Claims for Patent: 8,158,573

Summary for Patent: 8,158,573

Title:	Therapeutic and diagnostic conjugates for use with multispecific antibodies
Abstract:	Disclosed are compounds that include two or more haptens conjugated by a spacer or a carrier. The haptens may include diethylenetriaminepentaacetate (DTPA), histimine-succinyl-glutamine (HSG), or combinations of DTPA and HSG. The compound also includes an effector molecule which may be conjugated to one or more of the haptens, the spacer/carrier, or both. The effector molecule may be conjugated by a number of linkages including an ester linkage, an imino linkage, an amino linkage, a sulfide linkage, a thiosemicarbazone linkage, a semicarbazone linkage, an oxime linkage, an ether linkage, or combinations of these linkages. Also disclosed are methods of synthesizing the compounds and/or precursors of the compounds.
Inventor(s):	McBride; William J. (Boonton, NJ), Goldenberg; David M. (Mendham, NJ), Noren; Carl (Elizabeth, NJ), Hansen; Hans J. (Picayune, MS)
Assignee:	Immunomedics, Inc. (Morris Plains, NJ)
Application Number:	12/138,065
Patent Claims:	1. A compound comprising one or more of the sequences R.sup.1-Lys(X)-R.sup.2-Lys(Y) or Lys(X)-R.sup.2-Lys(Y)-R.sup.1, wherein (X) and (Y) are haptens selected from the group consisting of DTPA and HSG, wherein R.sup.1 and R.sup.2 are one or more amino acids, and wherein one or more effector molecules are conjugated to R.sup.1, R.sup.2, (X), or (Y). 2. The compound of claim 1, wherein DTPA is attached to an indium cation. 3. The compound of claim 1, wherein the effector molecule comprises one or more drugs, prodrugs, toxins, enzymes, oligonucleotides, radioisotopes, immunomodulators, cytokines, hormones, binding molecules, lipids, polymers, micelles, liposomes, nanoparticles, or combinations thereof. 4. The compound of claim 3, wherein the binding molecule comprises an antibody or a fragment thereof. 5. The compound of claim 1, wherein the effector molecule comprises aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, Pseudomonas endotoxin, an antisense oligonucleotide, an interference RNA, or combinations thereof. 6. The compound of claim 1, wherein the effector molecule comprises camptothecin, doxorubicin, a camptothecin derivative or a doxorubicin derivative. 7. The compound of claim 1, further comprising an isotope selected from .sup.18F, .sup.32P, .sup.33P, .sup.45Ti, .sup.47Sc, .sup.52Fe, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.75Se, .sup.77As, .sup.86Y, .sup.89Sr, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.94mTc, .sup.99Mo, .sup.99mTc, .sup.105Pd, .sup.105Rh, .sup.111Ag, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.153Sm, .sup.154-158Gd, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.169Er, .sup.175Lu, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.194Ir, .sup.198Au, .sup.199Au, .sup.211At, .sup.211Pb .sup.212Pb, .sup.212Pb, .sup.213Bi, .sup.223Ra, .sup.225Ac, or combinations thereof. 8. A method of treating and/or diagnosing a disease or condition that may lead to a disease in a patient comprising: (A) administering to the patient a bispecific antibody that has at least one arm that binds a targeted tissue and at least one other arm that binds a targetable construct; (B) optionally, administering to the patient a clearing composition and allowing the composition to clear non-localized bispecific antibodies from circulation; and (C) administering to the patient a targetable construct comprising the compound of claim 1. 9. The method of claim 8, wherein the effector molecule comprises one or more drugs, prodrugs, toxins, enzymes, radioisotopes, immunomodulators, oligonucleotides, cytokines, hormones, antibodies, or combinations thereof. 10. The method of claim 8, wherein the effector molecule comprises aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, 2-pyrrolinodoxorubicin (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, Pseudomonas endotoxin, an antisense oligonucleotide, an interference RNA, or combinations thereof. 11. The method of claim 8, wherein the effector molecule comprises camptothecin, doxorubicin, a camptothecin derivative or a doxorubicin derivative. 12. The method of claim 8, wherein the compound further comprises an isotope selected from .sup.18F, .sup.32P, .sup.33P, .sup.45Ti, .sup.47Sc, .sup.52Fe, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.75Se, .sup.77As, .sup.86Y, .sup.89Sr, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.94mTc, .sup.99Mo, .sup.99mTc, 105Pd, .sup.105Rh, .sup.111Ag, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.153Sm, .sup.154-158Gd, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.169Er, .sup.175Lu, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.194Ir, .sup.198Au, .sup.199Au, .sup.211At, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.223Ra, .sup.225Ac, or combinations thereof. 13. The method of claim 8, wherein the effector molecule comprises an enzyme selected from the group consisting of carboxylesterases, glucuronidases, carboxypeptidases, beta-lactamases, phosphatases, and mixtures thereof. 14. The method of claim 8, wherein the bispecific antibody comprises a human, chimeric or humanized antibody or a fragment of a human, chimeric or humanized antibody. 15. The method of claim 8, wherein the bispecific antibody comprises a fusion protein. 16. The method of claim 8, wherein the disease or condition comprises a malignant disease, a cardiovascular disease, an infectious disease, an inflammatory disease, an autoimmune disease, a metabolic disease, or a neurological disease. 