Claims for Patent: 7,906,121

Summary for Patent: 7,906,121

Title:	Methods and compositions for generating bioactive assemblies of increased complexity and uses
Abstract:	The present invention concerns methods and compositions for making and using bioactive assemblies of defined compositions, which may have multiple functionalities and/or binding specificities. In particular embodiments, the bioactive assembly is formed using dock-and-lock (DNL) methodology, which takes advantage of the specific binding interaction between dimerization and docking domains (DDD) and anchoring domains (AD) to form the assembly. In various embodiments, one or more effectors may be attached to a DDD or AD sequence. Complementary AD or DDD sequences may be attached to an adaptor module that forms the core of the bioactive assembly, allowing formation of the assembly through the specific DDD/AD binding interactions. Such assemblies may be attached to a wide variety of effector moieties for treatment, detection and/or diagnosis of a disease, pathogen infection or other medical or veterinary condition.
Inventor(s):	Chang; Chien-Hsing (Downingtown, PA), Goldenberg; David M. (Mendham, NJ), McBride; William J. (Boonton, NJ), Rossi; Edmund A. (Woodland Park, NJ)
Assignee:	IBC Pharmaceuticals, Inc. (Morris Plains, NJ)
Application Number:	12/417,917
Patent Claims:	1. A method of delivering a diagnostic or therapeutic agent comprising: a) obtaining a complex comprising, (i) an adaptor module selected from the group consisting of HSP70, .alpha..sub.2 macroglobulin, HSA (human serum albumin), hP1 (human protamine 1), a heat shock protein, a human protamine and an Fc fragment of a human antibody; (ii) a first peptide and a second peptide, each peptide attached to the adaptor module and each peptide consisting of an AD moiety or a DDD moiety, wherein the AD moiety consisting of the peptide sequence from an anchoring domain of an AKAP (A-kinase anchoring protein) and the DDD moiety consisting of the peptide sequence from a dimerization and docking domain of protein kinase A RI.alpha., RI.beta., RII.alpha. or RII.beta. wherein the AD moiety consisting of peptide sequence selected from the group consisting of AD2 (SEQ ID NO: 2) and AD3 (SEQ ID NO: 5) and the DDD moiety consisting of the peptide sequence selected from the group consisting of DDD2 (SEQ ID NO: 1), DDD3 (SEQ ID NO:3) and DDD3C (SEQ ID NO:4); and (iii) at least one diagnostic agent or therapeutic agent attached to the first or second peptide; and b) administering the complex to a subject. 2. The method of claim 1, wherein the first peptide consisting of AD2 (SEQ ID NO:2), the second peptide consisting of AD3 (SEQ ID NO:5) and the complex further comprises a first effector attached to DDD2 (SEQ ID NO:1) and a second effector attached to DDD3C (SEQ ID NO:4), wherein two DDD2 (SEQ ID NO:1) form a dimer that binds to AD2 (SEQ ID NO:2) and two DDD3C (SEQ ID NO:4) form another dimer that binds to AD3 (SEQ ID NO:5). 3. The method of claim 1, wherein the first peptide consisting of DDD2 (SEQ ID NO:1), the second peptide consisting of DDD3C (SEQ ID NO:4) and the complex further comprises a first effector attached to AD2 (SEQ ID NO:2) and a second effector attached to AD3 (SEQ ID NO:5), wherein two DDD2 (SEQ ID NO:1) form a dimer that binds to the AD2 (SEQ ID NO:2) and two DDD3C (SEQ ID NO:4) form another dimer that binds to the AD3 (SEQ ID NO:5). 4. The method of claim 1, wherein the first peptide consisting of AD2 (SEQ ID NO:2), the second peptide consisting of DDD3 (SEQ ID NO:3) and the complex further comprises a first effector attached to DDD2 (SEQ ID NO:1), wherein two DDD2 (SEQ ID NO:1) form a dimer that binds to AD2 (SEQ ID NO:2) and two DDD3 (SEQ ID NO:3) form another dimer. 5. The method of claim 1, wherein the first peptide consisting of AD2 (SEQ ID NO:2), the second peptide consisting of DDD3C (SEQ ID NO:4) and the complex further comprises a first effector attached to DDD2 (SEQ ID NO:1) and a second effector attached to AD3 (SEQ ID NO:5), wherein two DDD2 (SEQ ID NO:1) form a dimer that binds to AD2 (SEQ ID NO:2) and two DDD3C (SEQ ID NO:4) form another dimer that binds to AD3 (SEQ ID NO:5). 6. The method of claim 1, wherein one peptide is attached to the N-terminal end of the adaptor module and the other peptide is attached to the C-terminal end of the adaptor module. 7. The method of claim 1, wherein the at least one diagnostic agent or therapeutic agent are selected from the group consisting of an antibody, an antigen-binding antibody fragment thereof and a cytokine and wherein the antibody or antigen-binding antibody fragment thereof has a binding affinity for a tumor-associated antigen. 8. The method of claim 7, wherein the antibody fragment is selected from the group consisting of a Fab, a Fab', a Fv, a scFv and a single domain (DAB) antibody fragments. 