Claims for Patent: 8,591,892

Summary for Patent: 8,591,892

Title:	FTY720 increases CD74 expression and sensitizes cancer cells to anti-CD74 antibody-mediated cell death
Abstract:	Disclosed herein are methods and compositions comprising fingolimod and anti-CD74 antibodies or fragments thereof. In preferred embodiments, the fingolimod increases the expression of CD74 in target cells and increases the sensitivity of the cells to the cytotoxic effects of the anti-CD74 antibodies. The compositions and methods are of use to treat diseases involving CD74.sup.+ cells, such as cancer cells, autoimmune disease cells or immune dysfunction disease cells.
Inventor(s):	Alinari; Lapo (Dublin, OH), Baiocchi; Robert A. (Dublin, OH), Muthusamy; Natarajan (Galloway, OH), Hansen; Hans J. (Picayune, MS), Goldenberg; David M. (Mendham, NJ)
Assignee:	The Ohio State University (Columbus, OH) Immunomedics, Inc. (Morris Plains, NJ)
Application Number:	13/551,866
Patent Claims:	1. A method of killing a CD74-expressing cell comprising a) exposing the cell to fingolimod; and b) exposing the cell to an anti-CD74 antibody or antigen-binding fragment thereof. 2. The method of claim 1, wherein the cell is a diseased cell. 3. The method of claim 2, wherein the disease is selected from the group consisting of cancer, autoimmune disease and immune dysfunction disease. 4. The method of claim 3, wherein the cancer is selected from the group consisting of hematopoietic cancer, B-cell leukemia, B-cell lymphoma, non-Hodgkin's lymphoma (NHL), multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, glioblastoma, follicular lymphoma, diffuse large B cell lymphoma, colon cancer, pancreatic cancer, renal cancer, lung cancer, stomach cancer, breast cancer, prostate cancer, ovarian cancer and melanoma. 5. The method of claim 3, wherein the immune dysregulation disease is graft-versus-host disease or organ transplant rejection. 6. The method of claim 3, 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 and fibrosing alveolitis. 7. The method of claim 1, wherein the fingolimod is administered before or concurrently with the anti-CD74 antibody. 8. The method of claim 1, wherein the anti-CD74 antibody competes for binding to CD74 with, or binds to the same epitope of CD74 as, an antibody comprising the light chain complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:1), CDR2 (TVSNRFS; SEQ ID NO:2), and CDR3 (SQSSHVPPT; SEQ ID NO:3) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:4), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:5), and CDR3 (SRGKNEAWFAY; SEQ ID NO:6). 9. The method of claim 1, wherein the anti-CD74 antibody comprises the light chain CDR sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:1), CDR2 (TVSNRFS; SEQ ID NO:2), and CDR3 (SQSSHVPPT; SEQ ID NO:3) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:4), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:5), and CDR3 (SRGKNEAWFAY; SEQ ID NO:6). 10. The method of claim 1, wherein the anti-CD74 antibody or fragment thereof is a naked antibody or fragment thereof. 11. The method of claim 10, further comprising exposing the cell to at least one therapeutic agent selected from the group consisting of a radionuclide, a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, a hormone, an oligonucleotide, an antisense molecule, a siRNA, a second antibody and a second antibody fragment. 12. The method of claim 1, wherein the anti-CD74 antibody or fragment thereof is conjugated to at least one therapeutic agent selected from the group consisting of a radionuclide, a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, a hormone, an oligonucleotide, an antisense molecule, a siRNA, a second antibody and a second antibody fragment. 13. The method of claim 12, wherein the anti-CD74 antibody or fragment thereof is conjugated to a second antibody or fragment thereof to form a bispecific antibody. 14. The method of claim 13, wherein the second antibody or fragment thereof binds to an antigen selected from the group consisting of carbonic anhydrase IX, CCCL19, CCCL21, CSAp, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, IGF-1R, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CXCR4, CXCR7, CXCL12, HIF-1.alpha., AFP, PSMA, CEACAM5, CEACAM6, B7, ED-B of fibronectin, Factor H, FHL-1, Flt-3, folate receptor, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin-like growth factor-1 (IGF-1), IFN-.gamma., IFN-.alpha., IFN-.beta., IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, PP-10, MAGE, mCRP, MCP-1, MPP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, NCA-95, NCA-90, Ia, HM1.24, EGP-1, EGP-2, HLA-DR, tenascin, Le(y), RANTES, T101, TAC, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, TNF-.alpha., TRAIL receptor (R1 and R2), VEGFR, EGFR, PlGF, complement factors C3, C3a, C3b, C5a, C5, and an oncogene product. 15. The method of claim 13, wherein the bispecific antibody is a dock-and-lock complex. 16. The method of claim 12, wherein the therapeutic agent is selected from the group consisting of 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, 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, and Pseudomonas endotoxin. 17. The method of claim 13, wherein the therapeutic agent is a radionuclide selected from the group consisting of .sup.103mRh, to .sup.103Rh, .sup.105Rh, .sup.105Ru, to .sup.107Hg, to .sup.109Pd, .sup.109Pt, .sup.111Ag, .sup.111In, .sup.113mIn, .sup.119Sb, .sup.11C, .sup.121mTe, .sup.122mTe, .sup.125I, .sup.125mTe, .sup.126I, .sup.131I, .sup.133I, .sup.13N, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.152Dy, .sup.153Sm, .sup.15O, .sup.161HO, .sup.161Tb, .sup.165Tm, .sup.166Dy, .sup.166Ho, .sup.167Tm, .sup.168Tm, .sup.169Er, .sup.169Yb, .sup.177Lu, .sup.186Re, .sup.189mOs, .sup.188Re, .sup.189Re, .sup.192Ir, .sup.194Ir, .sup.197Pt, .sup.198Au, .sup.199Au, .sup.201Tl, .sup.203Hg, .sup.211At, .sup.211Bi, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.215Po, .sup.217At, .sup.219Rn, .sup.221Fr, .sup.223Ra, .sup.224Ac, .sup.225Ac, .sup.225Fm, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.62Cu, .sup.67Cu, .sup.67Ga, .sup.75Br, .sup.75Se, .sup.76Br, .sup.77As, .sup.77Br, .sup.80mBr, .sup.89Sr, .sup.90Y, .sup.95Ru, .sup.97Ru, .sup.99Mo and .sup.99mTc. 18. The method of claim 12, wherein the therapeutic agent is an enzyme selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. 19. The method of claim 12, wherein the therapeutic agent is an immunomodulator selected from the group consisting of erythropoietin, thrombopoietin tumor necrosis factor-.alpha. (TNF), TNF-.beta., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., stem cell growth factor designated "S1 factor", human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-.beta., platelet-growth factor, TGF-.alpha., TGF-.beta., insulin-like growth factor-I, insulin-like growth factor-II, macrophage-CSF (M-CSF), IL-1, IL-1.alpha., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin and LT. 20. The method of claim 1, wherein the CD74-expressing cell is killed by the combination of fingolimod and anti-CD74 antibody, but not by anti-CD74 antibody alone. 21. The method of claim 1 wherein exposure of the cell to fingolimod increases the expression of CD74 by the cell. 22. The method of claim 1, wherein the antibody fragment is selected from the group consisting of F(ab').sub.2, F(ab).sub.2, Fab', Fab, Fv, scFv and single domain antibody. 23. The method of claim 1, wherein the anti-CD74 antibody is a chimeric, humanized or human anti-CD74 antibody. 24. The method of claim 1, further comprising exposing the cell to interferon-.gamma.. 25. The method of claim 1, further comprising exposing the cell to an anti-HLA-DR antibody or antigen-binding fragment thereof. 26. The method of claim 25, wherein the anti-HLA-DR antibody competes for binding to HLA-DR with, or binds to the same epitope of HLA-DR as, an antibody comprising the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:7), CDR2 (WINTYTREPTYADDFKG, SEQ ID NO:8), and CDR3 (DITAVVPTGFDY, SEQ ID NO:9) and the light chain CDR sequences CDR1 (RASENIYSNLA, SEQ ID NO:10), CDR2 (AASNLAD, SEQ ID NO:11), and CDR3 (QHFWTTPWA, SEQ ID NO:12). 27. The method of claim 25, wherein the anti-HLA-DR antibody comprises heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:7), CDR2 (WINTYTREPTYADDFKG, SEQ ID NO:8), and CDR3 (DITAVVPTGFDY, SEQ ID NO:9) and the light chain CDR sequences CDR1 (RASENIYSNLA, SEQ ID NO:10), CDR2 (AASNLAD, SEQ ID NO:11), and CDR3 (QHFWTTPWA, SEQ ID NO:12). 28. The method of claim 25, wherein the anti-HLA-DR antibody or fragment thereof is a naked antibody or fragment thereof. 29. The method of claim 25, wherein the anti-HLA-DR antibody or fragment thereof is conjugated to at least one therapeutic agent selected from the group consisting of a radionuclide, a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, a hormone, an oligonucleotide, an antisense molecule, a siRNA, a second antibody and a second antibody fragment. 30. A method of treating a disease selected from the group consisting of cancer, autoimmune disease and immune dysfunction disease comprising: a) administering fingolimod to an individual suspected of having the disease; and b) administering to the individual an anti-CD74 antibody or antigen-binding fragment thereof. 