17. The method of claim 16, wherein the disease or condition comprises a malignant disease and the targeted tissue comprises an antigen selected from the group consisting of carcinoembryonic antigen, tenascin, epidermal growth factor receptor, platelet derived growth factor receptor, fibroblast growth factor receptors, vascular endothelial growth factor receptors, gangliosides, HER/2neu receptors and mixtures thereof. 18. The method of claim 8, wherein the targeted tissue comprises a tumor. 19. The method of claim 18, wherein the tumor produces or is associated with antigens selected from the group consisting of colon-specific antigen-p (CSAp), carcinoembryonic antigen (CEA), CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD80, HLA-DR, Ia, Ii, MUC 1, MUC 2, MUC 3, MUC 4, NCA, EGFR, HER 2/neu, PAM-4, TAG-72, EGP-1, EGP-2, A3, KS-1, Le(y), S100, PSMA, PSA, tenascin, folate receptor, VEGF, PIGF, ILGF-1, necrosis antigens, IL-2, IL-6, T101, MAGE, and combinations thereof. 20. The method of claim 8, wherein the targeted tissue comprises a multiple myeloma, a B-cell malignancy, a T-cell malignancy, or combinations thereof. 21. The method of claim 20, wherein the B-cell malignancy is selected from the group consisting of indolent forms of B-cell lymphomas, aggressive forms of B-cell lymphomas, chronic leukemias, multiple myeloma, and acute lymphatic leukemias. 22. The method of claim 8, wherein the targeted tissue comprises a lymphoma including a non-Hodgkin's lymphoma or a Hodgkin's lymphoma. 23. The method of claim 8, wherein the targeted tissue comprises a melanoma, a carcinoma, a sarcoma, a glioma, or combinations thereof. 24. The method of claim 16, wherein the disease or condition comprises a cardiovascular disease and the antibody or antibody fragment is specific for granulocytes, lymphocytes, monocytes, fibrin, D-dimer or a mixture thereof. 25. The method of claim 16, wherein the infectious disease is selected from the group consisting of a bacterial disease, fungal disease, parasitic disease, viral disease, protozoan disease, mycoplasmal disease, and combinations thereof. 26. The method of claim 16, wherein the autoimmune disease is selected from the group consisting of 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, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, 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, thromboangitis obliterans, 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, fibrosing alveolitis, and combinations thereof. 27. The method of claim 8, further comprising administering one or more therapeutic or diagnostic agents. 28. The method of claim 8, further comprising administering a therapeutic agent selected from antibodies, antibody fragments, drugs, prodrugs, toxins, enzymes, enzyme-inhibitors, nuclease, hormones, hormone antagonists, oligonucleotides, immunomodulators, cytokines, chelators, boron compounds, uranium atoms, photoactive agents, radionuclides, and combinations thereof. 29. The method of claim 8, further comprising administering a cytokine selected from the group consisting of IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, IL-21, interferon-.alpha., interferon-.beta., interferon-.gamma., G-CSF, and GM-CSF, and mixtures thereof. 30. The method of claim 8, further comprising administering an anti-angiogenic agent selected from the group consisting of angiostatin, endostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-placental growth factor antibodies, anti-vascular growth factor antibodies, and mixtures thereof. 31. The method of claim 8, further comprising administering a diagnostic agent selected from radioisotopes, dyes, radioopaque materials, contrast agents, fluorescent compounds, enhancing agents, and combinations thereof. 32. The method of claim 8, further comprising administering a metal selected from zinc, aluminum, gallium, lutetium, palladium, boron, gadolinium, uranium, manganese, iron, chromium, copper, cobalt, nickel, dysprosium, rhenium, europium, terbium, holmium, neodymium, and combinations thereof. 33. The method of claim 8, wherein the diagnostic agent comprises one or more agents for photodynamic therapy. 34. The method of claim 8, further comprising administering a therapeutic or diagnostic nuclide selected from the group consisting of .sup.18F, .sup.32P, .sup.33P, .sup.45Ti, .sup.47Sc, .sup.52Fe, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.75Se, .sup.77As, .sup.86Y, .sup.89Sr, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.94mTc, .sup.99Mo, .sup.99mTc, .sup.105Pd, .sup.105Rh, .sup.111Ag, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.153Sm, .sup.154-158Gd, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.169Er, .sup.175Lu, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.194Ir, .sup.198Au, .sup.199Au, .sup.211At, .sup.211Pb .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.223Ra, .sup.225Ac, and mixtures thereof. 35. The method of claim 27, wherein the therapeutic agent comprises a therapeutic nuclide. 36. The method of claim 35, wherein the therapeutic nuclide comprises .sup.32P, .sup.33P, .sup.47Sc, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.90Y, .sup.111Ag, .sup.111In, .sup.123I .sup.131I, .sup.142Pr, .sup.153Sm, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.211At, .sup.212Pb, .sup.212Bi, .sup.213Bi, .sup.223Ra, .sup.225Ac, or mixtures thereof. 37. The method of claim 8, further comprising performing an operative, intravascular, laparoscopic, or endoscopic procedure. 38. The method of claim 8, wherein the binding molecule is administered intravenously and the targetable construct is administered orally.

Details for Patent 8,158,573

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2018-06-22