METHODS OF TREATMENT USING AN IFN gamma INHIBITOR

Abstract

The invention encompasses methods of treatment of interferon gamma (IFN-γ)-mediated diseases using IFN-γ inhibitors, such as anti-huIFN-γ antibodies, wherein levels of expression of one or more biomarkers are determined either before administration of the IFN-γ inhibitor and/or after administration. Also contemplated are methods of treatment using particular, pharmacodynamically effective doses of an anti-huIFN-γ antibody.

What is claimed is: 
     
         1 . A method for treating a patient suffering from an IFN-γ-mediated disease comprising administering to the patient a monoclonal anti-human interferon gamma (anti-huIFN-γ) antibody at a dose of from about 15 milligrams to about 200 milligrams,
 wherein the anti-huIFN-γ antibody has a heavy chain complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:34, a heavy chain complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:35, a heavy chain complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. 
 
     
     
         2 . The method of  claim 1 , wherein the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:36, the light chain CDR1 comprises the amino acid sequence of SEQ ID NO:38, the light chain CDR2 comprises the amino acid sequence of SEQ ID NO:41, and the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:43. 
     
     
         3 . The method of  claim 1 , wherein the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30. 
     
     
         4 . The method of  claim 3 , wherein the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. 
     
     
         5 . The method of  claim 4 , wherein the heavy chain variable region and the light chain variable region comprise, respectively, SEQ ID NO:6 and SEQ ID NO:8, SEQ ID NO:10 and SEQ ID NO:12, SEQ ID NO:14 and SEQ ID NO:16, SEQ ID NO:30 and SEQ ID NO:12, or SEQ ID NO:14 and SEQ ID NO:31. 
     
     
         6 . The method of  claim 1 , wherein the dose is from about 40 milligrams to about 200 milligrams. 
     
     
         7 . The method of  claim 6 , wherein the dose is from about 60 milligrams to about 150 milligrams. 
     
     
         8 . The method of  claim 6 , wherein the dose is from about 100 milligrams to about 180 milligrams. 
     
     
         9 . The method of  claim 1 , wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient. 
     
     
         10 . The method of  claim 1 , wherein expression at the RNA or protein level of one or more gene(s) listed in Table 1, 2, 4, 5, and/or 6 in a biological sample from the patient taken before the antibody is administered deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-γ.15. 
     
     
         11 . The method of  claim 10 , wherein the expression of at least five genes listed in Table 5 and/or 6 in the biological sample from the patient deviates from the expression of those genes in the control biological sample in a direction consistent with excess IFN-γ. 
     
     
         12 . The method of  claim 10 , wherein the biological sample from the patient exhibits elevated expression at the RNA or protein level as compared to expression in the control biological sample of one or more of the following genes: indoleamine 2,3-dioxygenase 1 (INDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C—X—C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C—X—C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. 
     
     
         13 . The method of  claim 12 , wherein the biological sample from the patient exhibits elevated expression at the RNA or protein level of GBP1 as compared to expression in the control biological sample. 
     
     
         14 . The method of  claim 1 , wherein the IFN-γ-mediated disease is selected from the group consisting of systemic lupus erythematosus (SLE), including discoid lupus and lupus nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis. 
     
     
         15 . The method of  claim 14 , wherein the IFN-γ-mediated disease is SLE. 
     
     
         16 . The method of  claim 15 , wherein the IFN-γ-mediated disease is lupus nephritis. 
     
     
         17 . The method of  claim 1 , wherein the antibody is a human IgG1 antibody. 
     
     
         18 . A method for treating a patient having an IFN-γ-mediated disease comprising administering to the patient a therapeutically effective dose an anti-huIFN-γ antibody, wherein the anti-huIFN-γ antibody has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44, and
 wherein the level(s) of expression in a biological sample taken from the patient before administration of the antibody of one or more genes listed in Table 1, 2, 4, 5, and/or 6 at the RNA or protein level deviate from the level(s) of expression of the gene(s) in a control biological sample in a direction consistent with excess IFN-γ. 
 
     
     
         19 . The method of  claim 18 , wherein the levels expression in the biological sample of at least 5 genes from Table 5 and/or 6 deviate from the levels of expression of the genes in the control biological sample in a direction consistent with excess IFN-γ. 
     
     
         20 . The method of  claim 18 , wherein the antibody comprises the amino acid sequences of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. 
     
     
         21 . The method of  claim 18 , wherein the dose administered is from 40 mg to 300 mg. 
     
     
         22 . The method of  claim 21 , wherein the dose administered is from 60 mg to 200 mg. 
     
     
         23 . The method of  claim 18 , wherein the IFN-γ-mediated disease is SLE, an inflammatory bowel disease, or psoriasis patient. 
     
     
         24 . The method of  claim 23 , wherein the IFN-γ-mediated disease is SLE. 
     
     
         25 . The method of  claim 24 , wherein IFN-γ-mediated disease is lupus nephritis. 
     
     
         26 . The method of  claim 18 , wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient. 
     
     
         27 . A method for treating an IFN-γ mediated disease comprising administering to a patient in need thereof a dose of a human IgG anti-huIFN-γ antibody such that the concentration of total IFN-γ protein in the patient's serum is maintained at a plateau concentration for at least about two weeks following administration, wherein the antibody comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8. 
     
