WO2012116453A1 - Multivalent heteromultimer scaffold design and constructs - Google Patents
Multivalent heteromultimer scaffold design and constructs Download PDFInfo
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- WO2012116453A1 WO2012116453A1 PCT/CA2012/050131 CA2012050131W WO2012116453A1 WO 2012116453 A1 WO2012116453 A1 WO 2012116453A1 CA 2012050131 W CA2012050131 W CA 2012050131W WO 2012116453 A1 WO2012116453 A1 WO 2012116453A1
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- heteromultimer
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4721—Lipocortins
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- C07K14/475—Growth factors; Growth regulators
- C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
-
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
-
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
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- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6454—Dibasic site splicing serine proteases, e.g. kexin (3.4.21.61); furin (3.4.21.75) and other proprotein convertases
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- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21061—Kexin (3.4.21.61), i.e. proprotein convertase subtilisin/kexin type 9
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- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
Definitions
- the field of the invention is the rational design of a scaffold for custom development of biotherapeutics.
- HSA Human serum albumin
- HA Human serum albumin
- HSA is considered to be the most abundant protein of the serum and is responsible for maintaining osmolarity. HSA has favorable pharmacokinetic properties and is cleared very slowly by the liver and kidney displaying in vivo half-lives up to several weeks (Yeh et al, Proc. Natl. Acad. Sci. USA, 89: 1904-1908 (1992) ;
- HSA lacks enzymatic activity and antigenicity thereby eliminating potentially undesirable side effects. HSA acts as a carrier for endogenous as well as exogenous ligands. Combined, these features can be extended, at least partially, onto albumin based fusion protein. The poor pharmacokinetic properties displayed by therapeutic proteins can then be circumvented.
- heteromultimers comprising: at least a first monomer unit that comprises at least one cargo molecule, and a first transporter polypeptide; and at least a second monomer unit that comprises at least one cargo molecule and a second transporter polypeptide; wherein at least one transporter polypeptide is derived from a monomeric protein and wherein said transporter polypeptides self-assemble to form a quasi-native structure of said monomeric protein or analog thereof.
- at least one cargo molecule is a drug, or a therapeutic agent.
- at least one cargo molecule is a biomolecule.
- the at least one biomolecule is a DNA, RNA, PNA or polypeptide.
- at least one cargo molecule is a polypeptide.
- each monomeric transporter polypeptide is unstable and preferentially forms a heteromultimer with at least one other transporter polypeptide.
- each monomeric transporter polypeptide is stable and preferentially forms a
- heteromultimer with at least one other transporter polypeptide.
- the heteromultimerization interface comprises at least one disulfide bond. In certain embodiments, the heteromultimerization interface does not comprise a disulfide bond.
- heteromultimer that comprises: at least two monomers, wherein each monomer comprises at least one cargo molecule attached to a transporter polypeptide, such that said monomers self-assemble to form the heteromultimer.
- a heteromultimer that comprises: at least two monomeric proteins, wherein each monomeric protein comprises at least one cargo polypeptide, attached to a transporter polypeptide, wherein at least one transporter polypeptide is derived from a monomeric protein and wherein said transporter polypeptides self-assemble to form a quasi-native structure of said monomeric protein or analog thereof.
- heteromultimer that comprises: at least two monomeric proteins, wherein each monomeric protein comprises at least one cargo polypeptide attached to a transporter polypeptide, such that said monomeric proteins self-assemble via the transporter polypeptide to form the heteromultimer, and wherein at least one transporter polypeptide is derived from a monomeric protein and wherein said transporter polypeptides self-assemble to form a quasi-native structure of said monomeric protein or analog thereof.
- the heteromultimer is a heterodimer.
- the heteromultimer is bispecific.
- the heteromultimer is multispecific.
- the heteromltimer is bivalent.
- the heteromultimer is multivalent.
- the heteromultimer is
- the transporter polypeptides are multifunctional.
- at least one transporter polypeptide is not derived from an antibody.
- the transporter polypeptides are not derived from an antibody.
- the transporter polypeptides are derivatives of albumin.
- the transporter polypeptides are derived from human serum albumin (HSA or HA) of SEQ ID No. 1.
- the transporter polypeptides are derived from alloalbumins (HAA).
- the transporter polypeptides are derived from sequence homologous to the human serum albumin (HSA or HA) of SEQ ID No. 1.
- the transporter In some embodiments of the heteromultimer described herein, the transporter
- polypeptides are derivatives of an annexin protein.
- the transporter polypeptides are derived from different annexin proteins.
- the transporter polypeptides are derived from the same annexin protein.
- at least one transporter polypeptide is derived from Annexin Al or lipocortin I.
- all transporter polypeptides are derived from
- At least one transporter polypeptides is derived from a sequence homologous to SEQ ID NO: 14. In an embodiment, at least one transporter polypeptide is derived from Annexin A2 or annexin II. In certain embodiments of the heteromultimer, all transporter polypeptides are derived from Annexin A2 or lipocortin II. In an embodiment, at least one transporter polypeptide is derived from Annexin like protein. In certain embodiments of the heteromultimer, all transporter polypeptides are derived from Annexin like protein. In an embodiment, at least one transporter polypeptide is derived from the group comprising Annexin Al-Annexin A7.
- all transporter polypeptides are derived from the group comprising Annexin Al-Annexin A7. 14.
- the first annexin based transporter polypeptide has a sequence comprising SEQ ID NO: 15
- the second annexin based transporter polypeptide has a sequence comprising SEQ ID NO: 16.
- the transporter In some embodiments of the heteromultimer described herein, the transporter
- polypeptides are derivatives of transferrin.
- at least one transporter polypeptide is derived from transferrin.
- at least one transporter polypeptides are derived from transferrin of SEQ ID NO: 19 or analog thereof.
- at least one transporter polypeptide is derived from a polypeptide seuquence homologous to the transferrin.
- at least one transporter polypeptide is derived from apo-transferrin.
- the first transferrin based transporter polypeptide has a sequence comprising SEQ ID NO: 15 and the second transferrin based transporter polypeptide has a sequence comprising SEQ ID NO: 16.
- At least one cargo molecule is a cargo polypeptide.
- all cargo molecules are cargo polypeptides.
- the cargo polypeptides are therapeutic proteins or fragments or variants thereof.
- the cargo polypeptides are antigens or fragments or variants thereof.
- the cargo polypeptides are antigen receptors or fragments or variants thereof.
- the cargo polypeptide is an antibody, an antibody domain, a ligand or a receptor that binds a target polypeptide.
- at least one cargo polypeptide is fused to the transporter polypeptide.
- At least one cargo polypeptide is attached to the N-terminus of the transporter polypeptide. In some embodiments, at least one cargo polypeptide is attached to the C-terminus of the transporter polypeptide. In some embodiments, at least one cargo polypeptide is chemically linked to the transporter polypeptide. In some embodiments of the heteromultimers described herein, at least one cargo polypeptide comprises GLP- 1 or fragment or variant thereof. In some embodiments, at least one cargo polypeptide comprises glucagon or fragment or variant thereof. In an embodiment, at least one cargo polypeptide comprises an EGF-A like domain.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide; and at least a second monomeric protein that comprises at least one cargo polypeptide and a second transporter polypeptide.
- the heteromultimer is a heterodimer.
- the heteromultimer is multispecific.
- the heteromultimer is bispecific.
- the transporter polypeptides are derivatives of the same protein.
- the transporter polypeptides are derivatives of albumin.
- the transporter polypeptides are derived from human serum albumin of SEQ ID No. 1. In certain embodiments, the transporter polypeptides are derivatives of an annexin. In an embodiment, the transporter polypeptides are derivatives of Annexin A2. In some embodiments, the transporter polypeptides are derivatives of transferrin.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide comprising a first segment of human serum albumin; and at least a second monomeric protein that comprises at least one cargo polypeptide, fragment and a second transporter polypeptide comprising a second segment of human serum albumin; wherein said transporter polypeptides self-assemble to form a quasi-native structure of albumin or analog thereof.
- the first and second segments of human serum albumin are from non-overlapping regions of the protein.
- the overlap is a 5% overlap.
- the overlap is a 10% overlap.
- the first segment of human serum albumin comprises a sequence of SEQ ID NO:2, and the second segment of human serum albumin comprises a sequence of SEQ ID NO: 3.
- the first segment of human serum albumin comprises a sequence of SEQ ID NO:8, and the second segment of human serum albumin comprises a sequence of SEQ ID NO: 10.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide comprising a sequence of SEQ ID NO:2; and at least a second monomeric protein that comprises at least one cargo polypeptide, and a second transporter polypeptide comprising a sequence of SEQ ID NO: 3.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide comprising a sequence of SEQ ID NO:8; and at least a second monomeric protein that comprises at least one cargo polypeptide and a second transporter polypeptide comprising a sequence of SEQ ID NO: 10.
- at least one transporter polypeptide is derived from alloalbumins.
- both transporter polypeptides are derived from alloalbumins.
- all transporter polypeptides are derivatives of the same alloalbumin.
- the transporter polypeptides are derivatives of different alloalbumins.
- each transporter polypeptide is an alloalbumin derivative based on an alloalbumin selected from Table 2.
- the first monomeric protein comprises two cargo polypeptides.
- the second monomeric protein comprises two cargo polypeptides.
- at least one of the monomeric proteins is engineered by introducing mutations.
- the introduced mutations improve the functionality of the monomeric protein as compared to the native, non-mutated form of the monomer.
- the introduced mutations improve one or more of the stability, half-life and heteromultimer formation of the transporter polypeptide.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide; and at least a second monomeric protein that comprises at least one cargo polypeptide and a second transporter polypeptide.
- at least one cargo polypeptide is selected from the proteins listed in Table 2 or fragments, variants or derivatives thereof.
- at least one cargo polypeptide is selected from ligand, receptor, or antibody to one or more proteins listed in Table 2, or fragment, variant or derivative of said ligand, receptor or antibody.
- At least one cargo polypeptide targets a cell surface antigen from the group consisting of CD 19, CD20, CD22, CD25, CD30, CD33, CD40, CD56, CD64, CD70, CD74, CD79, CD105, Cdl 38, CD174, CD205, CD227, CD326, CD340, MUC16, GPNMB, PSMA, Cripto, ED- B, TMEFF2, EphB2, EphA2, FAP, integrin, Mesothelin, EGFR, TAG-72, GD2, CAIX, 5T4.
- a cell surface antigen from the group consisting of CD 19, CD20, CD22, CD25, CD30, CD33, CD40, CD56, CD64, CD70, CD74, CD79, CD105, Cdl 38, CD174, CD205, CD227, CD326, CD340, MUC16, GPNMB, PSMA, Cripto, ED- B, TMEFF2, EphB2, EphA2, FAP, integrin
- heteromultimers comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide; and at least a second monomeric protein that comprises at least one cargo polypeptide and a second transporter polypeptide, wherein at least one at least one cargo polypeptide is an antibody, or fragment or variant thereof.
- all cargo polypeptides are antibodies or fragments or variants thereof.
- the cargo polypeptide is an antibody that binds to a protein listed in Table 2.
- the antibody fragment comprises antibody Fc or Fab or Fv region.
- the cargo polypeptide is a non-antibody protein like nanobodies, affibody, maxibody, adnectins, domain antibody, evibody, ankyrin repeat proteins, anticalins, camlids or ligand protein or polypeptide binding to a therapeutically relavant target.
- the antibody or its fragment is derived from an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, and IgM.
- the IgG is of subtype selected from IgGl , IgG2a, IgG2b, IgG3 and IgG4.
- the antibody is multispecific.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide; and at least a second monomeric protein that comprises at least one cargo polypeptide and a second transporter polypeptide, wherein at least one cargo polypeptide is a therapeutic antibody.
- At least one cargo polypeptide is a therapeutic antibody or fragment or variant thereof, wherein the antibody is selected from antibody is selected from abagovomab, adalimumab, alemtuzumab, aurograb, bapineuzumab, basiliximab, belimumab, bevacizumab, briakinumab, canakinumab, catumaxomab, certolizumab pegol, certuximab, daclizumab, denosumab, efalizumab, galiximab, gemtuzumab ozagamicin, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, lumiliximab, mepolizumab, motavizumab, muromonab, mycograb, natalizumab, nimotuzumab,
- the therapeutic antibody binds a disease related target antigen such as cancer antigen, inflammatory disease antigen or a metabolic disease antigen.
- the target antigen could be a protein on a cell surface and the cell could belong to the group of B-cell, T- cell, stromal cell, endothelial cell, vascular cell, myeloid cell, hematopoietic cell or carcinoma cell.
- heteromultimers each heteromultimer comprising: at least a first monomer that comprises at least one cargo molecule, fragment; and at least a second monomer that comprises at least one cargo molecule and a second transporter polypeptide, wherein at least one cargo polypeptide is an enzyme, enzyme inhibitor, hormone, therapeutic polypeptide, antigen, radiotoxin and chemotoxin inclusive of but not restricted to neurotoxins, interferons, cytokine fusion toxins and chemokine fusion toxins, cytokine, antibody fusion protein or variant or fragment thereof.
- at least one cargo polypeptide comprises GLP-1 or fragment or variant thereof.
- At least one cargo polypeptide comprises glucagon or fragment or variant thereof. In an embodiment, at least one cargo polypeptide comprises an EGF-A like domain.
- the toxin is an immunotoxin such as Denileukin diftitox and Anti-CD22 immunotoxin such as CAT-3888 and CAT-8015. In certain embodiments, the toxin is saporin. In some embodiments, the toxin is a mitotoxin. In some embodiments, the toxin is a diphtheria toxin. In some embodiments, the toxin is botulinux toxin type A. In some embodiments, the toxin is ricin or a fragment there of. In some embodiments, the toxin is a toxin from RTX family of toxins.
- heteromultimers each heteromultimer comprising: at least a first monomeric protein that comprises at least one cargo polypeptide and a first transporter polypeptide; and at least a second monomeric protein that comprises at least one cargo polypeptide and a second transporter polypeptide, wherein the cargo polypeptide is attached to the transporter polypeptide by chemical conjugation, native ligation, chemical ligation, a disulfide bond or direct fusion or fusion via a linker.
- linkers for attaching cargo molecules such as cargo polypeptides to transporter polypeptides are selected from the linkers described in US5482858, US5258498 and US5856456, US2009060721 , US6492123, US4946778, US5869620, US7385032, US5073627, US5108910, US7977457, US5856456, US7138497,US5837846,
- host cells comprising nucleic acid encoding a heteromultimer
- the nucleic acid encoding the first monomeric protein and the nucleic acid encoding the second monomeric protein are present in a single vector. In certain embodiments, the nucleic acid encoding the first monomeric protein and the nucleic acid encoding the second monomeric protein are present in separate vectors.
- a method of making a heteromultimer comprises: culturing a host cell described herein such that the nucleic acid encoding a
- the host cell is a prokaryotic cell or a eukaryotic cell. In some embodiments, the host cell is E. coli. In certain embodiments, the host cell is yeast cell. In some embodiments, the yeast is S. cerevisiae. In some embodiments, the yeast is Pichia. In a certain embodiment, the yeast is Pichia pastoris. In some
- the yeast is glycosylation deficient, and/or protease deficient.
- the host cell is a bacterial cell.
- the host cell expressing a heteromultimer descried herein is a mammalian cell.
- the mammalian cell is a CHO cell, a BHK cell, NSO cell, COS cell or a human cell.
- a pharmaceutical composition that comprises a heteromultimer described herein and a pharmaceutically acceptable adjuvant.
- methods of treating an individual suffering from a disease or disorder comprising administering to the individual an effective amount of a formulation or pharmaceutical composition described herein.
- a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a heteromultimer described herein.
- a method of treating an immune disorder in a patient comprising administering to the patient a therapeutically effective amount of a heteromultimer described herein.
- a method of treating an infectious disease in a patient said method comprising
- a method of treating a cardiovascular disorder in a patient comprising administering to the patient a therapeutically effective amount of a heteromultimer described herein.
- a method of treating a respiratory disorder in a patient comprising
- a method of treating a metabolic disorder in a patient comprising administering to the patient a therapeutically effective amount of a heteromultimer described herein.
- kits for detecting the presence of a biomarker of interest in an individual comprising (a) an amount of a heteromultimer described herein, wherein said heteromultimer comprises at least one cargo polypeptide such that said cargo polypeptide is capable of binding to the biomarker of interest; and (b) instructions for use.
- heteromultimer proteins that comprise at least two monomeric
- each monomeric protein comprises at least one cargo polypeptide, and an albumin based polypeptide, such that said monomeric proteins self-assemble to form the heteromultimer.
- the cargo polypeptide is fused to the albumin or alloalbumin based transporter polypeptide. In some embodiments, the cargo polypeptide is fused to the transferrin based transporter polypeptide. In certain embodiments, the cargo polypeptide is fused to the annexin based transporter polypeptide. In some embodiments, the fusion is at the N terminus of the transporter polypeptide. In certain embodiments, the fusion is at the C terminus of the transporter polypeptide. In some embodiments, the fusion involves a bridging linker or spacer molecule. In some embodiments, the cargo polypeptide is chemically conjugated to the transporter polypeptide. In certain embodiments, the cargo polypeptide is attached to the transporter polypeptide by means of chemical ligation or a disulfide bond.
- heteromultimer proteins that comprise at least two monomeric
- each monomeric protein comprises at least one cargo polypeptide, and a transporter polypeptide, such that said transporter polypeptides self-assemble to form the heteromultimer.
- each transporter polypeptide is an alloalbumin based polypeptide, such that said alloalbumin based polypeptides self-assemble to form the heteromultimer.
- each transporter polypeptide is a transferrin based polypeptide.
- each transporter polypeptide is an annexin based polypeptide.
- each monomeric transporter polypeptide is unstable and preferentially forms a heteromultimer with at least one other transporter polypeptide.
- a heteromultimer described herein is a heterodimer.
- cargo polypeptide is an antibody, enzyme, hormone, therapeutic polypeptide, antigen, chemotoxin, radiotoxin, cytokine or variant or fragment thereof.
- the cargo polypeptide of one monomeric protein functions in synergy with the cargo polypeptide of another monomeric protein.
- heteromultimer proteins that comprise at least two monomeric
- each monomeric protein comprises at least one cargo polypeptide, and an annexin based polypeptide, such that said annexin based polypeptides self-assemble to form the heteromultimer with a quasi-native structure of annexin or analog thereof.
- the annexin is Annexin Al.
- a heteromultimer described herein is a heterodimer.
- cargo polypeptide is an antibody, enzyme, hormone, therapeutic polypeptide, antigen, chemotoxin, radiotoxin, cytokine, ligand to a receptor, receptor or variant or fragment thereof.
- the cargo polypeptide of one monomeric protein functions in synergy with the cargo polypeptide of another monomeric protein.
- the cargo polypeptide can be an agonist or antagonist to the cargo polypeptide of another monomeric protein.
- heterodimer proteins that comprise at least two monomeric fusion proteins, wherein each monomeric fusion proteins comprises at least one cargo polypeptide fused to an albumin derived polypeptide, such that said albumin derived polypeptides self-assemble to form the multifunctional heterodimer.
- heterodimeric proteins comprising a first monomer which comprises at least one cargo polypeptide fused to an albumin derived polypeptide; and a second monomer that comprises at least one cargo polypeptide fused to an albumin derived polypeptide.
- the at least one cargo polypeptide of the first monomer is different from the at least one cargo polypeptide of the second monomer.
- the at least one cargo polypeptide of the first monomer is the same as the at least one cargo polypeptide of the second monomer.
- heteromultimer proteins that comprise at least two monomeric fusion proteins, wherein each monomeric fusion proteins comprises at least one cargo polypeptide fused to an alloalbumin derived polypeptide, such that said alloalbumin derived polypeptides self-assemble to form the multifunctional heteromultimer.
- heteromultimer proteins that comprise at least two monomeric fusion proteins, wherein each monomeric fusion proteins comprises at least one cargo polypeptide fused to a transferrin derived polypeptide, such that said transferrin derived polypeptides self-assemble to form the heteromultimer.
- heteromultimer proteins that comprise at least two monomeric fusion proteins, wherein each monomeric fusion proteins comprises at least one cargo polypeptide fused to an annexin derived polypeptide, such that said annexin derived polypeptides self-assemble to form the heteromultimer.
- the annexin is Annexin A2.
- heteromultimer proteins comprising a first monomer which comprises at least one cargo polypeptide fused to an alloalbumin derived polypeptide; and a second monomer that comprises at least one cargo polypeptide fused to an alloalbumin derived polypeptide.
- the at least one cargo polypeptide of the first monomer is different from the at least one cargo polypeptide of the second monomer.
- the at least one cargo polypeptide of the first monomer is the same as the at least one cargo polypeptide of the second monomer.
- heteromultimer that comprises: at least two monomers, each
- each transporter polypeptide is obtained by segmentation of a whole protein such that said transporter polypeptides self-assemble to form quasi-native whole protein.
- the heteromultimer is multispecific.
- the transporter polypeptides are not derived from an antibody.
- each monomer preferentially forms the
- each transporter polypeptide is a derivate of albumin or alloalbumin.
- each transporter polypeptide is a derivate of annexin.
- each transporter polypeptide is a derivate of transferrin.
- compositions that comprise an albumin-based and/or alloalbumin-based heteromultimeric protein described herein and a
- a formulation described herein is provided as part of a kit or container. In certain embodiments, the kit or container is packaged with instructions pertaining to extended shelf life of the therapeutic protein.
- a heteromultimer described herein is used in a method of treating (e.g., ameliorating) preventing, or diagnosing a disease or disease symptom in an individual, comprising the step of administering said formulation to the individual.
- fusion protein scaffolds with a known number of conjugation sites based on any transport protein of interest.
- transgenic organisms modified to contain nucleic acid molecules
- Figure 1 depicts the structure of the Human Serum Albumin (HSA) molecule.
- HSA Human Serum Albumin
- Figure 2 is a plot of buried solvent accessible surface area at the interface of two
- Figure 3 depicts two albumin-based polypeptides expressed separately. The two
- polypeptides are shown in light and dark grey respectively. Each polypeptide comprises two fusion sites for functional cargo proteins and these sites are represented as spheres. The disulphide residues in structure are shown as sticks.
- FIG 4 is a schematic representation of bispecific and other multifunctional therapeutics based on the multispecific heteromultimer described herein.
- the albumin-based, or alloalbumin-based polypeptides are denoted Al and A2.
- Multifunctional heteromultimers are obtained by conjugating antigen binding motifs, cytokines and other forms of signaling molecules, chemotoxin, radiotoxins or other functionally relevant
- Figure 5 is a schematic of a bispecific antibody derived from a heterodimeric Fc domain.
- Albumin or alloalbumin based polypeptides are connected to the C-terminal of the Fc to selectively drive the formation of heterodimers.
