Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease

Abstract

Disclosed are methods, compositions and uses of concentrated formulations of anti-CD74 antibody, of use for treating autoimmune diseases. In a specific non-limiting embodiment, the autoimmune disease is systemic lupus erythematosus (SLE). In a preferred embodiment, the anti-CD74 antibody is milatuzumab (IMMU-115). The antibody is administered subcutaneously, preferably at a dosage of 250 mg once a week for four weeks. The subcutaneous administration of anti-CD74 antibody ameliorates the symptoms of autoimmune diseases, with only manageable side effects.

What is claimed is: 
     
         1 . A method of treating autoimmune disease comprising subcutaneously administering to a human patient with autoimmune disease an anti-CD74 antibody. 
     
     
         2 . The method of  claim 1 , wherein the antibody is administered at a dosage of 200, 250, 300 or 350 mg/week. 
     
     
         3 . The method of  claim 1 , wherein the antibody is administered at a dosage of 250 mg/week. 
     
     
         4 . The method of  claim 3 , wherein the antibody is administered once a week for four weeks. 
     
     
         5 . The method of  claim 1 , wherein the antibody is at a concentration of 100, 150, 200 or 250 mg/ml. 
     
     
         6 . The method of  claim 1 , wherein the volume of administration is 1 ml or less, 2 ml or less, or 3 ml or less. 
     
     
         7 . The method of  claim 1 , wherein the anti-CD74 antibody competes with, blocks binding to, or binds to the same epitope of CD74 as an LL1 antibody comprising 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). 
     
     
         8 . The method of  claim 1 , wherein the anti-CD74 antibody is a humanized an LL1 antibody comprising 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). 
     
     
         9 . The method of  claim 1 , wherein the antibody is administered in a high concentration formulation buffer at a pH of 5.2, comprising citrate, phosphate, sodium chloride, polysorbate 80 and mannitol. 
     
     
         10 . The method of  claim 9 , wherein the high concentration formulation buffer comprises 6.2 mM citric acid monohydrate, 105 mM sodium chloride, 1.2 mM sodium citrate dihydrate, 8.7 mM sodium phosphate dibasic, 5.5 mM sodium phosphate monobasic, 0.1% polysorbate 80 and 66 mM mannitol. 
     
     
         11 . The method of  claim 9 , wherein the high concentration formulation buffer further comprises arginine and glutamic acid. 
     
     
         12 . The method of  claim 1 , wherein the antibody is a non-G1m1 (nG1m1) antibody. 
     
     
         13 . The method of  claim 12 , wherein the antibody has a G1m3 heavy chain allotype. 
     
     
         14 . The method of  claim 12 , wherein the antibody has a Km3 light chain allotype. 
     
     
         15 . The method of  claim 1 , wherein the antibody is purified from cell culture medium by sequential column chromatography on a Protein A resin, an anion-exchange resin and a cation-exchange resin, before the antibody is concentrated. 
     
     
         16 . The method of  claim 1 , wherein the antibody is selected from the group consisting of a monoclonal antibody, an antigen-binding fragment of a monoclonal antibody, a bispecific antibody, a multispecific antibody, an immunoconjugate and an antibody fusion protein. 
     
     
         17 . The method of  claim 16 , wherein the immunoconjugate comprises at least one non-cytotoxic therapeutic or diagnostic agent. 
     
     
         18 . The method of  claim 17 , wherein the therapeutic agent is selected from the group consisting of an immunomodulator, a cytokine, a chemokine, a tyrosine kinase inhibitor, a growth factor, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interleukin (IL), an interferon (IFN), a hormone and an enzyme. 
     
     
         19 . The method of  claim 17 , wherein the therapeutic agent is selected from the group consisting of erythropoietin, thrombopoietin tumor necrosis factor-α (TNF), TNF-β, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, 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-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-23, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin and LT. 
     
     
         20 . The method of  claim 1 , wherein the antibody is a naked antibody. 
     
     
         21 . The method of  claim 20 , further comprising administering at least one therapeutic agent to said individual. 
     
     
         22 . The method of  claim 21 , wherein the therapeutic agent is selected from the group consisting of a drug, a prodrug, an enzyme, a tyrosine kinase inhibitor, a sphingosine inhibitor, an immunomodulator, a cytokine, a hormone, a second antibody, a second antibody fragment, an immunoconjugate, an antisense oligonucleotide, an RNAi, an anti-angiogenic agent, a pro-apoptosis agent and a cytotoxic agent. 
     
     
         23 . The method of  claim 21 , wherein the therapeutic agent is selected from the group consisting of erythropoietin, thrombopoietin tumor necrosis factor-α (TNF), TNF-β, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, 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-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-23, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin and LT. 
     
     
         24 . The method of  claim 21 , wherein the second antibody binds to an antigen selected from the group consisting of CD19, CD20, CD21, CD22, CD23, CD37, CD40, CD4OL, CD52, CD80, IL-6, CXCR4 or HLA-DR. 
     
     
         25 . The method of  claim 1 , 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, Sjögren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, bullous pemphigoid, 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. 
     
     
         26 . The method of  claim 1 , wherein the antibody comprises human constant regions selected from the group consisting of IgG1, IgG2a, IgG3 and IgG4.