31. The method of claim 30, wherein the cancer is selected from the group consisting of hematopoietic cancer, B-cell leukemia, B-cell lymphoma, non-Hodgkin's lymphoma (NHL), multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, glioblastoma, follicular lymphoma, diffuse large B cell lymphoma, colon cancer, pancreatic cancer, renal cancer, lung cancer, stomach cancer, breast cancer, prostate cancer, ovarian cancer and melanoma. 32. The method of claim 30, wherein the immune dysregulation disease is graft-versus-host disease or organ transplant rejection. 33. The method of claim 30, 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 and fibrosing alveolitis. 34. The method of claim 30, wherein the fingolimod is administered before or concurrently with the antibody or fragment thereof. 35. The method of claim 30, wherein the antibody or fragment thereof is a naked antibody or fragment thereof. 36. The method of claim 35, further comprising administering at least one therapeutic agent selected from the group consisting of a radionuclide, a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, a hormone, an oligonucleotide, an antisense molecule, a siRNA, a second antibody and a second antibody fragment. 37. The method of claim 36, further comprising administering both an anti-CD74 and an anti-HLA-DR antibody or fragment thereof. 38. The method of claim 30, wherein the antibody or fragment thereof is conjugated to at least one therapeutic agent selected from the group consisting of a radionuclide, a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, a hormone, an oligonucleotide, an antisense molecule, a siRNA, a second antibody and a second antibody fragment. 39. The method of claim 38, wherein the therapeutic agent is selected from the group consisting of 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, 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, and Pseudomonas endotoxin. 40. The method of claim 38, wherein the therapeutic agent is a radionuclide selected from the group consisting of .sup.103mRh, .sup.103Ru, .sup..PSI.Rh, .sup.105Ru, .sup.107Hg, .sup.109Pd, .sup.109Pt, .sup.111Ag, .sup.111In, .sup.113mIn, .sup.119Sb, .sup.11C, .sup.121mTe, .sup.122mTe, .sup.125I, .sup.125mTe, .sup.126I, .sup.131I, .sup.133I, .sup.13N, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.152Dy, .sup.153Sm, .sup.15O, .sup.161Ho, .sup.161Tb, .sup.165Tm, .sup.166Dy, .sup.166Ho, .sup.167Tm, .sup.168Tm, .sup.169Er, .sup.169Yb, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189mOs, .sup.189Re, .sup.192Ir, .sup.194Ir, .sup.197Pt, .sup.198Au, .sup.199Au, .sup.201Tl, .sup.203Hg, .sup.211At, .sup.211Bi, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.215Po, .sup.217At, .sup.219Rn, .sup.221Fr, .sup.223Ra, .sup.224Ac, .sup.225Ac, .sup.225Fm, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.62Cu, .sup.67Cu, .sup.67Ga, .sup.75Br, .sup.75Se, .sup.76Br, .sup.77As, .sup.77Br, .sup.80mBr, .sup.89Sr, .sup.90Y, .sup.95Ru, .sup.97Ru, .sup.99Mo and .sup.99mTc. 41. The method of claim 38, wherein the therapeutic agent is an enzyme selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. 42. The method of claim 38, wherein the therapeutic agent is an immunomodulator selected from the group consisting of erythropoietin, thrombopoietin tumor necrosis factor-.alpha. (TNF), TNF-.beta., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., stem cell growth factor designated "S1 factor", human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-.beta., platelet-growth factor, TGF-.alpha., TGF-.beta., insulin-like growth factor-I, insulin-like growth factor-II, macrophage-CSF (M-CSF), IL-1, IL-1.alpha., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin and LT. 43. The method of claim 30, wherein the antibody fragment is selected from the group consisting of F(ab').sub.2, F(ab).sub.2, Fab', Fab, Fv, scFv and single domain antibody. 44. The method of claim 30, wherein the antibody is a chimeric, humanized or human antibody. 45. A therapeutic composition comprising: a) fingolimod; and b) an anti-CD74 antibody or antigen-binding fragment thereof. 46. The composition of claim 45, wherein the antibody or fragment thereof is a naked antibody or fragment thereof. 47. The composition of claim 45 wherein the antibody or fragment thereof is conjugated to at least one therapeutic agent. 48. The composition of claim 46, further comprising at least one therapeutic agent.

Details for Patent 8,591,892

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2031-07-18
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2031-07-18