- Figures 6A-6C show native gel electrophoresis profiles of full-length HSA and
- Figure 7 shows stability of wild type HSA and heterodimer scaffolds ABH1 and ABH2 stuided using Differential Scanning Calorimetry
- Figures 8A-8B show equilibrium binding isotherms 3000 nM FcRN 3x dilution series over 3000 RUs.
- Figure 8A shows Albumin and
- Figure 8B shows heteromultimer scaffold
- Figure 9 shows scheme for multivalent Albumin based heteromultimers comprising anti- Her2/neu and anti-CD 16 scFv bioactive fusions
- Figures 10A-10B contain a non-reducing SDS PAGE analysis of the heteromultimer ABH2 fusions described in table 8. The gel indicates all constructs form the correct complex with expected MW.
- Figure 11 shows structure of Annexin molecule based on the PDB structure IMCX.
- the two monomers that will be derived by splitting the Annexin molecule are color coded as light and dark grey units.
- the sites of fusion for the cargo protein are represented as spheres.
- Figure 12 shows a plot of the buried solvent accessible surface area at the interface of Annexin based tranporter polypeptide- 1 , and Annexin based tranporter polypeptide-2.
- Figure 13 shows structure of transferrin molecule based on the PDB structure 1H76.
- the two monomers derived by splitting the transferrin molecule are color coded as light and dark grey units.
- the sites of fusion for the cargo protein are represented as spheres.
- Figure 14 shows a plot of the buried solvent accessible surface area at the interface of two transferrin based transporter polypeptides described herein.
- Figure 15 shows sequences of multimers comprising transporter polypeptides based on human serum albumin.
- bispecific molecules exhibit dual target specificities or are able to simultaneously perform multiple functional roles by providing the necessary spatiotemporal organization necessary for drug action.
- bispecific molecules are particularly interesting when the mode of therapeutic action involves retargeting of effector cells or molecules to a target such as a tumor cell [Muller D. and Kontermann R.E. (2010) Biodrugs 24, 89-98] .
- a target such as a tumor cell [Muller D. and Kontermann R.E. (2010) Biodrugs 24, 89-98] .
- the development of bispecific therapeutic proteins with favorable pharmacokinetics and functional activity in stable and homogeneous condition has been a challenge. Attempts have been made to assemble bispecific units from multiple antigen binding domains using a number of approaches.
- the Fc portion of the antibody is involved in interactions with the neonatal Fc receptor (FcRn) which mediates an endocytic salvage pathway and this is attributed to improved serum half-life of the antibody molecule [Roopenian D. & Akilesh S. (2007) Nature Rev Immunol ! , 715-725] .
- FcRn neonatal Fc receptor
- antibody based bispecific molecules have been problematic in clinical trials because of the strong cytokine responses as a result of the concurrent effector activity induced via the Fc portion of the bispecific antibody [Weiner L.M.; Alpaugh R.K. et al. (1996) Cancer Immunol
- HSA human serum album
- HSA (shown in Figure 1) is a non-glycosylated 585-residue single polypeptide protein and the 3-dimensional structure of the protein was first observed using X-ray
- the HSA protein consists of three homologous domains: DI, DII, Dili, attributed to gene duplication, a feature common to the serum albumin in other species as well [Gray J.E. & Doolittle R.F. (1992) Protein Sci 1 , 289-302] .
- Each of the three domains have been expressed and characterized separately and shown to be independently stable [Dockal M., Carter D.C. & Ruker F. (1999) J Biol Chem Tl ⁇ , 29303-29310] .
- Each domain is made up of 10 helical segments and based on the inter- helical organization each domain can be further classified into 2 sub-domains comprised of helix 1-6 and 7-10 respectively.
- HSA has 17 disulphide bonds in total and all these cysteine pairs forming the linkages are within the individual domains. In general, HSA is a very stable due to the large number of disulphide bonds as well as the predominantly helical fold.
- sequence identities of albumin molecules across a number of species is quite large, greater than 70% among albumin cDNA derived from humans, horse, bovine, rat, etc. [Carter, D.C. & Ho, J.X. (1994) AdvProt Chem 45, 153-203] .
- split protein pairs have been used as sensors to understand protein-protein interactions in the area of functional proteomics.
- the approach involves identifying suitable segments from a protein that can reconstitute to form an active native-like protein. Generating new split proteins is technically demanding.
- the segmentation site has to yield two segments that efficiently reconstitute into the quasi-native protein when associated to each other.
- the component protein segments should be soluble enough to stay in solution and selectively associate with the partner segments such that manufacture yields and purification will be economical.
- split protein segments that would recombine to form the quasi-native structure is quite challenging [Tafelmeyer P., Johnsson N. & Johnsson K. Chem & Biol 11, 681-689] .
- split proteins have not been used in the design of protein therapeutics, or as cargo delivery vehicles in the past.
- a “heteromultimer” or “heteromultimeric polypeptide” is a molecule comprising at least a first monomer comprising a first transporter polypeptide and a second monomer comprising a second transporter polypeptide, wherein the second polypeptide differs in amino acid sequence from the first polypeptide by at least one amino acid residue.
- the heteromultimer can comprise a "heterodimer” formed by the first and second transporter polypeptides.
- the heteromultimer can form higher order tertiary structures such as, but not restricted to trimers and tetramers.
- transporter polypeptides in addition to the first and second transporter polypeptides are present.
- the assembly of transporter polypeptides to form the heteromultimer is driven by surface area burial.
- the transporter polypeptides interact with each other by means of electrostatic interactions and/or salt- bridge interactions that drive heteromultimer formation by favoring heteromultimer formation and/or disfavoring homomultimer formation.
- the transporter polypeptides inteact with each other by means of hydrophobic interactions that drive heteromultimer formation by favoring heteromultimer formation and/or disfavoring homomultimer formation.
- the transporter polypeptides inteact with each other by means of covalent bond formation.
- the covalent bonds are formed between naturally present or introduced cysteines that drive heteromultimer formation.
- the transporter polypeptides inteact with each other by means of packing/size-complementarity/knobs-into-holes/protruberance-cavity type interactions that drive heteromultimer formation by favoring heteromultimer formation and/or disfavoring homomultimer formation.
- the transporter polypeptides inteact with each other by means of cation-pi interactions that drive heteromultimer formation by favoring heteromultimer formation and/or disfavoring homomultimer formation.
- the individual transporter polypeptides cannot exist as isolated monomers in solution.
- the heteromultimer is the preferred state of the individual transporter polypeptides as compared to the monomer.
- bispecific is intended to include any agent, e.g., heteromultimer, monomer, protein, peptide, or protein or peptide complex, which has two different binding specificities.
- the molecule may bind to, or interact with, (a) a cell surface target molecule and (b) an Fc receptor on the surface of an effector cell.
- at least one monomer is bispecific formed by attaching to the same transporter polypeptide, two cargo molecules with different binding specificities.
- heteromultimer described herein, the heteromultimer is itself bispecific formed by attaching to the transporter polypeptides, at least two cargo molecules with different specificities.
- multispecific molecule or “heterospecific molecule” is intended to include any agent, e.g., a protein, peptide, or protein or peptide complex, which has more than two different binding specificities.
- the molecule may bind to, or interact with, (a) a cell surface target molecule such as but not limited to cell surface antigens, (b) an Fc receptor on the surface of an effector cell, and (c) at least one other component.
- heteromultimers described herein are inclusive of, but not limited to, bispecific, trispecific, tetraspecific, and other multispecific molecules.
- these molecules are directed to cell surface antigens, such as CD30, and to other targets, such as Fc receptors on effector cells.
- the multivalent heteromultimer is designed to have multiple binding sites for desired targets.
- the binding sites are on at least one cargo molecules attached to a transporter polypeptide.
- at least one binding site is on a transporter polypeptide.
- the expression "bivalent” is used throughout this specification to denote a heteromultimer comprising two target binding sites. In certain embodiments of a bivalent heteromultimer, both binding sites are on the same monomer.
- the expression "trivalent” is used throughout this specification to denote a heteromultimer comprising three target binding sites.
- the expression “tetravalent” is used throughout this specification to denote a heteromultimer comprising four target binding sites.
- Fusion proteins and polypeptides are created by joining two or more genes that
- At least one monomer may comprise a fusion protein formed by the fusion of at least one cargo polypeptide to the N- or C-terminus of a transporter polypeptide.
- substantially purified refers to a heteromultimer described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e. a native cell, or host cell in the case of recombinantly produced heteromultimer that in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating protein.
- the protein in certain embodiments is present at about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of the dry weight of the cells.
- the protein in certain embodiments, is present in the culture medium at about 5 g/L, about 4 g/L, about 3 g/L, about 2 g/L, about 1 g/L, about 750 mg/L, about 500 mg/L, about 250 mg/L, about 100 mg/L, about 50 mg/L, about 10 mg/L, or about 1 mg/L or less of the dry weight of the cells.
- the culture medium at about 5 g/L, about 4 g/L, about 3 g/L, about 2 g/L, about 1 g/L, about 750 mg/L, about 500 mg/L, about 250 mg/L, about 100 mg/L, about 50 mg/L, about 10 mg/L, or about 1 mg/L or less of the dry weight of the cells.
- substantially purified heteromultimer produced by the methods described herein has a purity level of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, specifically, a purity level of at least about 75%, 80%, 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, a purity level of at least about 99% or greater as determined by appropriate methods such as SDS/PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.
- a "recombinant host cell” or “host cell” refers to a cell that includes an exogenous
- polynucleotide regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.
- the exogenous polynucleotide may be maintained as a nonintegrated vector, for example, a plasmid, or alternatively, may be integrated into the host genome.
- the term “medium” or “media” includes any culture medium, solution, solid, semi-solid, or rigid support that may support or contain any host cell, including bacterial host cells, yeast host cells, insect host cells, plant host cells, eukaryotic host cells, mammalian host cells, CHO cells, prokaryotic host cells, E. coli, or Pseudomonas host cells, and cell contents.
- the term may encompass medium in which the host cell has been grown, e.g., medium into which the protein has been secreted, including medium either before or after a proliferation step.
- the term also may encompass buffers or reagents that contain host cell lysates, such as in the case where a heteromultimer described herein is produced intracellularly and the host cells are lysed or disrupted to release the heteromultimer.
- Refolding describes any process, reaction or method which transforms disulfide bond containing polypeptides from an improperly folded or unfolded state to a native or properly folded conformation with respect to disulfide bonds.
- Cofolding refers specifically to refolding processes, reactions, or methods which employ at least two monomeric polypeptides which interact with each other and result in the transformation of unfolded or improperly folded polypeptides to native, properly folded polypeptides.
- modulated serum half-life means the positive or negative change in circulating half-life of a cargo polypeptide that is comprised by a
- Serum half-life is measured by taking blood samples at various time points after administration of heteromultimer, and determining the concentration of that molecule in each sample. Correlation of the serum concentration with time allows calculation of the serum half-life.
- Increased serum half-life desirably has at least about two-fold, but a smaller increase may be useful, for example where it enables a satisfactory dosing regimen or avoids a toxic effect. In some embodiments, the increase is at least about three-fold, at least about five-fold, or at least about ten-fold.
- modulated therapeutic half-life means the positive or negative change in the half-life of the therapeutically effective amount of a cargo polypeptide comprised by a heteromultimer described herein, relative to its non-modified form. Therapeutic half-life is measured by measuring pharmacokinetic and/or
- Increased therapeutic half-life desirably enables a particular beneficial dosing regimen, a particular beneficial total dose, or avoids an undesired effect.
- the increased therapeutic half-life results from increased potency, increased or decreased binding of the modified molecule to its target, increased or decreased breakdown of the molecule by enzymes such as proteases, or an increase or decrease in another parameter or mechanism of action of the non-modified molecule or an increase or decrease in receptor-mediated clearance of the molecule.
- isolated when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is free of at least some of the cellular components with which it is associated in the natural state, or that the nucleic acid or protein has been concentrated to a level greater than the concentration of its in vivo or in vitro production. It can be in a homogeneous state. Isolated substances can be in either a dry or semi-dry state, or in solution, including but not limited to, an aqueous solution. It can be a component of a pharmaceutical composition that comprises additional pharmaceutically acceptable carriers and/or excipients.
- Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography.
- a protein which is the predominant species present in a preparation is substantially purified.
- an isolated gene is separated from open reading frames which flank the gene and encode a protein other than the gene of interest.
- the term "purified” denotes that a nucleic acid or protein gives rise to substantially one band in an electrophoretic gel. Particularly, it may mean that the nucleic acid or protein is at least 85% pure, at least 90% pure, at least 95% pure, at least 99% or greater pure.
- nucleic acid refers to deoxyribonucleotides, deoxyribonucleosides,
- ribonucleosides or ribonucleotides and polymers thereof in either single- or double- stranded form.
- the term encompasses nucleic acids containing known analogues of natural nucleotides which have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
- the term also refers to oligonucleotide analogs including PNA (peptidonucleic acid), analogs of DNA used in antisense technology (phosphorothioates, phosphoroamidates, and the like).
- nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (including but not limited to, degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated.
- degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al, Nucleic Acid Res. 19:5081 (1991) ; Ohtsuka et al, J. Biol. Chem. 260:2605-2608 (1985) ; Rossolini et al, Mol. Cell. Probes 8:91-98 (1994)) .
- polypeptide and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. That is, a description directed to a polypeptide applies equally to a description of a peptide and a description of a protein, and vice versa.
- the terms apply to naturally occurring amino acid polymers as well as amino acid polymers in which one or more amino acid residues is a non-naturally encoded amino acid.
- the terms encompass amino acid chains of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds.
- amino acid refers to naturally occurring and non-naturally occurring amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
- Naturally encoded amino acids are the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine, and valine) and pyrrolysine and selenocysteine.
- Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, such as, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
- Such analogs have modified R groups (such as, norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
- Reference to an amino acid includes, for example, naturally occurring proteogenic L-amino acids; D-amino acids, chemically modified amino acids such as amino acid variants and derivatives; naturally occurring non-proteogenic amino acids such as ⁇ -alanine, ornithine, etc.; and chemically synthesized compounds having properties known in the art to be characteristic of amino acids.
- non-naturally occurring amino acids include, but are not limited to, a-methyl amino acids (e.g.
- a-methyl alanine D-amino acids
- histidine-like amino acids e.g., 2-amino-histidine, ⁇ -hydroxy-histidine, homohistidine
- amino acids having an extra methylene in the side chain (“homo" amino acids)
- amino acids having an extra methylene in the side chain (“homo” amino acids)
- amino acids having an extra methylene in the side chain (“homo” amino acids)
- amino acids in which a carboxylic acid functional group in the side chain is replaced with a sulfonic acid group e.g., cysteic acid.
- the incorporation of non-natural amino acids, including synthetic non-native amino acids, substituted amino acids, or one or more D-amino acids into the proteins of the present invention may be advantageous in a number of different ways.
- D-amino acid-containing peptides, etc. exhibit increased stability in vitro or in vivo compared to L-amino acid-containing counterparts.
- the construction of peptides, etc., incorporating D-amino acids can be particularly useful when greater intracellular stability is desired or required.
- D-peptides, etc. are resistant to endogenous peptidases and proteases, thereby providing improved bioavailability of the molecule, and prolonged lifetimes in vivo when such properties are desirable.
- D-peptides, etc. cannot be processed efficiently for major histocompatibility complex class II-restricted presentation to T helper cells, and are therefore, less likely to induce humoral immune responses in the whole organism.
- Amino acids may be referred to herein by either their commonly known three letter
- nucleic acid sequences “conservatively modified variants” refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations.
- Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid.
- each codon in a nucleic acid except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan
- TGG which is ordinarily the only codon for tryptophan
- amino acid sequences one of ordinary skill in the art will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the deletion of an amino acid, addition of an amino acid, or substitution of an amino acid with a chemically similar amino acid.
- Conservative substitution tables providing functionally similar amino acids are known to those of ordinary skill in the art.
- Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.
- nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same. Sequences are "substantially identical” if they have a percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% identity over a specified region) , when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms (or other algorithms available to persons of ordinary skill in the art) or by manual alignment and visual inspection.
- This definition also refers to the complement of a test sequence.
- the identity can exist over a region that is at least about 50 amino acids or nucleotides in length, or over a region that is 75- 100 amino acids or nucleotides in length, or, where not specified, across the entire sequence of a polynucleotide or polypeptide.
- a polynucleotide encoding a polypeptide of the present invention may be obtained by a process comprising the steps of screening a library under stringent hybridization conditions with a labeled probe having a polynucleotide sequence of the invention or a fragment thereof, and isolating full-length cDNA and genomic clones containing said polynucleotide sequence.
- Such hybridization techniques are well known to the skilled artisan.
- sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
- sequence comparison algorithm test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated.
- the sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.
- a “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
- Methods of alignment of sequences for comparison are known to those of ordinary skill in the art.
- Optimal alignment of sequences for comparison can be conducted, including but not limited to, by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol.
- BLAST and BLAST 2.0 algorithms are described in Altschul et al. (1997) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively.
- Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information available at the World Wide Web at ncbi.nlm.nih.gov.
- the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
- W wordlength
- E expectation
- E expectation
- E amino acid sequence
- the BLAST algorithm is typically performed with the "low complexity" filter turned off.
- the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873- 5787).
- One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
- P(N) the smallest sum probability
- a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, or less than about 0.01, or less than about 0.001.
- the phrase "selectively (or specifically) hybridizes to” refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence under stringent hybridization conditions when that sequence is present in a complex mixture (including but not limited to, total cellular or library DNA or RNA) .
- stringent hybridization conditions refers to hybridization of sequences of
- DNA, RNA, or other nucleic acids, or combinations thereof under conditions of low ionic strength and high temperature as is known in the art.
- a probe will hybridize to its target subsequence in a complex mixture of nucleic acid (including but not limited to, total cellular or library DNA or RNA) but does not hybridize to other sequences in the complex mixture.
- Stringent conditions are sequence- dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures.
- the term "eukaryote” refers to organisms belonging to the phylogenetic domain Eucarya such as animals (including but not limited to, mammals, insects, reptiles, birds, etc.) , ciliates, plants (including but not limited to, monocots, dicots, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc.
- prokaryote refers to prokaryotic organisms.
- a non-eukaryotic organism can belong to the Eubacteria (including but not limited to, Escherichia coli, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, or the Archaea (including but not limited to, Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1 , Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.
- Eubacteria including but not limited to, Escherichia coli, Thermus thermophilus
- subject refers to an animal, in some embodiments a mammal, and in other embodiments a human, who is the object of treatment, observation or experiment.
- An animal may be a companion animal (e.g., dogs, cats, and the like) , farm animal (e.g., cows, sheep, pigs, horses, and the like) or a laboratory animal (e.g., rats, mice, guinea pigs, and the like) .
- compositions containing the heteromultimer described herein can be administered for prophylactic, enhancing, and/or therapeutic treatments.
- the terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
- the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
- An “enhancing-effective amount, " as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
- modified refers to any changes made to a given polypeptide, such as changes to the length of the polypeptide, the amino acid sequence, chemical structure, co-translational modification, or post-translational modification of a polypeptide.
- modified means that the polypeptides being discussed are optionally modified, that is, the polypeptides under discussion can be modified or unmodified.
- post-translationally modified refers to any modification of a natural or non-natural amino acid that occurs to such an amino acid after it has been incorporated into a polypeptide chain.
- the term encompasses, by way of example only, co- translational in vivo modifications, co-translational in vitro modifications (such as in a cell-free translation system) , post-translational in vivo modifications, and post- translational in vitro modifications.
- segmentation refers to a precise internal splice of the original protein sequence which results in "segments" of the protein sequence that preferentially associate as heteromultimers to form a quasi-protein.
- quasi-native proteins and/or 'quasi-native structures' present the native protein like functional and structural characteristics.
- Proteins are naturally dynamics molecules and display an ensemble of structural configurations although we ascribe a native structure to it, such as the one obtained by X-ray crystallography.
- the alternate structural configurations observed in the ensemble of geometries of that protein can be deemed to be quasi-native structures relative to each other or relative to the structure observed in the crystal.
- homologous proteins sequences or proteins belonging to common structural families tend to fold into similar structural geometries. The member proteins belonging to this family can be deemed to achieve a quasi-native structure relative to each other.
- Some of the unique sequences in the protein family could also exhibit similar functional attributes and hence can be referred to as quasi-native proteins relative to each other.
- the transporter polypeptides assemble to form a quasi-native structure.
- the reference native protein in this case is the protein from which the transporter polypeptide is derived and the reference native structure is the structure of the protein from which the transporter polypeptide is derived.
- transporter polypeptide As used herein, the term “transporter polypeptide” or “transporter polypeptide” or “transporter peptide” or “transporter” refers to a polypeptide, such that said transporter polypeptide is capable of forming heteromultimeric proteins with other such transporter polypeptides in solution, and wherein said heteromultimeric proteins have a quasi-native structure of a monomeric protein from which at least one transporter polypeptide is derived. In certain embodiments of the heteromultimers described herein, all transporter polypeptides are derived from the same albumin or alloalbumin protein. In certain other embodiments, the heteromultimers are formed by transporter polypeptides derived from various albumin and alloalbumin proteins.
- the transporter polypeptides are derived from transferrin. In certain embodiments of the heteromultimers described herein, all transporter polypeptides are derived from annexin proteins. In certain embodiments, the heteromultimers are formed by transporter polypeptides derived from the same annexin protein. In some
- the heteromultimers are formed by transporter polypeptides derived from different annexin proteins. In an embodiment, the heteromultimers are formed by transporter polypeptides derived from annexin A2.
- transporter polypeptides are segments of a whole protein, wherein said segments are capable of assembling to form a heteromultimer.
- the transporter polypeptides are segments derived from a coiled coil protein.
- the transporter polypeptides are segments derived from a leucine-zipper protein.
- the transporter polypeptides are segments from a beta-barrel protein.
- transporter polypeptides are segments obtained from a beta-propeller protein.
- the transporter polypeptides are segments obtained from a helical bundle protein.
- the trasporter polypeptides are generated from for instance, but not restricted to proteins comprising a zinc finger motif, a helix-turn-helix motif or a beta-hairpin motif.
- the transporter polypeptides are segments obtained from non-immunogenic proteins that are structurally stable, and have favorable biological properties.
- albumin refers collectively to albumin protein or amino acid sequence, or an albumin segment or variant, having one or more functional activities (e.g., biological activities) of albumin.
- albumin refers to human albumin or segments thereof (see for example, EP 201 239, EP 322 094 WO 97/24445,
- albumin refers to a truncated version of albumin.
- the term "quasi-albumin” refers to a heteromultimer molecule that has structure and/or function similar to the whole albumin, and wherein said heteromultimer molecule is formed by the assembly of two or more monomeric polypeptides designed based on the sequence of the whole albumin.
- the monomeric polypeptides are "segments" that preferentially associate as heteromultimeric pairs to form a quasi-protein.
- the quasi-albumin has 90% of the activity of the whole albumin.
- the quasi-albumin has 75% of the activity of whole-albumin.
- the quasi-albumin has 50% of the activity of whole albumin.
- the quasi-albumin has 50-75% of the activity of whole albumin. In an embodiment, quasi-albumin has 80% of the activity of whole albumin. In some embodiments, the quasi-albumin has 90% of the structure of whole albumin as determined by molecular modeling. In some embodiments, the quasi-albumin has 80% of the structure of whole albumin as determined by molecular modeling. In some embodiments, the quasi-albumin has 70% of the structure of whole albumin as determined by molecular modeling. In some embodiments, the quasi-albumin has 50% of the structure of whole albumin as determined by molecular modeling. In some embodiments, the quasi-albumin has 50%-75% of the structure of whole albumin as determined by molecular modeling.
- HSA human serum albumin
- HA human albumin
- albumin and serum albumin are broader, and encompass human serum albumin (and fragments and variants thereof) as well as albumin from other species (and fragments and variants thereof) .
- each albumin-based monomer of the heteromultimeric proteins described herein is based on a variant of normal HA.
- Each cargo polypeptide portion of the heteromultimeric proteins of the invention may also be variants of the Therapeutic proteins as described herein.
- variants includes insertions, deletions and substitutions, either conservative or non conservative, where such changes do not substantially alter one or more of the oncotic, useful ligand-binding and non- immunogenic properties of albumin, or the active site, or active domain which confers the therapeutic activities of the Therapeutic proteins.
- heteromultimeric proteins described herein include naturally occurring polymorphic variants of human albumin and fragments of human albumin, for example those fragments disclosed in EP 322 094 (namely HA (Pn) , where n is 369 to 419) .
- the albumin is derived from any vertebrate, especially any mammal that includes but is not limited to human, cow, sheep, rat, mouse, rabbit, horse, dog or pig. In certain embodiments, the albumin is derived from non-mammalian albumins including, but are not limited to hen and salmon.
- An alloalbumin is a genetic variant of albumin.
- alloalbumin is human alloalbumin (HAA). Alloalbumins that differ in electrophoretic mobility from albumin have been identified through population genetics surveys in the course of clinical electrophoresis, or in blood donor surveys. As markers of mutation and migration, alloalbumins are of interest to geneticists, biochemists, and anthropologists, but most of these alloalbumin are not associated with disease (Minchioti et al. Human Mutations 29(8), 1007-1016(2008)) .
- Table 1 List of substitutions comprised by various alloalbumins as compared to HA of SEQ ID NO: 1. Thermostability, half-life information and other HAAs are provided in Krogh-hansen et al. Biochim Biophys Acta 1747, 81-88(2005) ; and
- annexin refers to a group of cellular proteins found in
- Annexin is also known as lipocortin.
- annexin may refer to any annexin protein, or to specific annexin proteins such as “annexin Al ,” “annexin A2,” and “annexin A5.”
- Annexins are characterized by their calcium dependent ability to bind negatively charged phospholipids (i.e. membrane walls) .
- Annexins are characterized by a repeat protein scaffold limited to 30-50 kDa in size with fairly ubiquitous tissue distribution.
- the basic structure of an annexin is composed of two domains: a structurally conserved C terminal "core" region and a divergent N terminal domain. The core region binds the phospholipid cellular membrane in a Ca + dependent manner.
- the N terminal region binds cytoplasmic proteins.
- Annexins are important in various cellular and physiological processes and provide a membrane scaffold.
- the C terminal core is composed of four annexin repeats.
- Annexin is characterized by its flexible repeat-like nature that influences its intrinsic membrane- sensing abilities. For instance, the affinity towards specific biomembranes can be controlled by the number of repeats. With the characteristic phospholipid sensing, annexin can be useful to sense/target intestinal junctions for drug delivery. Another potential application for an annexin is targeting intestinal tight junctions and the Zonula Occludens region (ZO- 1), which is known to be particularly difficult to traverse for larger protein therapeutics, significantly impairing drug absorption.
- ZO-1 Zonula Occludens region
- the term "quasi-annexin” refers to a heteromultimer molecule that has structure and/or function similar to the whole annexin, and wherein said heteromultimer molecule is formed by the assembly of two or more monomeric polypeptides designed based on the sequence of the whole annexin.
- the monomeric polypeptides are "segments" that preferentially associate as heteromultimeric pairs to form a quasi-protein.
- the quasi- annexin has 90% of the activity of the whole annexin.
- the quasi- annexin has 75% of the activity of whole- annexin.
- the quasi- annexin has 50% of the activity of whole annexin.
- the quasi- annexin has 50-75% of the activity of whole annexin. In an embodiment, quasi- annexin has 80% of the activity of whole annexin. In some embodiments, the quasi- annexin has 90% of the structure of whole annexin as determined by molecular modeling. In some embodiments, the quasi- annexin has 80% of the structure of whole annexin as determined by molecular modeling. In some embodiments, the quasi- annexin has 70% of the structure of whole annexin as determined by molecular modeling. In some embodiments, the quasi- annexin has 50% of the structure of whole annexin as determined by molecular modeling. In some embodiments, the quasi- annexin has 50%-75% of the structure of whole annexin as determined by molecular modeling.
- Transferrins are monomeric proteins of about 76 kDa molecular weight present in all vertebrates and function as a iron-binding and transporting protein. Recombinant human transferrin and its fusions is being considered for the management of various diseases including thalassemia, atransferrinemia, age related macular degeneration, type 2 diabetes, during stem cell transplantation and in the treatment of acute infectious disease caused by the anthrax bacteria. Transferrin is stable in the gastrointestinal environment and a number of studies have shown that intact protein-transferrin conjugates can be orally delivered and remain bioactive.
- the term "quasi-transferrin” refers to a heteromultimer molecule that has structure and/or function similar to the whole transferrin, and wherein said heteromultimer molecule is formed by the assembly of two or more monomeric polypeptides designed based on the sequence of the whole transferrin.
- the monomeric polypeptides are "segments" that preferentially associate as heteromultimeric pairs to form a quasi-protein.
- the quasi- transferrin has 90% of the activity of the whole transferrin.
- the quasi- transferrin has 75% of the activity of whole- transferrin.
- the quasi- transferrin has 50% of the activity of whole transferrin.
- the quasi- transferrin has 50-75% of the activity of whole transferrin. In an embodiment, quasi- transferrin has 80% of the activity of whole transferrin. In some embodiments, the quasi- transferrin has 90% of the structure of whole transferrin as determined by molecular modeling. In some
- the quasi- transferrin has 80% of the structure of whole transferrin as determined by molecular modeling. In some embodiments, the quasi- transferrin has 70% of the structure of whole transferrin as determined by molecular modeling. In some embodiments, the quasi- transferrin has 50% of the structure of whole transferrin as determined by molecular modeling. In some embodiments, the quasi- transferrin has 50%-75% of the structure of whole transferrin as determined by molecular modeling.
- a heteromultimer described herein comprises monomers that comprise at least one cargo molecule, and at least one transporter polypeptide, said cargo molecule and transporter polypeptide associated with one another, by means inclusive of, but not restricted to genetic fusion or chemical conjugation.
- at least one cargo molecule is a therapeutic agent.
- the cargo molecule is a toxin.
- the cargo molecule is an antigen, or analogs thereof.
- the cargo molecule is a natural product, analog, or prodrug thereof.
- the cargo molecule is a therapeutic agent such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha- emitters such as, for example, 213BL
- a cytotoxin or cytotoxic agent includes any agent that is detrimental to cells.
- Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.
- Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6mercaptopurine, 6thioguanine, cytarabine, 5-fluorouracil decarbazine) , alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU) , cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin) , antibiotics (e.g., dactinomycin (formerly actinomycin) , bleomycin, mithramycin, and anthramycin (AMC)) , and
- the cargo molecule is a biomolecule.
- the cargo molecule is a natural or synthetic nucleic acid.
- at least one cargo molecule is one or more of a DNA, PNA, and/or RNA oligomer.
- a heteromultimer described herein comprises monomeric proteins that comprise at least one cargo polypeptide, or fragments or variants thereof, and at least one transporter polypeptide, said cargo polypeptide and transporter polypeptide associated with one another, by means inclusive of, but not restricted to genetic fusion or chemical conjugation
- Cargo polypeptide refers to proteins, polypeptides, antibodies, peptides or fragments or variants thereof, having one or more therapeutic and/or biological activities.
- Cargo polypeptides encompassed by the invention include but are not limited to, proteins, polypeptides, peptides, antibodies, substrates or ligands to therapeutically relevant target proteins and biologies. (The terms peptides, proteins, and polypeptides are used interchangeably herein.)
- Cargo polypeptide encompasses antibodies and fragments and variants thereof.
- a heteromultimer described herein may contain at least a fragment or variant of a cargo polypeptide, and/or at least a fragment or variant of an antibody.
- the term “Cargo polypeptide” refers to the endogenous or naturally occurring correlate of a cargo polypeptide.
- a "Cargo biomolecule” is a biomolecule such as but not restricted to a protein, DNA, or RNA that is useful to treat, prevent or ameliorate a disease, condition or disorder.
- a "Cargo polypeptide” may be one that binds specifically to a particular cell type (normal (e.g., lymphocytes) or abnormal e.g., (cancer cells)) and therefore may be used to target a compound (drug, or cytotoxic agent) to that cell type specifically.
- a "Cargo molecule” is a molecule that has a biological, activity, and in particular, a biological activity that is useful for treating preventing or ameliorating a disease.
- a non-inclusive list of biological activities that may be possessed by a Cargo molecule, for instance a Cargo polypeptide includes, enhancing the immune response, promoting angiogenesis, inhibiting angiogenesis, regulating hematopoietic functions, stimulating nerve growth, enhancing an immune response, inhibiting an immune response, or any one or more of the biological activities described herein.
- Cargo polypeptides corresponding to a cargo polypeptide portion of a heteromultimer protein described herein, such as cell surface and secretory proteins, are often modified, by the attachment of one or more oligosaccharide groups.
- the modification referred to as glycosylation, can dramatically affect the physical properties of proteins and can be important in protein stability, secretion, and localization. Glycosylation occurs at specific locations along the polypeptide backbone.
- glycosylation characterized by O-linked oligosaccharides, which are attached to serine or threonine residues; and glycosylation characterized by N-linked oligosaccharides, which are attached to asparagine residues in an Asn-X-Ser/Thr sequence, where X can be any amino acid except proline.
- N-acetylneuramic acid also known as sialic acid
- Variables such as protein structure and cell type influence the number and nature of the carbohydrate units within the chains at different glycosylation sites. Glycosylation isomers are also common at the same site within a given cell type.
- Table 2 provides a non-exhaustive list of Cargo polypeptides that correspond to a Cargo polypeptide portion of a heteromultimer described herein.
- the "Cargo Polypeptide” column discloses Cargo polypeptide molecules followed by parentheses containing scientific and brand names that comprise, or alternatively consist of, that Cargo polypeptide molecule or a fragment or variant thereof.
- the cargo molecule is a molecule that binds to a protein disclosed in the "Cargo polypeptide” column, or in Zhu et al. (Nucleic Acids Res. 38(1), D787-D791 (2009)) ; Wishart et al.
- Cargo polypeptide as used herein may refer either to an individual Cargo polypeptide molecule (as defined by the amino acid sequence obtainable from the CAS and Genbank accession numbers) , or to the entire group of Cargo polypeptide associated with a given Cargo polypeptide molecule disclosed in this column, or a Cargo polypeptide that binds to a polypeptide molecule disclosed in this column.
- NEORECORMON terminally Patients; Chemotherapy;
- ARANESP into erythrocytes; and Anemia in zidovudine-treated modulates the level of HIV patients; Anemia in circulating zidovudine-treated patients; erythrocytes. Anemia in HIV patients; Anemia in premature infants; Surgical patients (pre and/or post surgery) ;
- Transfusion avoidance for surgical patients Transfusion avoidance for elective surgical patients; Transfusion avoidance for elective orthopedic surgical patients; Patients who want to
- G-CSF G-CSF (Granulocyte Stimulates the Proliferation of murine Chemoprotection; Adjunct to colony- stimulating proliferation and NFS-60 cells (Weinstein Chemotherapy; Inflammatory factor; Granulokine; differentiation of the et al, Proc Natl Acad Sci disorders; Cancer; Leukemia;
- KRN 8601 Filgrastim; progenitor cells for USA 1986; 83, pp5010- Myelocytic leukemia;
- Meograstim monocytes- neutropenias (e.g.; Kostmann
- Granulokine treatment of neutropenia in HIV-
- GM-CSF Granulocyte- Regulates Colony Stimulating Bone Marrow Disorders
- Bone macrophage colony- hematopoietic cell Assay Testa, N. G., et marrow transplant;
- PROKINE Prostate Cancer
- Interberin Interberin; Leukine; Ulcers (such as Diabetic, Venous
- Somatrem Somatropin; signal transduction novel specific bioassay Growth hormone deficiency;
- PROTROPIN BIO- dimerization hormone. J Clin Deficiency; Adult Growth
- Insulin Human insulin; Stimulates glucose Insulin activity may be Hyperglycemia; Diabetes;
- Insulin aspart Insulin uptake and promotes assayed in vitro using a Diabetes Insipidus; Diabetes
- Glargine Insulin lispro; glycogenesis and [3-H] -glucose uptake mellitus; Type 1 diabetes; Type 2 Cargo Polypeptide Biological Activity Exemplary Activity Indication
- Lys-B28 Pro- B29 lipogenesis. assay. (J Biol Chem 1999 diabetes; Insulin resistance; lyspro; LY 275585; Oct 22; 274(43): 30864- Insulin deficiency;
- NOVORAPID (IDDM) ; A Condition Associated
- ILETIN HU ALOG; Ulcers; Metabolic Disorders; ACRULIN; Immune Disorders; Obesity;
- Interferon alfacon-1 production of two Y, et al (1999) Sensitivity Condylomata Acuminata; HIV; interferon consensus; enzymes: a protein of an epstein-barr virus- HIV Infection; Oncology; Cancer;
- interferon- alpha oligoadenylate Daudi to alpha interferon Malignant Melanoma; Renal consensus; recombinant synthetase. correlates with Cancer (e.g., Renal Cell methionyl consensus expression of a GC-rich Carcinoma) ; Lung Cancer (e.g,. interferon; recombinant viral transcript. ol Cell Non-Small Cell Lung Cancer or consensus interferon; Biol. 19(11): 7305-13. Small Cell Lung Cancer) Colon
- ROFERON A Multiforme
- Cervical Dysplasia Cervical Dysplasia
- VIRAFERON Multiple Myeloma; Bacterial
- Diabetes Insipidus Diabetes mellitus; Type 1 diabetes; Type 2 diabetes; Insulin resistance;
- NIDDM Insulin-dependent Diabetes Mellitus
- Calcitonin (Salcatonin) ; calcium and phosphate Bioassay, bone resorbing prevention; Hypercalcemia;
- Calcitonin human- in serum causes a assay and the pit assay, Malignant hypercalcemia;
- Calcitonin Calcitonina opposite to that of assay: J Bone Miner Res osteolysis; osteomyelitis;
- Cibacalcin Cibacalcina; differentiation inhibition; bone
- Cibacalcine disorders; bone healing and
- Renal Cancer e.g., Renal Cell
- BCDF beta-2 IF
- monocytes 37(2): 755-8; Anti- Non-Small Cell Lung Cancer or
- Diabetes Insipidus Diabetes mellitus; Type 1 diabetes; Type 2 diabetes; Insulin resistance; Insulin deficiency;
- Hyperlipidemia Hyperketonemia; Non- insulin dependent Diabetes Mellitus (NIDDM) ; Insulin- dependent Diabetes Mellitus (IDDM) ; A Condition Associated With Diabetes Including, But Not Limited To Obesity, Heart Disease, Hyperglycemia, Infections, Retinopathy, And/Or Cargo Polypeptide Biological Activity Exemplary Activity Indication
- Growth hormone Acts on the anterior Growth hormone- Acromegaly; Growth failure; releasing factor; Growth pituitary to stimulate releasing peptides Growth hormone replacement; hormone releasing the production and (GHRPs) are known to Growth hormone deficiency; hormone (Sermorelin secretion of growth release growth hormone Pediatric Growth Hormone acetate; Pralmorelin; hormone and exert a (GH) in vivo and in vitro Deficiency; Adult Growth hormone
- Gerel; Groliberin pituitary cells. Biological Growth retardation; Prader- Willi activity can be measured Syndrome; Prader-Willi in cell lines expressing Syndrome in children 2 years or growth hormone older; Growth deficiencies; releasing factor receptor Growth failure associated with
- IL-2 (Aldesleukin; Promotes the growth of T cell proliferation assay Cancer; Solid Tumors; Metastatic interleukin-2 fusion B and T cells and "Biological activity of Renal Cell Carcinoma; Metastatic toxin; T cell growth augments NK cell and recombinant human Melanoma; Malignant Melanoma; factor; PROLEUKIN; CTL cell killing interleukin-2 produced in Melanoma; Renal Cell
- IMMUNACE activity. Escherichia coli. Carcinoma; Renal Cancer; Lung
- MACROLIN cell and CTL cytotoxicity Cancer
- Colon Cancer Breast assay "Control of Cancer; Liver Cancer; Leukemia; homeostasis of CD8+ Preleukemia; Hematological Cargo Polypeptide Biological Activity Exemplary Activity Indication
- Parathyroid hormone Acts in conjuction with Adenylyl cyclase Bone Disorders; Fracture parathyrin (PTH; calcitonin to control stimulation in rat prevention; Hypercalcemia;
- hPTH 1-34 LY metabolism; elevates ovariectomized rat model Osteoporosis; Paget's disease;
- osteoporosis IUBMB Osteopenia, Osteoclastogenesis; parathyroid hormone (1- stimulates the activity Life 2000 Feb; 49(2): osteolysis; osteomyelitis;
- PARATHAR absorption of Ca+ Pi loss; osteoarthritis; rheumatoid from small intestine arthritis; osteopetrosis;
- Resistin Mediates insulin Ability of resistin to Hyperglycemia; Diabetes;
- Type II diabetes Diabetes Insipidus influence type II diabetes Diabetes Insipidus; Diabetes diabetes; inhibits can be determined using mellitus; Type 1 diabetes; Type 2 insulin-stimulated assays known in the art: diabetes; Insulin resistance; glucose uptake Pontoglio et al., J Clin Insulin deficiency;
- NIDDM Insulin-dependent Diabetes Mellitus
- IDDM IDDM
- IDDM A Condition Associated With Diabetes Including, But Not Limited To Obesity, Heart Disease, Hyperglycemia, Infections, Retinopathy, And/Or Ulcers; Metabolic Disorders; Immune Disorders; Obesity; Vascular Disorders; Suppression of Body Weight; Suppression of Appetite; Syndrome X.
- TR6 DcR3; Decoy Inhibits Fas Ligand and Cellular apoptosis can be Fas Ligand or LIGHT induced Receptor 3; FASTR)
- AIM-2 T5, LIGHT measured by annexin apoptotic disorders: hepatitis;
- Assay refs inflammatory bowel disease; cytotoxicity assay on autoimmune disease; toxic human fibrosarcoma epidermal necrolysis; multiple (Epsevik and Nissen- sclerosis.
- DeCAF (D- SLAM; Inhibits proliferation
- DeCAF activity can be B cell and/or T cell mediated BCM ike membrane and differentiation of B determined using assays immune disorders;
- BLAME B cells; Antagonize BLyS known in the art, such as Immunodeficiency (e.g., Common lymphocyte activator activity for example, those Variable Immunodeficiency, macrophage described in Examples Selective IgA Deficiency) expressed))x 32-33 of International
- BLyS B Lymphocyte Promotes proliferation
- BLyS activity can be B cell and/or T cell mediated Stimulator; Neutrokine differentiation and determined using assays immune disorders, particularly alpha; TL7; BAFF; survival of B cells; known in the art, such as, immune system disorders TALL- 1 ; THANK; Promotes for example, the associated with low B cell radiolabeled BLyS) immunoglobulin costimulatory numbers or low serum
- Radiolabeled forms lymphoma, non-Hodgkins lymphoma, chronic lymphocytic leukemia, multiple myeloma.
- Anti-BLyS single chain Agonize or antagonize BLyS agonist or B cell and/or T cell mediated antibody (scFvI116A01, BlyS activity. antagonist activity can be immune disorders; Autoimmune scFvI050Bl l, determined using assays disorders, particularly scFvI006D08) and known in the art, such as, autoimmune diseases associated others. for example, a modified with the production of
- lymphocytes are lymphocytes.
- MPIF-1 Myeloid Inhibits myeloid MPIF-1 activity can be Chemoprotection; Adjunct to Progenitor Inhibitory progenitor cells; and measured using the Chemotherapy; Inflammatory Factor; CK beta-8; activates monocytes myeloprotection assay disorders; Cancer; Leukemia; Mirostipen) and chemotaxis assay Myelocytic leukemia;
- neutropenias e.g.; Kostmann syndrome
- Secondary neutropenia Prevention of neutropenia
- Prevention and treatment of neutropenia in HIV- infected patients Prevention and treatment of neutropenia associated with chemotherapy; Infections associated with neutropenias; Myelopysplasia; Autoimmune disorders; Psoriasis; Mobilization of hematopoietic Cargo Polypeptide Biological Activity Exemplary Activity Indication
- KDI Keratinocyte Inhibits bone marrow KDI activity can be Multiple sclerosis; Hepatitis; Derived Interferon; proliferation; and measured using the Cancer; Viral infections, HIV Interferon Kappa shows antiviral activity. antiviral and cell infections, Leukemia.
- TNFR2 (p75) Binds both TNFa and T-cell proliferation can Autoimmune disease; Rheumatoid (ENBREL) TNF ; mediates T-cell be measured using assays Arthritis; Psoriatic arthritis; Still's proliferation by TNF; known in the art. For Disease; Ankylosing Spondylitis; reduces signs and example, "Lymphocytes: Cardiovascular Diseases;
- Vasulitis Wegener's patients with edited by: SL Rowland, granulomatosis; Amyloidosis; moderately to severely AJ c ichael - chapter Systemic Lupus Erythematosus, active rheumatoid 6, pages 138-160 Oxford Insulin-Dependent Diabetes arthritis (RA). University Press (2000) ; Mellitus; Immunodeficiency and "Current Protocols Disorders; Infection;
- Keratinocyte growth Stimulates epithelial KGF-2 activity can be Stimulate Epithelial Cell factor 2 (Repifermin; cell growth. measured using the Proliferation; Stimulate Basal KGF-2; Fibroblast wound healing assays and Keratinocytes; Wound Healing; Growth Factor- 10; epithelial cell Stimulate Hair Follicle
- Wounds Wounds, Oral Cavity Wounds, Diabetic Ulcers, Dermal Ulcers, Cubitus Ulcers, Arterial Ulcers, Venous Stasis Ulcers, Burns Resulting From Heat Exposure Or Chemicals, or Other Abnormal Wound Healing Conditions such as Uremia, Malnutrition, Vitamin Deficiencies or Complications Associated With Systemic Treatment With Steroids, Radiation Therapy or
- Antineoplastic Drugs or Antimetabolites Promote Dermal Reestablishment Subsequent To Dermal Loss; Increase the Adherence Of Skin Grafts To A Wound Bed; Stimulate Re- Epithelialization from The Wound Bed; To Promote Skin Strength; Improve The Appearance Of Aged Skin; Proliferate
- Hepatocytes Lung, Breast, Pancreas, Stomach, Bladder, Small Intestine, Large Intestine; Sebocytes, Hair Follicles, Type II Pneumocytes, Mucin- Producing Goblet Cells, or Other Epithelial Cells, Endothelial Cells, Keratinocytes, or Basal Keratinocytes (and Their Progenitors) Contained Within The Skin, Lung, Liver, Bladder, Eye, Salivary Glands, or Gastrointestinal Tract; Reduce The Side Effects Of Gut Toxicity That Result From Radiation, Chemotherapy Treatments Or Cargo Polypeptide Biological Activity Exemplary Activity Indication
- Viral Infections Cytoprotector, especially of the Small Intestine Mucosa or Bladder: Mucositis (Mouth Ulcers) ; Regeneration Of Skin: Full and/or Partial Thickness Skin Defects, including Burns, (e.g., Repopulation Of Hair Follicles, Sweat Glands, And Sebaceous Glands) : Psoriasis: Epidermolysis Bullosa: Blisters: Gastric and/or Doudenal Ulcers: Reduce Scarring: Inflamamatory Bowel Diseases: Crohn's Disease: Ulcerative Colitis: Gut Toxicity: Lung Damage: Repair Of Alveoli And/or Brochiolar Epithelium: Acute Or Chronic Lung Damage: Emphysema, ARDS: Inhalation Injuries: Hyaline Membrane Diseases: Infant Respiratory Distress Syndrome:
- TR2 (and TR2svl, Inhibits B cell Co-stimulation B-cell Herpes: immune disorders: TR2SV2; TNFRSF14; proliferation, and proliferation assay and Ig autoimmune disease: graft versus HVE ; Herpes Virus mediates and inhibits production assay (Moore host disease: graft rejection: Entry Mediator; ATAR) Herpes Simplex Virus et al., 1999, Science, variable immunodeficiency:
- HSV-1 and HSV-2 cancer are HSV-1 and HSV-2 cancer.
- Macrophage derived Chemotactic for 04658 Chemokine Inflammatory diseases: wound chemokine, MDC monocyte-derived activities can be healing:
- HAGDG59 Activates MlPla Dendritic cell assays Immune disorders: cancer: viral
- GnRH (Gonadotropin Promotes release of GnRH is known to cause Infertility: Kallmann's syndrome
- FSH hypergonadotropic luteinizing hormone
- LH luteinizing hypergonadism
- GnRH activity can be any GnRH activity.
- Teprotide Inhibits angiotensin Inhibition of ACE can be Hypertension: congestive heart converting enzyme determined using assays failure.
- HCC-1 (ckBeta-1 ; inflammation, allergy, be determined using Immunity; Vascular and
- HWFBD tissue rejection, viral assays known in the art: Inflammatory disorders; HIV;
- ACE2 inhibitor Inhibits production of Inhibition of angiotensin Treatment for elevated
- angiotensin II which can be determined using angiotensin II and/or aldosterone induces aldosterone assays known in the art. levels, which can lead to production, arteriolar
- in vitro vasoconstriction impaired cardiac smooth muscle using a proliferation output and/or hypertension; vasoconstriction, and assay with rat cardiac Cardiovascular Disease; Cardiac proliferation of cardiac fibroblasts as described in Failure; Diabetes; Type II fibroblasts, Induces Naunyn Schmiedebergs Diabetes; Proteinuria; Renal angiogenesis; an Arch Pharmacol 1999 disorders, congestive heart failure. enzyme that converts May; 359(5): 394-9.
- TR1 (OCIF; Inhibits Coculture Assay for Osteoporosis; Paget's disease;
- Osteoclastogenesis osteoclastogenesis and Osteoclastogenesis Bone osteopenia; osteolysis;
- osteomyelitis osteonecrosis
- osteoprotegerin OPG
- fibroblast proliferation periodontal, lytic, or metastatic assays are each described bone disease; osteoclast in Kwon et al, FASEB J. differentiation inhibition; bone 12: 845-854 (1998). disorders; bone healing and Cargo Polypeptide Biological Activity Exemplary Activity Indication
- Ckbeta-7 activated (CD3+) T be determined using Inflammatory disorders
- CD 14- lymphocytes Methods in Molecular Atherosclerosis; Parasitic and (CD4+) and Biology, 2000, vol. 138: Infection; Rheumatoid Arthritis;
- CKbeta4 (HGBAN46; Attracts and activates Chemokine activities can Cancer; Solid Tumors; Chronic
- HE9DR66 microbicidal be determined using Infection; Autoimmune Disorders;
- Attracts assays known in the art Psoriasis; Asthma; Allergy;
- mice radioimmunoassay Hyperlipidemia; Hyperketonemia;
- RIA Non-insulin dependent Diabetes
- NIDDM Mellitus
- IL-1 receptor antagonist Binds IL1 receptor 1) Competition for IL-1 Autoimmune Disease; Arthritis; (Anakinra; soluble without activating the binding to IL-1 receptors Rheumatoid Arthritis; Asthma; interleukin-1 receptor; target cells; inhibits the in YT-NCI or C3H/HeJ Diabetes; Diabetes Mellitus; IRAP; KINERET; binding of ILl-alpha cells (Carter et al., Nature GVHD; Inflammatory Bowel ANTRIL) and ILl-beta; and 344: 633-638, 1990) ; 2) Disorders; Chron's Disease;
- A375-C6 cells a human
- TREM-1 Triggering Mediates activation of Secretion of cytokines, Inflammation; Sepsis; bacterial Receptor Expressed on neutrophil and chemokines, infection; autoimmune diseases; Monocytes 1) monocytes; Stimulates degranulation, and cell GVHD.
- monocyte-mediated markers can be any substance that monocyte-mediated markers.
- T-cell FMAT Induces T-cell FMAT can be used to Autoimmune disorders
- T-cell surface Inflammation of the of CD 152 marker markers (CD69, CD152, gastrointestinal tract; Cancer; Stimulates release of CD71, HLA- DR) and T- Colon Cancer; Allergy; Crohn's TNF-a and MIP- la cell cytokine production disease.
- IFNg production from immature, (e.g., IFNg production).
- VEGF-2 (Vascular Promotes endothelial VEGF activity can be Coronary artery disease; Critical Endothelial Growth cell proliferation. determined using assays limb ischemia; Vascular disease; Factor-2; VEGF-C) known in the art, such as proliferation of endothelial cells, those disclosed in both vascular and lymphatic.
- International Publication Antagonists may be useful as anti- No. WO0045835, for angiogenic agents; Cancer. example.
- HCHNF25 flumping Activates MIP la Dendritic cell assays are Immune disorders; cancer. translocation Release in Dendritic well known in the art.
- HLDOU18 (Bone Activates L6/GSK3 Assays for activation of Hyperglycemia; Diabetes;
- GSK3 kinase activity are Diabetes Insipidus; Diabetes (B P9) ; Growth well known in the art. For mellitus; Type 1 diabetes; Type 2 differentiation factor-2 example, Biol. Chem. diabetes; Insulin resistance; precursor (GDF-2 379(8-9): (1998) 1101- Insulin deficiency; Cargo Polypeptide Biological Activity Exemplary Activity Indication
- NIDDM Insulin-dependent Diabetes Mellitus
- IDDM Insulin-dependent Diabetes Mellitus
- Glucagon- Like-Peptide Stimulates the GLP 1 activity may be Hyperglycemia; Diabetes;
- GLP1 synthesis and release of assayed in vitro using a Diabetes Insipidus; Diabetes Insulinotropin
- insulin enhances the [3-H] -glucose uptake mellitus
- Type 1 diabetes Type 2 sensitivity of adipose, assay.
- Hyperlipidemia Hyperketonemia; stimulates glucose Non- insulin dependent Diabetes uptake; slows the Mellitus (NIDDM) ; Insulin- digestive process; dependent Diabetes Mellitus suppresses appetite; (IDDM) ; A Condition Associated blocks the secretion of With Diabetes Including, But Not glucagon. Limited To Obesity, Heart
- Exendin-4 (AC-2993) Stimulates the Exendin-4 activity may Hyperglycemia; Diabetes;
- NIDD Non- insulin dependent Diabetes uptake
- IDDM dependent Diabetes Mellitus suppresses appetite
- T20 T20 HIV a peptide from residues Virus inhibition assays as HIV; AIDS; SIV (simian inhibitory peptide, 643-678 of the HIV described in Zhang et al., immunodeficiency virus)
- T1249 HIV a second generation Virus inhibition assays as HIV; AIDS; SIV (simian inhibitory peptide; HIV fusion inbitor described in Zhang et al., immunodeficiency virus)
- IFNalpha A/D hybrid including antiviral, PC, Pestka S. (1981) Hepatitis B; Chronic Hepatitis B;
- IFNalpha A/D hybrid antitumor and interferons. J. Virol. Hepatitis D; Chronic Hepatitis D;
- IFNalpha A/F hybrid activities stimulate proliferation assay: Gao Simplex Virus Infection; External
- IFNbeta 1/alpha D enzymes a protein of an epstein-barr virus- HIV Infection; Oncology; Cancer; hybrid (IFNbeta- kinase and an positive tumor line, Solid Tumors; Melanoma;
- IFNalpha/beta hybrid synthetase correlates with Cancer (e.g., Renal Cell
- Lung Cancer e.g., Cargo Polypeptide Biological Activity Exemplary Activity Indication
- NK viral transcript ol Cell Non-Small Cell Lung Cancer or cell activity and IFNg Biol. 19(11): 7305-13.
- Small Cell Lung Cancer Colon production and IL12 Cancer; Breast Cancer; Liver production in Cancer; Prostate Cancer; Bladder monocytes. Cancer; Gastric Cancer; Sarcoma;
- Diabetes Insipidus Diabetes mellitus; Type 1 diabetes; Type 2 diabetes; Insulin resistance;
- NIDDM Insulin-dependent Diabetes Mellitus
- IDDM Insulin-dependent Diabetes Mellitus
- B-type natriuretic stimulates smooth Inhibition of angiotensin Congestive heart failure; cardiac peptide (BNP, brain muscle relaxation and can be determined using volume overload; cardiac natriuretic peptide) vasodilation, assays known in the art, decompensation; Cardiac Failure;
- natriuresis and for example using an in Left Ventricular Dysfunction; suppression of renin- vitro proliferation assay Dyspnea angiotensin and with rat cardiac
- Vasodilation can be any vessel vascular vascular vascular vascular pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary
- ⁇ -defensin including Suppression of HIV Virus inhibition assays as HIV, AIDS; ARC.
- alpha 1 defensin, alpha replication active described in Zhang et al.
- defensin myeloid- and enveloped viruses. Sciencexpress Cargo Polypeptide Biological Activity Exemplary Activity Indication
- extracellular phosphate metabolism can be measured using Hyperphosphatemia in chronic phosphoglycoprotein; methods known in the art renal failure; hypophosphatemia; EPE) such as the Osteomalacia; Rickets; X-linked
- ADHR hypophosphatemic rickets/osteomalacia
- TIO rickets/osteomalacia
- Plpal-12 (pepducin, Regulation of protease- Platelet aggregation can Protection against systemic PARl-based pepducin) activated receptor be measured using platelet activation, thrombus,
- P4pal-10 (pepducin, Regulation of protease- Platelet aggregation can Protection against systemic PAR4-based pepducin) activated receptor be measured using platelet activation, thrombus,
- HRDFD27 Involved in the T-cell proliferation can Chemoprotection; Adjunct to proliferation of T cells; be measured using assays Chemotherapy; Inflammatory Production of known in the art.
- Chemotherapy Inflammatory Production of known in the art.
- Cancer Leukemia
- TNFgamma example, "Lymphocytes: Myelocytic leukemia;
- Neutropenia Primary edited by: SL Rowland, neutropenias (e.g.; Kostmann AJ McMichael - chapter syndrome) ; Secondary 6, pages 138-160 Oxford neutropenia; Prevention of University Press (2000) ; neutropenia; Prevention and and "Current Protocols treatment of neutropenia in HIV- on CD-ROM" section infected patients; Prevention and Cargo Polypeptide Biological Activity Exemplary Activity Indication
- HWHGZ51 (CD 59; Stimulates an immune The ability to affect Skeletal diseases and disorders;
- GPI-adhered protein inflammation by differentiation can be disorders; Bone fractures and/or homolog) inducing mononuclear measured using methods breaks; Osteoporosis
- Tumors Tumors; Melanoma; Malignant Melanoma; Renal Cancer (e.g., Renal Cell Carcinoma) ; Lung Cancer (e.g,. Non-Small Cell Lung Cancer or Small Cell Lung Cancer) Colon Cancer; Breast Cancer; Liver Cancer; Prostate Cancer; Bladder Cancer; Gastric Cancer; Sarcoma; AIDS-Related Kaposi's Sarcoma; Lymphoma; T Cell Lymphoma; Cutaneous T- Cell Lymphoma; Non-Hodgkin's Lymphoma; Brain Cancer; Glioma; Glioblastoma
- Cervical Dysplasia Leukemia; Preleukemia; Bone Marrow Disorders; Bone Disorders; Hairy Cell Leukemia; Chronic Myelogeonus Leukemia; Hematological Malignancies; Hematological Disorders;
- Kidney diseases and disorders Shonlein- Henoch purpura, Berger disease, celiac disease, dermatitis herpetiformis, Chron disease; Diabetes; Diabetes Insipidus; Diabetes mellitus; Type 1 diabetes; Type 2 diabetes; Insulin resistance; Insulin deficiency; Hyperlipidemia; Hyperketonemia; Non- insulin dependent Diabetes Mellitus (NIDDM) ; Insulin- dependent Diabetes Mellitus (IDDM) ; A Condition Associated With Diabetes Including, But Not Limited To Obesity, Heart Disease, Hyperglycemia, Infections, Retinopathy, And/Or Cargo Polypeptide Biological Activity Exemplary Activity Indication
- C17 cytokine- like Inhibits glucose and/or Proliferation of kidney Kidney diseases and disorders; protein CI 7
- FFA uptake by mesangial cells can be Shonlein- Henoch purpura, Berger adipocytes; Induces assayed using techniques disease, celiac disease, dermatitis proliferation of kidney described in J. Investig. herpetiformis, Chron disease; mesangial cells; Med. (1998) Aug; 46(6): Diabetes; Diabetes Insipidus; Regulation of cytokine 297-302. Diabetes mellitus; Type 1 production and antigen diabetes; Type 2 diabetes; Insulin presentation resistance; Insulin deficiency;
- Hyperlipidemia Hyperketonemia; Non-insulin dependent Diabetes Mellitus (NIDDM) ; Insulin-dependent Diabetes Mellitus (IDDM) ; A Condition Associated With Diabetes Including, But Not Limited To Obesity, Heart Disease, Hyperglycemia, Infections, Retinopathy, And/Or Cargo Polypeptide Biological Activity Exemplary Activity Indication
- Immunological disorders e.g. arthritis, asthma,
- AIDS rheumatoid arthritis, granulomatous disease, inflammatory bowl disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, T-cell mediated cytotoxicity, host- versus-graft disease, autoimmunity disorders, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjorgren's disease, scleroderma)
- HDPBQ71 Regulates production Such assays that may be Blood disorders and infection and secretion of used or routinely (e.g., viral infections,
- IFNgamma Activation modified to test tuberculosis, infections associated of myeloid cells and/or immunomodulatory with chronic granulomatosus hematopoietic cells activity of polypeptides disease and malignant
- rheumatoid arthritis e.g., rheumatoid arthritis, agonists or antagonists of systemic lupus erythematosis, the invention
- multiple sclerosis e.g., rheumatoid arthritis, agonists or antagonists of systemic lupus erythematosis, the invention
- ALL Acute lymphocytic anemia
- Plasmacytomas Multiple myeloma; Burkitt's lymphoma;
- osteochondromas benign chondromas, chondroblastomas, chondromyxoid fibromas, osteoid osteomas, giant cell tumors, multiple myelomas, osteosarcomas, fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, Ewing's tumors, and/or malignant lymphomas
- Bone and joint infections osteomyelitits and/or infectious arthritis
- Charcot's joints Heel spurs
- Sever's disease Sport's injuries
- Tumstatin T5, T7 or T8 Inhibits angiogenesis; A tumor cell proliferation Cancer; Solid Tumors;
- Renal Cancer e.g., Renal Cell synthesis 20395-20401. Protein Carcinoma
- Lung Cancer e.g,.
- Non-Small Cell Lung Cancer or measured as described in Small Cell Lung Cancer) Colon Science (2002) Jan 4; Cancer; Breast Cancer; Liver 295 (5552): 140-3. Cancer; Prostate Cancer; Bladder
- neurotrophic factor formation
- Reduces formation can be assayed and disorders, particularly
- LF response to GnRH can be measured as Diarrhea and Flushing; Prostatic
- Gallbladder disorders such as gallbladder contractility diseases and abnormal bile secretion; Psoriasis; Diabetes;
- Diabetes Insipidus Diabetes mellitus; Type 1 diabetes; Type 2 diabetes; Insulin resistance;
- NIDDM Insulin-dependent Diabetes Mellitus
- Alzheimers Disease, Parkinson's disease and dementia are Alzheimers Disease, Parkinson's disease and dementia
- Neuropsychotic disorders including Bipolar affective disorder; Rheumatoid arthritis; Hypertension; Intracranial hypertension; Esophageal varices; Graves' disease; Seizures;
- IL-22 Stimulates glucose IL-22 activity may be Hyperglycemia; Diabetes;
- interleukin-22 interleukin-22
- IL17D uptake in skeletal assayed in vitro using a Diabetes Insipidus
- Diabetes IL27 muscle cells
- Type 1 diabetes Type 2 skeletal muscle insulin assay.
- Non- insulin dependent Diabetes Mellitus NIDDM
- Insulin-dependent Diabetes Mellitus IDDM
- HCE1P80 Stimulates glucose HCE1P80 activity may Hyperglycemia; Diabetes;
- Non- insulin dependent Diabetes Mellitus NIDDM
- Insulin-dependent Diabetes Mellitus IDDM
- HDR I82 Stimulates glucose HDRMI82 activity may Hyperglycemia; Diabetes;
- Non- insulin dependent Diabetes Mellitus NIDDM
- Insulin-dependent Diabetes Mellitus IDDM
- HDALV07 Modulates insulin Insulin activity may be Diabetes; Diabetes Insipidus; (adiponectin; gelatin- action assayed in vitro using a Diabetes mellitus; Type 1 binding 28k protein [3-H] -glucose uptake diabetes; Type 2 diabetes; Insulin precursor; adipose most assay.
- adiponectin gelatin- action assayed in vitro using a Diabetes mellitus
- Type 1 binding 28k protein [3-H] -glucose uptake diabetes Type 2 diabetes
- Insulin precursor adipose most assay.
- GBP28 GBP28; ACRP30; Mellitus (NIDDM) ; Insulin-
- Hyperglycemia Familial combined hyperlipidemia
- C Peptide An insulin precursor C-peptide concentrations Diabetes; Diabetes Insipidus;
- Diabetes mellitus Type 1 regulation assays well known in the diabetes
- Type 2 diabetes Type 2 diabetes
- Insulin art such as the one resistance; Insulin deficiency; described in PNAS Hyperlipidemia; Hyperketonemia;
- Hyperglycemia Familial combined hyperlipidemia
- HCBOG68 enteric Controls proliferation/ Activation of cAMP- Treatment of Obesity; treatment adipokine; Fat SID; differentiation or mediated transcription in of Diabetes; suppression of body proline rich acidic metabolism/ adipocytes can be weight gain; suppression of protein) physiology/pathology/ assayed using methods appetite. Hyperglycemia;
- adipocytes adipocytes and known in the art (Berger Diabetes; Diabetes Insipidus; adipose tissue in et al, Gene 66: 1- 10 Diabetes mellitus; Type 1 response to dietary (1998) ; Cullen and diabetes; Type 2 diabetes; Insulin conditions. Malm, Methods in resistance; Insulin deficiency;
- NIDDM Proc Natl Acad Sci USA Mellitus
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Abstract
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Priority Applications (7)
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AU2012222833A AU2012222833B2 (en) | 2011-03-03 | 2012-03-02 | Multivalent heteromultimer scaffold design and constructs |
JP2013555717A JP6101638B2 (en) | 2011-03-03 | 2012-03-02 | Multivalent heteromultimer scaffold design and construction |
CA2828811A CA2828811C (en) | 2011-03-03 | 2012-03-02 | Multivalent heteromultimer scaffold design and constructs |
DK12751893.4T DK2681245T3 (en) | 2011-03-03 | 2012-03-02 | MULTIVALENT HEAT-MULTIMED SCAFFOLD DESIGN AND CONSTRUCTIONS |
CN201280021368.5A CN103732628B (en) | 2011-03-03 | 2012-03-02 | Multivalence heteropolymer frame design and construct |
ES12751893.4T ES2676878T3 (en) | 2011-03-03 | 2012-03-02 | Multivalent heteromultimer frame design and constructs |
EP12751893.4A EP2681245B1 (en) | 2011-03-03 | 2012-03-02 | Multivalent heteromultimer scaffold design and constructs |
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US201161449016P | 2011-03-03 | 2011-03-03 | |
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JP (1) | JP6101638B2 (en) |
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CA (1) | CA2828811C (en) |
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CN103732628B (en) | 2017-06-23 |
US9499605B2 (en) | 2016-11-22 |
CA2828811A1 (en) | 2012-09-07 |
CA2828811C (en) | 2021-09-21 |
AU2012222833B2 (en) | 2017-03-16 |
EP2681245B1 (en) | 2018-05-09 |
JP2014512343A (en) | 2014-05-22 |
US20190127443A1 (en) | 2019-05-02 |
US10155803B2 (en) | 2018-12-18 |
JP6101638B2 (en) | 2017-03-22 |
DK2681245T3 (en) | 2018-08-13 |
ES2676878T3 (en) | 2018-07-25 |
US20120244577A1 (en) | 2012-09-27 |
US20210009659A1 (en) | 2021-01-14 |
EP2681245A1 (en) | 2014-01-08 |
EP2681245A4 (en) | 2015-02-18 |
US10711051B2 (en) | 2020-07-14 |
AU2012222833A1 (en) | 2013-09-26 |
US20170174745A1 (en) | 2017-06-22 |
CN103732628A (en) | 2014-04-16 |
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