Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses

• US 20060228357A1
• Filed: 03/24/2006
• Published: 10/12/2006
• Est. Priority Date: 04/06/2005
• Status: Active Grant

• Current Assignee: IBC Pharmaceuticals Inc.
• Original Assignee: IBC Pharmaceuticals Inc.
• Inventors: McBride, William J., Goldenberg, David M., Rossi, Edmund A., Chang, Chien Hsing
• Granted Patent: US 7,550,143 B2
• Time in Patent Office: Days
• US Class Current: 424/144.100
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3007 Carcino-embryonic Antigens
• CPC Class Codes: C07K 16/3092 against tumour-associated mucins
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/70 containing domain for protein-protein interaction
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/11011 : cAMP-dependent protein kinase (2.7.11.11)

Abstract

The present invention concerns methods and compositions for stably tethered structures of defined compositions, which may have multiple functionalities and/or binding specificities. Particular embodiments concern homodimers comprising monomers that contain a dimerization and docking domain attached to a precursor. The precursors may be virtually any molecule or structure, such as antibodies, antibody fragments, antibody analogs or mimetics, aptamers, binding peptides, fragments of binding proteins, known ligands for proteins or other molecules, enzymes, detectable labels or tags, therapeutic agents, toxins, pharmaceuticals, cytokines, interleukins, interferons, radioisotopes, proteins, peptides, peptide mimetics, polynucleotides, RNAi, oligosaccharides, natural or synthetic polymeric substances, nanoparticles, quantum dots, organic or inorganic compounds, etc. Other embodiments concern tetramers comprising a first and second homodimer, which may be identical or different. The disclosed methods and compositions provide a facile and general way to obtain homodimers, homotetramers and heterotetramers of virtually any functionality and/or binding specificity.

Claims

1. A composition comprising a homodimer, each monomer of the homodimer comprising a dimerization and docking domain (DDD) attached to a precursor.

2. The composition of claim 1, wherein the DDD comprises the sequence of SEQ ID NO:

1 (DDD1) or SEQ ID NO;

2 (DDD2).

3. The composition of claim 1, wherein the monomer is a fusion protein comprising the precursor and the DDD.

4. The composition of claim 1, wherein the precursor is chemically linked to the DDD.

5. The composition of claim 3, further comprising a linker peptide between the precursor and the DDD.

6. The composition of claim 1, wherein the precursor comprises a protein, peptide, peptide mimetic, polynucleotide, RNAi, oligosaccharide, avimer, aptamer, antibody, antibody fragment, natural or synthetic polymeric substance, nanoparticle, quantum dot, organic compound or inorganic compound.

7. The composition of claim 3, wherein the precursor is an Fd fragment of an antibody.

8. The composition of claim 7, further comprising the light chain of the antibody.

9. The composition of claim 8, wherein the light chain binds to the Fd fragment to form an Fab fragment.

10. The composition of claim 6, wherein the antibody or fragment thereof is a humanized antibody, human antibody or chimeric antibody.

11. The composition of claim 9, wherein the Fab fragment is selected from the group consisting of the Fab fragments of hMN-14, L19, hA20, hLL2, L243, hCC49, 7E3, hLL1, hPAM4, hRS7, rH1, L49, anti-CD14, anti-CD111, Humira®

, REMICADE®

, Xolair®

, Synagis® and

hMN-15.

12. The composition of claim 6, wherein the precursor comprises a protein selected from the group consisting of a bacterial toxin, a plant toxin, ricin, abrin, a ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Pseudomonas exotoxin, Pseudomonas endotoxin, Ranpimase (Rap), Rap (N69Q), PE38, dgA, DT390, PLC, tPA, a cytokine, a growth factor, a soluble receptor component, surfactant protein D, IL-4, sIL-4R, sIL-13R, VEGF₁₂₁, TPO, EPO, a clot-dissolving agent, an enzyme, a fluorescent protein, sTNFα

-R, an avimer, a scFv, a dsFv and a nanobody.

13. The composition of claim 6, wherein the precursor comprises a polypeptide fused to an immunoglobulin light chain (VL-CL) or an immunoglobulin Fc domain (CH2-CH3).