9. The method of claim 7, wherein the cytokine is selected from the group consisting of G-CSF, interferon-.beta.1a, interferon-.alpha.2b and erythropoietin. 10. The method of claim 7, wherein the at least one therapeutic agents are antibodies or antigen-binding 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, anti-CD2 X anti-CD147, anti-CEACAM5 X anti-CD3, anti-CEACAM6 X anti-CD3, anti-EGFR X anti-CD3, anti-HER2/neu X anti-CD3, anti-CD20 X anti-CD3, anti-CD74 X anti-CD3 and anti-CCD22 X anti-CD3. 11. The method of claim 7, wherein therapeutic agent effector is selected from the group consisting of LL1 (anti-CD74), LL2 (anti-CD22), RFB4 (anti-CD22), A20 (anti-CD20), L243 (anti-HLA class II), CC49 (anti-TAG-72), MN-14 (anti-CEA), MN-15 (anti-CEA), 679 (anti-HSG), 734 (anti-In-DTPA), L19 (anti-ED-B fibronectin), R1 (anti-IGF-1R), PAM4 (anti-MUC1), RS7 (anti-EGP-1), adalimumab, infliximab, omalizumab and palivizumab. 12. The method of claim 7, wherein the antibody or antigen-binding antibody fragment is human, humanized or chimeric. 13. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of a chemotherapeutic agent, a cytokine, a chemokine, an anti-angiogenic agent, an apoptotic agent, a drug, a prodrug, a toxin, an enzyme, boron, a radioisotope, an immunomodulator, an antibiotic and a hormone. 14. The method of claim 13, wherein the therapeutic agent is selected from the group consisting of 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, celecoxib, chlorambucil, chloramphenicol, ciprofloxacin, 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, nitrosourea, nystatin, ranpirnase, oxacillin, paromomycin, penicillin, pentamidine, piperacillin, tazobactam, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, pokeweed antiviral protein, 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, bortezomib, vinblastine, vinorelbine, vincristine, zanamivir and zithromycin. 15. The method of claim 13, wherein the radioisotope is selected from the group consisting of .sup.212Pb, .sup.212Bi, .sup.213Bi, .sup.211At, .sup.223Ra, .sup.225Ac, .sup.32P, .sup.33P, .sup.47Sc, .sup.67Cu, .sup.67Ga, .sup.89Sr, .sup.90Y, .sup.111Ag, .sup.125I, .sup.131I, .sup.142Pr, .sup.161Tb, .sup.166Ho, .sup.166Dy, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re), .sup.111In, .sup.125I, .sup.67Ga, .sup.191Os, .sup.193mPt, .sup.195mPt and .sup.195mHg. 16. The method of claim 13, wherein the toxin is selected from the group consisting of ricin, abrin, ribonuclease, ranpirnase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin and Pseudomonas endotoxin. 17. The method of claim 1, wherein the diagnostic agent is selected from the group consisting of a radioisotope, a dye, a contrast agent, a fluorescent agent, an imaging agent, a chemiluminescent agent, a bioluminescent agent, a liposome and a paramagnetic ion. 18. The method of claim 17, wherein the paramagnetic ion 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). 19. The method of claim 17, wherein the radioisotope is selected from the group consisting of astatine.sup.211, carbon.sup.14, chromium.sup.51, chlorine.sup.36, cobalt.sup.57, cobalt.sup.58, copper.sup.62, copper.sup.64, Eu.sup.152, fluorine.sup.18, gallium.sup.67, gallium.sup.68, hydrogen.sup.3, iodine.sup.123, iodine.sup.124,iodine .sup.125, iodine.sup.131, indium.sup.111, iron.sup.52, iron.sup.59, lutetium.sup.177, phosphorus.sup.32, phosphorus.sup.33, rhenium.sup.186, rhenium.sup.188, Sc.sup.47, selenium.sup.75, silver.sup.111, sulphur.sup.35, technetium.sup.94m, technetium.sup.99m, yttrium.sup.86, yttrium.sup.90 and zirconium.sup.89. 20. The method of claim 17, wherein the fluorescent agent 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-T, 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, allophycocyanin B, phycocyanin C, phycocyanin R, thiamine, phycoerythrocyanin, phycoerythrin R, REG, Rhodamine Green, rhodamine isothiocyanate, Rhodamine Red, ROX, TAMRA, TET, TRIT (tetramethyl rhodamine isothiol), Tetramethylrhodamine, Edans and Texas Red. 21. The method of claim 17, wherein the chemiluminescent agent is selected from the group consisting of luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester. 22. The method of claim 1 wherein the subject has cancer. 23. The method of claim 22, further comprising administering one or more anti-cancer therapies in combination with the complex. 24. The method of claim 23, 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. 25. The method of claim 22, wherein the cancer is acute lymphocytic 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 and other brain and spinal cord tumors, sarcomas, liver cancer, prostate cancer, melanoma or urinary bladder cancer.

Details for Patent 7,906,121

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