     
         28 . The method of  claim 27 , wherein the plateau concentration of total IFN-γ protein in serum is maintained for at least about three weeks after administration. 
     
     
         29 . The method of  claim 28 , wherein the plateau concentration of total IFN-γ protein in serum is maintained for at least about six weeks after administration. 
     
     
         30 . The method of  claim 27 , wherein the plateau concentration of total IFN-γ protein in serum is from about 100 pg/mL to about 2000 pg/mL. 
     
     
         31 . The method of  claim 30 , wherein the plateau concentration of total IFN-γ protein in serum is at least about 200 pg/mL. 
     
     
         32 . The method of  claim 27 , wherein the antibody is a human IgG1 antibody. 
     
     
         33 . The method of  claim 27 , wherein the IFN-γ-mediated disease is psoriasis or SLE including lupus nephritis. 
     
     
         34 . A method of treating a patient suffering from a disease selected from the group consisting of SLE, discoid lupus, lupus nephritis, inflammatory bowel disease, and psoriasis, the method comprising
 selecting a patient, wherein expression at the RNA or protein level of one or more gene(s) listed in Table(s) 2, 4, 5, and/or 6 in a biological sample taken from the patient before treating the patient deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-γ pathway activation, and   administering to the patient a monoclonal human anti-human interferon gamma (anti-huIFN-γ) antibody at a dose of from about 20 milligrams to about 300 milligrams,   wherein the antibody is an IgG1 antibody and comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8.   
     
     
         35 . The method of  claim 34 , wherein the expression of at least five genes listed in Table(s) 5 and/or 6 in the biological sample from the patient deviates from the expression of those genes in the control biological sample in a direction consistent with excess IFN-γ pathway activation. 
     
     
         36 . The method of  claim 34 , wherein the biological sample from the patient exhibits elevated expression at the RNA or protein level as compared to expression in the control biological sample of one or more of the following genes: indoleamine 2,3-dioxygenase 1 (INDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C—X—C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C—X—C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. 
     
     
         37 . The method of  claim 34 , wherein the disease is SLE and/or lupus nephritis. 
     
     
         38 . A method for treating a patient suffering from SLE, an inflammatory bowel disease, or psoriasis comprising:
 (a) taking a biological sample from the patient before administering a human anti-huIFN-γ antibody in step (b), wherein the level(s) of expression at the RNA or protein level in the biological sample from the patient of one or more of the genes in Table(s) 2, 4, 5, and/or 6 is determined;   (b) administering to the patient a pharmacodynamically effective dose of the human anti-huIFN-γ antibody, wherein the antibody has a heavy chain complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:34, a heavy chain complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:35, a heavy chain complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44;   (c) taking a second biological sample taken from the patient after administration of the antibody, wherein the level(s) of expression of the gene(s) of step (a) in the second biological sample are determined; and   (d) if the level(s) of expression of the gene(s) in the second biological sample determined in step (c), as compared to the level(s) of expression in the biological sample determined in step (a)
 (i) is modulated in a direction consistent with inhibition of IFN-γ, then continuing treatment of the patient with another pharmacodynamically effective dose of the antibody or 
 (ii) is substantially the same as that in the biological sample of (a) or if the level of expression of the gene(s) in second biological sample of (c) deviates from the level of expression in the biological sample of (a) in a direction that is consistent with an excess of IFN-γ, then discontinuing treatment with the anti-human IFN-γ antibody. 
   
     
     
         39 . The method of  claim 38 , wherein the pharmacodynamically effective dose is from about 20 mg to about 80 mg. 
     
     
         40 . The method of  claim 38 , wherein the pharmacodynamically effective dose is from about 80 mg to about 250 mg. 
     
     
         41 . The method of  claim 38 , wherein the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:36, the light chain CDR1 comprises the amino acid sequence of SEQ ID NO:38, the light chain CDR2 comprises the amino acid sequence of SEQ ID NO:41, and the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:43. 
     
     
         42 . The method of  claim 38 , wherein the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. 
     
     
         43 . The method of  claim 42 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:6, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:8. 
     
     
         44 . The method of  claim 38 , wherein the patient has SLE. 
     
     
         45 . The method of  claim 44 , wherein the patient has lupus nephritis. 
     
     
         46 . The method of  claim 38 , wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient. 
     
     
         47 . The method of  claim 38 , wherein the patient has psoriasis, Crohn's disease, or ulcerative colitis. 
     
     
         48 . The method of  claim 38 , wherein the level(s) of expression of one or more of the following genes at the protein or RNA level is determined in steps (a) and (c): indoleamine 2,3-dioxygenase 1 (INDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C—X—C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C—X—C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. 
     
     
         49 . The method of  claim 48 , wherein the level of expression of CXCL10 is determined in steps (a) and (c). 
     
     
         50 . A method for treating a patient suffering from SLE comprising administering to the patient a dose of at least about 60 milligrams, and not more than about 180 milligrams, of an anti-human IFN-γ antibody,
 wherein the anti-human IFN-γ antibody comprises SEQ ID NOs: 6 and 8. 
 
     
     
         51 . The method of  claim 50 , wherein the level of total IFN-γ in the patient's serum remains above about 200 pg/mL for at least about 2 weeks subsequent to a single dose. 
     
     
         52 . The method of  claim 50 , wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient.