Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies

Abstract

The present invention concerns compositions and methods of use of anti-HLA-DR antibodies or fragments thereof. In preferred embodiments, the antibodies are subcutaneously administered to a human patient with a hematologic cancer or autoimmune disease. The subcutaneously administered anti-HLA-DR antibody is effective to treat hematologic cancer or autoimmune disease in patients that have relapsed from or are refractory to standard therapies for hematologic cancer or autoimmune disease, such as administration of anti-CD20 antibodies, such as rituximab.

What is claimed is: 
     
         1 . A method of treating hematologic cancer comprising administering a dosage of anti-HLA-DR antibody or antigen-binding fragment thereof to a human patient with a hematologic cancer by parenteral injection. 
     
     
         2 . The method of  claim 1 , wherein the administration is by subcutaneous injection. 
     
     
         3 . The method of  claim 1 , wherein administration by subcutaneous injection does not induce infusion-related toxicity. 
     
     
         4 . The method of  claim 2 , wherein the patient has failed at least one prior therapy for the hematologic cancer. 
     
     
         5 . The method of  claim 4 , wherein the patient has failed therapy with an anti-CD20 antibody, prior to administration of the anti-HLA-DR antibody. 
     
     
         6 . The method of  claim 5 , wherein the patient has failed therapy with rituximab, prior to administration of the anti-HLA-DR antibody. 
     
     
         7 . The method of  claim 4 , wherein the patient who has failed at least one prior therapy responds to the subcutaneous anti-HLA-DR antibody. 
     
     
         8 . The method of  claim 1 , wherein the cancer is recurrent or relapsed NHL (non-Hodgkin's lymphoma) or CLL (chronic lymphocytic leukemia). 
     
     
         9 . The method of  claim 1 , wherein the dosage of anti-HLA-DR antibody administered to the patient is 200 mg. 
     
     
         10 . The method of  claim 9 , wherein the dosage is administered once, twice or three times a week. 
     
     
         11 . The method of  claim 1 , wherein the cancer is selected from the group consisting of DLBCL (diffuse large B-cell lymphoma), follicular lymphoma, SLL (small lymphocytic lymphoma), mantle cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, CLL, ALL (acute lymphocytic leukemia), CML (chronic myeloid leukemia), Burkitt lymphoma, hairy cell leukemia and marginal zone lymphoma. 
     
     
         12 . The method of  claim 1 , wherein the anti-HLA-DR antibody comprises a human heavy chain γ4 constant region sequence with a Ser241Pro substitution. 
     
     
         13 . The method of  claim 1 , wherein the anti-HLA-DR antibody is a chimeric, humanized or human antibody. 
     
     
         14 . The method of  claim 13 , wherein the anti-HLA-DR antibody comprises the heavy chain complementarity determining region (CDR) sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44). 
     
     
         15 . The method of  claim 14 , wherein the anti-HLA-DR antibody is a humanized antibody comprising light chain murine L243 FR residues R37, K39, V48, F49, and G100 and heavy chain murine L243 FR residues F27, K38, K46, A68, and F91. 
     
     
         16 . The method of  claim 1 , wherein the anti-HLA-DR antibody binds to the same epitope of HLA-DR as a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44). 
     
     
         17 . The method of  claim 1 , wherein the anti-HLA-DR antibody competes for binding to HLA-DR with a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44). 
     
     
         18 . The method of  claim 1 , wherein the anti-HLA-DR antibody is a naked antibody. 
     
     
         19 . The method of  claim 1 , wherein the anti-HLA-DR antibody is attached to at least one therapeutic agent. 
     
     
         20 . The method of  claim 19 , wherein the therapeutic agent is selected from the group consisting of a drug, a toxin, an enzyme, a radioisotope, an immunomodulator, a cytokine, a hormone, a antibody or fragment thereof, an anti-angiogenic agent, a cytotoxic agent, a pro-apoptosis agent, an oligonucleotide, an siRNA and a photodynamic agent. 
     
     
         21 . The method of  claim 20 , wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, estramustine, epipodophyllotoxin, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, gemcitabine, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosurea, plicomycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, streptozocin, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids. 
     
     
         22 . The method of  claim 20 , wherein the toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), ranpirnase, DNase I,  Staphylococcal  enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin,  Pseudomonas  exotoxin and  Pseudomonas  endotoxin. 
     