14. The composition of claim 13, wherein the cysteine at the carboxyl-terminus of the CL that connects the CL to CH1 is deleted or mutated to a non-cysteine.

15. The composition of claim 13, wherein the immunoglobulin light chain or the Fc domain is selected from a human or humanized antibody.

16. The composition of claim 1, wherein the DDD sequence is derived from the regulatory subunits of cAMP-dependent protein kinase (PKA).

17. The composition of claim 6, wherein the precursor has at least one binding site for carbonic anhydrase IX, alpha-fetoprotein, A3, antigen specific for A33 antibody, Ba 733, BrE3-antigen, CA125, CD1, CD1a, CD3, CD5, CD15, CD16, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD33, CD38, CD45, CD74, CD79a, CD80, CD138, colon-specific antigen-p (CSAp), CEA (CEACAM5), CEACAM6, CSAp, EGFR, EGP-1, EGP-2, Ep-CAM, Flt-1, Flt-3, folate receptor, HLA-DR, human chorionic gonadotropin (HCG) and its subunits, HER2/neu, hypoxia inducible factor (HIF-1), Ia, IL-2, IL-6, IL-8, insulin growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUC1, MUC2, MUC3, MUC4, NCA66, NCA95, NCA90, antigen specific for PAM-4 antibody, placental growth factor, p53, prostatic acid phosphatase, PSA, PSMA, RS5, S100, TAC, TAG-72, tenascin, TRAIL receptors, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGF, ED-B fibronectin, 17-1A-antigen, an angiogenesis marker, an oncogene marker or an oncogene product.

18. The composition of claim 1, further comprising one or more effectors or carriers conjugated to the homodimer by either covalent or non-covalent linkage.

19. The composition of claim 18, wherein the effector is a diagnostic agent, a therapeutic agent, a chemotherapeutic agent, a radioisotope, an imaging agent, an anti-angiogenic agent, a cytokine, a chemokine, a growth factor, a drug, a prodrug, an enzyme, a binding molecule, a ligand for a cell surface receptor, a chelator, an immunomodulator, an oligonucleotide, a hormone, a photodetectable label, a dye, a peptide, a toxin, a contrast agent, a paramagnetic label, an ultrasound label, a pro-apoptotic agent, a liposome, a nanoparticle or a combination thereof.

20. The composition of claim 19, wherein the anti-angiogenic agent is angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies or peptides, anti-placental growth factor antibodies or peptides, anti-Flk-1 antibodies, anti-Flt-1 antibodies or peptides, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin 12, IP-10, Gro-β

, thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM101, Marimastat, pentosan polysulphate, angiopoietin 2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 or minocycline.

21. The composition of claim 19, wherein the therapeutic agent is abrin, amantadine, amoxicillin, amphotericin B, ampicillin, aplidin, azaribine, anastrozole, azacytidine, aztreonam, azithromycin, bacitracin, bactrim, Batrafen®

, bifonazole, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carbenicillin, caspofungin, carmustine, cefaclor, cefazolin, cephalosporins, cefepime, ceftriaxone, cefotaxime, celebrex, chlorambucil, chloramphenicol, Cipro®

, cisplatin, irinotecan (CPT-11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, diphtheria toxin, DNase I, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), doxycycline, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, estrogen receptor binding agents, etoposide, etoposide glucuronide, etoposide phosphate, erythrocycline, erythromycin, flagyl, farnesyl-protein transferase inhibitors, floxuridine (FUdR), 3′

,5′

-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, ganciclovir, gentamycin, gelonin, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, isoniazid, itraconazole, kanamycin, ketoconazole, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, minocycline, naftifine, nalidixic acid, neomycin, navelbine, nitrosurea, nystatin, onconase, oxacillin, paromomycin, penicillin, pentamidine, piperacillin-tazobactam, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, pokeweed antiviral protein, PSI-341, Pseudomonas exotoxin, Pseudomonas endotoxin, raloxifene, rapLR1, ribonuclease, ricin, semustine, rifabutin, rifampin, rimantadine, streptomycin, sulfamethoxazole, sulfasalazine, Staphylococcal enterotoxin-A, streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, tetracycline, thalidomide, thioguanine, thiotepa, teniposide, topotecan, transplatinum, trimethoprim sulfamethoxazole, uracil mustard, valacyclovir, vancomycin, velcade, vinblastine, vinorelbine, vincristine, zanamir, zithromycin, an antisense oligonucleotide, an interference RNA, or a combination thereof.

