutritional drug, a cytokine, or a cytokine antagonist.

19 . A device, comprising at least one isolated CHI deleted mimetibody polypeptide, antibody or nucleic acid according to any of claims 1-5, wherein said device is suitable for contacting or administerting said at least one of said CHI deleted mimetibody polypeptide, antibody or nucleic acid, by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.

20 . An article of manufacture for human pharmaceutical or diagnostic use, comprising packaging material and a container comprising at least one isolated CHI deleted mimetibody polypeptide, antibody or nucleic acid according to any of claims 1-5.

:τ

21 . The article of manufacture of claim 20, wherein said container is a component of a parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery device or system.

22 . A method for producing at least one isolated CHI deleted mimetibody polypeptide, antibody or nucleic acid according to any of claims 1-5, comprising providing at least one host cell, transgenic animal, transgenic plant, plant cell capable of expressing in detectable or recoverable amounts said polypeptide, antibody or nucleic acid.

23 . At least one CHI deleted mimetibody polypeptide, antibody or nucleic acid, produced by a method according to claim 22.