     
         23 . The method of  claim 20 , wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-P1GF peptides and antibodies, anti-vascular growth factor antibodies, anti-Flk-1 antibodies, anti-Flt-1 antibodies and peptides, anti-Kras antibodies, anti-cMET antibodies, anti-MIF (macrophage migration-inhibitory factor) antibodies, 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 (roquinimex), thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline. 
     
     
         24 . The method of  claim 20 , wherein the immunomodulator is selected from the group consisting of erythropoietin, thrombopoietin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, “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, tumor necrosis factor-α, tumor necrosis factor-β, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-β, platelet-growth factor, TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, macrophage-CSF (M-CSF), IL-1, IL-1α, 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, kit-ligand, angiostatin, thrombospondin, endostatin, tumor necrosis factor and LT. 
     
     
         25 . The method of  claim 20 , wherein the radionuclide is selected from the group consisting of  18 F,  32 P,  33 P,  45 Ti,  47 Sc,  52 Fe,  59 Fe,  62 CU,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  75 Se,  77 As,  86 Y,  89 Sr,  89 Zr,  90 Y,  94 Tc,  94m Tc,  99 Mo,  99m Tc,  105 Pd,  105 Rh,  111 Ag,  111 In,  123 I,  124 I,  125 I,  131 I,  142 Pr,  143 Pr,  149 Pm,  153 Sm,  154-158 Gd,  161 Tb,  166 Dy,  166 Ho,  169 Er,  175 Lu,  177 Lu,  186 Re,  188 Re,  189 Re,  194 Ir,  198 Au  199 Au,  211 At,  211 Pb  212 Bi,  212 Pb,  213 Bi,  223 Ra,  227 Th and  225 Ac. 
     
     
         26 . The method of  claim 1 , further comprising administering to the patient an anti-CD20 antibody or fragment thereof, wherein administration of the anti-HLA-DR antibody and the anti-CD20 antibody inhibits proliferation of the hematologic cancer more than either anti-HLA-DR antibody or anti-CD20 antibody alone. 
     
     
         27 . The method of  claim 18 , further comprising administering at least one therapeutic agent to the patient. 
     
     
         28 . A method of treating an autoimmune or immune dysfunction disease comprising administering a dosage of anti-HLA-DR antibody or antigen-binding fragment thereof to a human patient with an autoimmune disease by subcutaneous injection. 
     
     
         29 . The method of  claim 28 , wherein the autoimmune or immune dysfunction 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, GVHD (graft-versus-host disease) and organ transplant rejection. 
     
     
         30 . The method of  claim 29 , wherein the patient has failed at least one prior therapy for the autoimmune disease. 
     
     
         31 . The method of  claim 30 , wherein the patient has failed therapy with an anti-CD20 antibody, prior to administration of the anti-HLA-DR antibody. 
     
     
         32 . The method of  claim 28 , wherein the dosage of anti-HLA-DR antibody is 200 mg. 
     
     
         33 . The method of  claim 32 , wherein the dosage is administered once, twice or three times a week. 
     
     
         34 . The method of  claim 28 , wherein the anti-HLA-DR antibody comprises a human heavy chain γ4 constant region sequence with a Ser241Pro substitution. 
     
     
         35 . The method of  claim 28 , wherein the anti-HLA-DR antibody is a chimeric, humanized or human antibody. 
     
     
         36 . The method of  claim 35 , wherein the anti-HLA-DR antibody comprises the heavy chain complementarity determining region (CDR) sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44). 
     
     
         37 . The method of  claim 36 , wherein the anti-HLA-DR antibody is a humanized antibody comprising light chain murine L243 FR residues R37, K39, V48, F49, and G100 and heavy chain murine L243 FR residues F27, K38, K46, A68, and F91. 
     
     
         38 . The method of  claim 28 , wherein the anti-HLA-DR antibody binds to the same epitope of HLA-DR as a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44). 
     
     
         39 . The method of  claim 28 , wherein the anti-HLA-DR antibody competes for binding to HLA-DR with a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44). 
     
     
         40 . The method of  claim 28 , wherein the anti-HLA-DR antibody is a naked antibody. 
     
     
         41 . The method of  claim 28 , wherein the anti-HLA-DR antibody is attached to at least one therapeutic agent selected from the group consisting of a drug, an enzyme, an immunomodulator, a cytokine, a hormone, an antibody or fragment thereof, an oligonucleotide, an siRNA and a photodynamic agent.