22. The composition of claim 19, wherein the diagnostic or therapeutic agent is selected from the group consisting of ²²⁵Ac, ²¹¹At, ²¹²Bi, ²¹³Bi, ¹⁴C, ⁵¹Cr, ³⁶Cl, ⁴⁵Ti, ⁵⁷Co, ⁵⁸Co, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ¹⁶⁶Dy, ¹⁵²Eu, ¹⁸F, ⁶⁷Ga, ⁶⁸Ga, ^195mHg, ¹⁶⁶Ho, ³H, ¹¹¹In, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ⁵²Fe, ⁵⁹Fe ¹⁷⁷Lu, ¹⁹¹Os, ²¹²Pb, ³²P, ³³P, ¹⁴²Pr, ^195mPt, ²²³Ra, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ⁴⁷Sc, ⁷⁵Se ¹¹¹Ag, ¹⁵³Sm, ⁸⁹Sr, ³⁵S, ¹⁶¹Tc, ^94mTc, ^99mTc, ⁸⁶Y, ⁹⁰Y, and ⁸⁹Zr.

23. The composition of claim 19, wherein the imaging agent is selected from the group consisting of chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) erbium (III), lanthanum (III), gold (III), lead (II) and bismuth (III).

24. The composition of claim 19, wherein the photodetectable label is selected from the group consisting of Alexa 350, Alexa 430, AMCA, aminoacridine, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, 5-carboxy-4′

,5′

-dichloro-2′

,7′

-dimethoxy fluorescein, 5-carboxy-2′

,4′

,5′

,7′

-tetrachlorofluorescein, 5-carboxyfluorescein, 5-carboxyrhodamine, 6-carboxyrhodamine, 6-carboxytetramethyl amino, Cascade Blue, Cy2, Cy3, Cy5,6-FAM, dansyl chloride, Fluorescein, HEX, 6-JOE, NBD (7-nitrobenz-2-oxa-1,3-diazole), Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, phthalic acid, terephthalic acid, isophthalic acid, cresyl fast violet, cresyl blue violet, brilliant cresyl blue, para-aminobenzoic acid, erythrosine, phthalocyanines, azomethines, cyanines, xanthines, succinylfluoresceins, rare earth metal cryptates, europium trisbipyridine diamine, a europium cryptate or chelate, diamine, dicyanins, La Jolla blue dye, allopycocyanin, allococyanin B, phycocyanin C, phycocyanin R, thiamine, phycoerythrocyanin, phycoerythrin R, REG, Rhodamine Green, rhodamine isothiocyanate, Rhodamine Red, ROX, TAMRA, TET, TRIT (tetramethyl rhodamine isothiol), Tetramethylrhodamine, and Texas Red.

25. The composition of claim 18, wherein the effectors or carriers are chemically cross-linked to the homodimer.

26. The composition of claim 18, wherein the homodimer is attached to two or more effectors or two or more carriers.

27. The composition of claim 26, wherein the two or more carriers or two or more effectors are either identical or different.

28. The composition of claim 18, wherein the one or more carriers comprise at least one diagnostic or therapeutic agent.

29. A composition comprising two homodimers according to claim 1, wherein two homodimers are covalently bound to form a tetramer.

30. The composition of claim 29, wherein the DDD comprises the sequence of SEQ ID NO:

2 (DDD2).

31. The composition of claim 30, wherein the two homodimers are covalently bound by disulfide bonds between the DDD2 sequences.

32. The composition of claim 30, wherein the two homodimers in the tetramer are identical.

33. The composition of claim 30, wherein the two homodimers in the tetramer are different.

34. The composition of claim 29, wherein the first homodimer comprises a first monomer that comprises a DDD sequence linked to a first precursor and the second homodimer comprises a second monomer that comprises a DDD sequence linked to a second precursor.

35. The composition of claim 34, wherein the two homodimers are held together by disulfide bonds between the DDD moieties of each of the homodimers.

36. The composition of claim 34, wherein the first precursor and second precursor have binding affinities for target molecules, composites, aggregates, cells, antigens or tissues.

37. The composition of claim 36, wherein the first and second precursors have affinities for the same target molecules, composites, aggregates, cells, antigens or tissues.

38. The composition of claim 36, wherein the first and second precursors have affinities for two different target molecules, composites, aggregates, cells, antigens or tissues.

39. The composition of claim 34, wherein the first precursor has a binding site for a target molecule, composite, aggregate, cell, antigen or tissue and the second precursor has a binding site for a hapten.

40. The composition of claim 34, wherein the first precursor has a binding affinity for a cell surface receptor, alkaline phosphatase, horseradish peroxidase, β

-galactosidase, tpA, streptokinase, hirudin, urokinase, CA19-9, CEA, CEACAM6, CD19, CD20, CD22, CD30, CD33, CD40, CD74, ED-B fibronectin, EGFR, G_D2, G250-antigen, HER2/neu, hTR, HLA class II, HMWMAA, HN/NDV, IGF1R, IL-2R/Tac, IL-17, MUC, PSMA, M13 coat protein, GpIIb/IIIa, CD74, EGP-1, CD25/Tac, Le^Y, mesothelin, Erb-B2, Erb-B3, EpCAM, GP240, GPIIb/IIIa, p97, CD3, IL-4R, IL-4, IL-13, VEGFR-2, CD14, CD111/nectin-1, folate receptor α

, gp120, IL-6, 11-5, IL-8, CD154, IgE, LFA-1, β

-tryptase, CD105/endoglin, TNFα

, RSV F-protein, A1B1 of CEA, N domain of CEA, PfMSP-1, TAG-72, MUC1, MUC2, MUC3, MUC4, VEFGR1/Flt-1, VEGFR2/KDR or VEGRF3fFlt-4.

41. The composition of claim 34, wherein the second precursor has a binding affinity for IL-17, histamine-succinyl-glycine (HSG), indium-DTPA, CD22, CD20, EGFR, IGF1R, VEFGR1/Flt-1, VEGFR2/KDR, VEGRF3/Flt-4, CD3, CD16, CD64, CD89, CD2, adenovirus fiber knob, M13 coat protein, GpIIb/IIIa, alkaline phosphatase, horseradish peroxidase, β

-galactosidase, tpA, streptokinase, hirudin or urokinase.

42. The composition of claim 34, wherein the first precursor has an affinity for a cell surface antigen selected from the group consisting of CEA, ED-B fibronectin, CD20, CD22, CD19, EGFR, IGF1R, VEFGR1/Flt-1, VEGFR2/KDR, VEGRF3/Flt-4, HER2/neu, CD30, CD33, PfMSP-1, HN/NDV, EpCAM/17-1A, hTR, IL-2R/Tac, CA19-9, MUC1, HLA class II, G_D2, G250, TAG-72, PSMA, CEACAM6, HMWMAA, CD40, M13 coat protein, and GPIIb/IIIa, and wherein the second precursor has an affinity either for a hapten selected from the group consisting of histamine-succinyl-glycine (HSG) and indium-DTPA, or for a cell surface antigen selected from the group consisting of CD22, CD20, EGFR, IGF1R, VEFGR1/Flt-1, VEGFR2/KDR, VEGRF3/Flt-4, CD3, CD16, CD64, CD89, CD2, and adenovirus fiber knob.

43. The composition of claim 34, wherein the first precursor has an affinity either for a cell surface antigen selected from the group consisting of M13 coat protein and GpIIb/IIIa, or for a biomolecule selected from the group consisting of alkaline phosphatase, horseradish peroxidase, β

-galactosidase, tpA, streptokinase, hirudin, and urokinase, and wherein the second precursor has an affinity either for a cell surface antigen selected from the group consisting of M13 coat protein and GpIIb/IIIa, or for a biomolecule selected from the group consisting of alkaline phosphatase, horseradish peroxidase, β

-galactosidase, tpA, streptokinase, hirudin, and urokinase,

44. The composition of claim 34, wherein the first precursor has an affinity for a cell surface antigen selected from the group consisting of CD3, CD74, CD19, CD22, MUC1, EGP-1, IGF1R CD30, CD25/Tac, LeY, mesothelin, Erb-B2, EpCAM, GP240, GPIIb/IIIa, and p97, and wherein the second precursor is selected from the group consisting of a ribonuclease, Ranpimase, a bacterial toxin, a plant toxin, PE38, dgA, DT390, phospholipase C (PLC), gelonin, a clot-dissolving protein, tPA, urokinase and hirudin.

45. The composition of claim 34, wherein the first precursor has an affinity for any cell surface antigen associated with a disease or a medical condition and the second precursor is selected from the group consisting of a cytokine, a growth factor, carboxypeptidase G2, penicilliamidase, β

-lactamase, cytosine deaminase, nitroreductase, β

-galactosidase, green fluorescence protein (GFP) or its various engineered analogs, alkaline phosphatase, horseradish peroxidase, and streptavidin.

46. The composition of claim 34, wherein the first precursor is selected from the group consisting of a ribonuclease, a bacterial toxin, a plant toxin, a cytokine, a growth factor and surfactant protein D (Sp-D), and the second precursor has an affinity for any cell surface antigen associated with a disease or a medical condition.

47. The composition of claim 34, wherein the first precursor and the second precursor are selected from the group consisting of a ligand for a cell surface receptor, IL-4, VEGF₁₂₁, a soluble receptor component, sIL-4R, sIL-13R, a toxin, PE38, shiga-like toxin and diphtheria toxin.

48. The composition of claim 34, wherein the first and the second precursors are the same and are selected from the group consisting a binding molecule for CD14, CD11/nectin-1, folate receptor α

, gp120, IL-6, IL-5, IL-8, CD154, IgE, LFA-1, β

-tryptase, CD105/endoglin, GpIIb/IIIa, TNFα

, RSV F-protein, A1B1 of CEA, and N-domain of CEA.

49. The composition of claim 34, wherein the first and the second precursors are the same and are selected from the group consisting a cytokine, a growth factor, a soluble receptor component, tPA, TPO, EPO, and sTNFα

-R.

50. A method comprising:

a) obtaining a homodimer according to claim 1;

and

b) administering the homodimer to a subject with a condition;

wherein the homodimer has a therapeutic effect on the condition.

51. The method of claim 50, wherein the condition is cancer, hyperplasia, diabetic retinopathy, juvenile diabetes, macular degeneration, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, rheumatoid arthritis, sarcoidosis, asthma, edema, pulmonary hypertension, psoriasis, comeal graft rejection, neovascular glaucoma, Osler-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, restenosis, neointima formation after vascular trauma, telangiectasia, hemophiliac joints, angiofibroma, fibrosis associated with chronic inflammation, lung fibrosis, deep venous thrombosis or wound granulation.

52. The method of claim 51, wherein the condition is cancer and the precursor has a binding affinity for a tumor-associated antigen selected from the group consisting of carbonic anhydrase IX, alpha-fetoprotein, A3, antigen specific for A33 antibody, Ba 733, BrE3-antigen, CA125, CD1, CD1a, CD3, CD5, CD15, CD16, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD33, CD38, CD45, CD74, CD79a, CD80, CD138, colon-specific antigen-p (CSAp), CEA (CEACAM5), CEACAM6, EGFR, EGP-1, EGP-2, Ep-CAM, Flt-1, Flt-3, folate receptor, G250 antigen, HLA-DR, human chorionic gonadotropin (HCG) and its subunits, HER2/neu, hypoxia inducible factor (HIF-1), Ia, IL-2, IL-6, IL-8, insulin growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUC1, MUC2, MUC3, MUC4, NCA66, NCA95, NCA90, antigen specific for PAM-4 antibody, placental growth factor, p53, prostatic acid phosphatase, PSA, PSMA, RS5, S100, TAC, TAG-72, tenascin, TRAIL receptors, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGF, ED-B fibronectin, 17-1A-antigen, an angiogenesis marker, an oncogene marker and an oncogene product.

53. The method of claim 52, wherein the cancer is acute lymphoblastic leukemia, acute myelogenous leukemia, renal cell carcinoma, biliary cancer, brain cancers, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, Hodgkin'"'"'s lymphoma, lung cancer, medullary thyroid cancer, non-Hodgkin'"'"'s lymphoma, ovarian cancer, testicular cancer, pancreatic cancer, glioma, liver cancer, prostate cancer, melanoma or urinary bladder cancer.

54. The method of claim 53, further comprising administering one or more anti-cancer therapies in combination with the homodimer.

55. The method of claim 54, wherein the therapy comprises administering a chemotherapeutic agent, a cytokine, radiation therapy, immunotherapy, radioimmunotherapy, localized hyperthermia, laser irradiation, an anti-angiogenic agent or surgical excision.

56. A method comprising:

a) obtaining a tetramer according to claim 34;

and

b) administering the tetramer to a subject with a condition;

wherein the tetramer has a therapeutic effect on the condition.

57. The method of claim 56, further comprising administering to the subject a hapten that binds to the second precursor.

58. The method of claim 57, wherein the hapten is administered after the tetramer has localized to a tissue associated with the condition.

59. The method of claim 58, wherein the hapten is attached to an agent selected from the group consisting of an anti-angiogenic agent, a chemotherapeutic agent, a cytokine, a drug, a prodrug, a toxin, an enzyme, an oligonucleotide, a radioisotope, an immunomodulator, an antibiotic, an anti-viral agent, an anti-fungal agent, a hormone, a binding molecule, a lipid, a polymer, a micelle, a liposome, a nanoparticle or a combination thereof.

60. The method of claim 59, wherein the condition is caused by a fungus.

61. The method of claim 60, wherein the fungus is Microsporum, Trichophyton, Epidermophyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis or Candida albican.

62. The method of claim 59, wherein the condition is caused by a virus.

63. The method of claim 62, wherein the virus is human immunodeficiency virus (HIV), herpes virus, cytomegalovirus, rabies virus, influenza virus, human papilloma virus, hepatitis B virus, hepatitis C virus, Sendai virus, feline leukemia virus, Reo virus, polio virus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein-Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus or blue tongue virus.

64. The method of claim 59, wherein the condition is caused by a bacterium.

65. The method of claim 64, wherein the bacterium is Bacillus anthracis, Streptococcus agalactiae, Legionella pneumophilia, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitidis, Pneumococcus spp., Hemophilis influenzae B, Treponema pallidum, Lyme disease spirochetes, Pseudomonas aeruginosa, Mycobacterium leprae, Brucella abortus, Mycobacterium tuberculosis or a Mycoplasma.

66. The method of claim 59, wherein the condition is an autoimmune disease.

67. The method of claim 66, wherein the autoimmune disease is acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham'"'"'s chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, juvenile diabetes mellitus, Henoch-Schonlein purpura, post-streptococcalnephritis, erythema nodosum, Takayasu'"'"'s arteritis, Addison'"'"'s disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture'"'"'s syndrome, thromboangitisubiterans, Sjogren'"'"'s syndrome, primary biliary cirrhosis, Hashimoto'"'"'s thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pemphigus vulgaris, Wegener'"'"'s granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, psoriasis or fibrosing alveolitis.

68. The method of claim 59, wherein the condition is myocardial infarction, ischemic heart disease, atherosclerotic plaques, graft rejection, Alzheimer'"'"'s disease, atopic tissue or inflammation caused by accretion of activated granulocytes, monocytes, lymphoid cells or macrophages.

69. A method of diagnosing a condition comprising:

a) obtaining a tetramer according to claim 34, wherein the first precursor binds to a target molecule, composite, aggregate, cell, antigen or tissue associated with the condition and the second precursor binds to a diagnostic hapten;

b) administering the tetramer to a subject suspected of having a condition;

c) administering to the same subject a diagnostic hapten that binds to the second precursor; and

d) detecting the presence of the hapten bound to the tetramer;

wherein localization of the hapten to a tissue associated with the condition is diagnostic of the presence of the condition in the subject.

70. The method of claim 69, wherein the hapten is conjugated to a radionuclide selected from the group consisting of ¹⁸F, ⁴⁵Ti, ⁵²Fe, ⁶²Cu, ⁶⁷Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, ^94mTc, ⁹⁴Tc, ⁹⁹mTc, ¹¹¹In, ¹²³I, ¹²⁵I, ^154-158Gd, ¹⁷⁷Lu, ³²P, ¹⁸⁸Re and ⁹⁰Y.

71. The method of claim 70, wherein the radionuclides are detected using an isotope detector or imaged using gamma scintigraphy, single photon emission computed tomography or positron emission tomography.

72. The method of claim 69, wherein the condition is cancer and the first precursor binds to a tumor-associated antigen selected from the group consisting of carbonic anhydrase IX, alpha-fetoprotein, A3, antigen specific for A33 antibody, Ba 733, BrE3-antigen, CA125, CD1, CD1a, CD3, CD5, CD15, CD16, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD33, CD45, CD74, CD79a, CD80, CD138, colon-specific antigen-p (CSAp), CEA (CEACAM5), CEACAM6, CSAp, EGFR, EGP-1, EGP-2, Ep-CAM, Flt-1, Flt-3, folate receptor, G250 antigen, HLA-DR, human chorionic gonadotropin (HCG) and its subunits, HER2/neu, hypoxia inducible factor (HIF-1), Ia, IL-2, IL-6, IL-8, insulin growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUC1, MUC2, MUC3, MUC4, NCA66, NCA95, NCA90, antigen specific for PAM-4 antibody, placental growth factor, p53, prostatic acid phosphatase, PSA, PSMA, RS5, S100, TAC, TAG-72, tenascin, TRAIL receptors, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGF, ED-B fibronectin, 17-1A-antigen, an angiogenesis marker, an oncogene marker and an oncogene product.

73. The method of claim 69, wherein the hapten is conjugated to a magnetic resonance imaging (MRI) contrast agent and the hapten bound to tetramer is detected by MRI.

74. The method of claim 73, wherein the MRI contrast agent is chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysporium (III), holmium (III) or erbium (III).

75. The method of claim 69, wherein the hapten is conjugated to an ultrasound imaging enhancing agent and the hapten bound to binary complex is detected by ultrasound imaging.

76. The method of claim 69, wherein either the first precursor or the second precursor has a binding affinity for CD19, CD20, CD22 or IL-17.

77. The method of claim 56, wherein administration of the tetramer induces apoptosis in a target cell population.

78. The method of claim 77, wherein the tetramer comprises a combination of antibodies or antibody fragments selected from the group consisting of anti-CD74 X anti-CD20, anti-CD74 X anti-CD22, anti-CD22 X anti-CD20, anti-CD20 X anti-HLA-DR, anti-CD19 X anti-CD20, anti-CD20 X anti-CD80, anti-CD2 X anti-CD25, anti-CD8 X anti-CD25, and anti-CD2 X anti-CD147.

79. The method of claim 77 wherein the first and/or second precursors have a binding affinity for an antigen selected from the group consisting of CD2, CD3, CD8, CD10, CD21, CD23, CD24, CD25, CD30, CD33, CD37, CD38, CD40, CD48, CD52, CD55, CD59, CD70, CD74, CD80, CD86, CD138, CD 147, HLA-DR, CEA, CSAp, CA-125, TAG-72, EFGR, HER2, HER3, HER4, IGF-1R, c-Met, PDGFR, MUC1, MUC2, MUC3, MUC4, TNFR1, TNFR2, NGFR, Fas (CD95), DR3, DR4, DR5, DR6, VEGF, PIGF, ED-B fibronectin, tenascin, PSMA, PSA, carbonic anhydrase IX, and IL-6.