Compositions and methods of treating lupus nephritis

Abstract

The invention provides methods for treating or delaying progression of lupus nephritis in an individual that has lupus. In some embodiments, the methods comprise administering to the individual an effective amount of a type II anti-CD20 antibody. The invention also provides methods for treating or delaying progression of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) in an individual. In some embodiments, the methods comprise administering an effective amount of an anti-CD20 antibody.

1 . A method for treating or delaying progression of lupus nephritis in an individual that has lupus, comprising administering to the individual at least a first antibody exposure to a type II anti-CD20 antibody and a second antibody exposure to the type II anti-CD20 antibody, the second antibody exposure not being provided until from about 18 weeks to about 26 weeks after the first antibody exposure;
 wherein the first antibody exposure comprises one or two doses of the type II anti-CD20 antibody, the first antibody exposure comprising a total exposure of between about 1800 mg and about 2200 mg of the type II anti-CD20 antibody;   wherein the second antibody exposure comprises one or two doses of the type II anti-CD20 antibody, the second antibody exposure comprising a total exposure of between about 1800 mg and about 2200 mg of the type II anti-CD20 antibody; and   wherein the type II anti-CD20 antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:1, HVR-H2 sequence of SEQ ID NO:2, and HVR-H3 sequence of SEQ ID NO:3, and a light chain comprising HVR-L1 sequence of SEQ ID NO:4, HVR-L2 sequence of SEQ ID NO:5, and HVR-L3 sequence of SEQ ID NO:6.   
     
     
         2 . The method of  claim 1 , wherein the first antibody exposure comprises a first dose of between about 900 mg and about 1100 mg of the type II anti-CD20 antibody and a second dose of between about 900 mg and about 1100 mg of the type II anti-CD20 antibody. 
     
     
         3 . The method of  claim 1 , wherein the first antibody exposure comprises a first dose of the type II anti-CD20 antibody and a second dose of the type II anti-CD20 antibody, and wherein the second dose of the first antibody exposure is not provided until from about 1.5 weeks to about 2.5 weeks after the first dose of the first antibody exposure. 
     
     
         4 . The method of  claim 3 , wherein the first antibody exposure comprises a first dose of the type II anti-CD20 antibody and a second dose of the type II anti-CD20 antibody, and wherein the second dose of the first antibody exposure is not provided until about 2 weeks after the first dose of the first antibody exposure. 
     
     
         5 . The method of  claim 3 , wherein the first dose of the first antibody exposure is about 1000 mg of the type II anti-CD20 antibody. 
     
     
         6 . The method of  claim 3 , wherein the second dose of the first antibody exposure is about 1000 mg of the type II anti-CD20 antibody. 
     
     
         7 . The method of  claim 1 , wherein the second antibody exposure comprises a first dose of between about 900 mg and about 1100 mg of the type II anti-CD20 antibody and a second dose of between about 900 mg and about 1100 mg of the type II anti-CD20 antibody. 
     
     
         8 . The method of  claim 1 , wherein the second antibody exposure comprises a first dose of the type II anti-CD20 antibody and a second dose of the type II anti-CD20 antibody, and wherein the second dose of the second antibody exposure is not provided until from about 1.5 weeks to about 2.5 weeks after the first dose of the second antibody exposure. 
     
     
         9 . The method of  claim 8 , wherein the second antibody exposure comprises a first dose of the type II anti-CD20 antibody and a second dose of the type II anti-CD20 antibody, and wherein the second dose of the second antibody exposure is not provided until about 2 weeks after the first dose of the second antibody exposure. 
     
     
         10 . The method of  claim 8 , wherein the first dose of the second antibody exposure is about 1000 mg of the type II anti-CD20 antibody. 
     
     
         11 . The method of  claim 8 , wherein the second dose of the second antibody exposure is about 1000 mg of the type II anti-CD20 antibody. 
     
     
         12 . The method of  claim 1 , wherein the first antibody exposure and the second antibody exposure are administered intravenously. 
     
     
         13 . The method of  claim 1 , wherein the individual has class III or class IV lupus nephritis. 
     
     
         14 . The method of  claim 1 , wherein the individual is at risk for developing class III or class IV lupus nephritis. 
     
     
         15 . A method for treating or delaying progression of lupus nephritis in an individual that has lupus, comprising administering to the individual an effective amount of a type II anti-CD20 antibody; wherein the type II anti-CD20 antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:1, HVR-H2 sequence of SEQ ID NO:2, and HVR-H3 sequence of SEQ ID NO:3, and a light chain comprising HVR-L1 sequence of SEQ ID NO:4, HVR-L2 sequence of SEQ ID NO:5, and HVR-L3 sequence of SEQ ID NO:6; and wherein the individual has class III or class IV lupus nephritis. 
     
     
         16 . The method of  claim 14 , wherein the type II anti-CD20 antibody is administered intravenously. 
     
     
         17 . The method of  claim 1 , wherein the individual does not have class III (C) or class IV (C) lupus nephritis. 
     
     
         18 . The method of  claim 1 , wherein the individual has class V lupus nephritis. 
     
     
         19 . The method of  claim 1 , further comprising administering to the individual an effective amount of an immunosuppressive agent. 
     
     
         20 . The method of  claim 19 , wherein the immunosuppressive agent comprises mycophenolic acid, a derivative thereof, or a salt thereof. 
     
     
         21 . The method of  claim 20 , wherein the immunosuppressive agent comprises mycophenolate mofetil. 
     
     
         22 . The method of  claim 1 , further comprising administering to the individual an effective amount of a glucocorticoid or corticosteroid. 
     
     
         23 . The method of  claim 22 , wherein the glucocorticoid or corticosteroid comprises methylprednisolone. 
     
     
         24 . The method of  claim 22 , wherein the glucocorticoid or corticosteroid comprises prednisone. 
     
     
         25 . The method of  claim 1 , further comprising administering to the individual an effective amount of an antihistamine. 
     
     
         26 . The method of  claim 25 , wherein the antihistamine comprises diphenhydramine. 
     
     
         27 . The method of  claim 1 , further comprising administering to the individual an effective amount of a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         28 . The method of  claim 27 , wherein the NSAID comprises acetaminophen. 
     
     
         29 . The method of  claim 1 , further comprising administering to the individual an effective amount of an antihypertensive agent. 
     
     
         30 . The method of  claim 29 , wherein the antihypertensive agent is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker. 
     
     
         31 . The method of  claim 1 , further comprising administering to the individual a standard of care treatment. 
     
     
         32 . The method of  claim 31 , wherein the standard of care treatment comprises treatment with one or more of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker, cyclophosphamide, mycophenolate mofetil, azathioprine, and a glucocorticoid or corticosteroid. 
     
     
         33 . The method of  claim 1 , wherein the method results in a complete renal response (CRR) in the individual. 
     
     
         34 . The method of  claim 1 , wherein the method results in a depletion of circulating peripheral B cells in the individual. 
     
     
         35 . The method of  claim 34 , wherein the circulating peripheral B cells are CD19+ B cells. 
     
     
         36 . The method of  claim 1 , wherein the type II anti-CD20 antibody is a humanized or human antibody. 
     
     
         37 . The method of  claim 1 , wherein the type II anti-CD20 antibody is afucosylated. 
     
     
         38 . The method of  claim 1 , wherein the heavy chain of the type II anti-CD20 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7. 
     
     
         39 . The method of  claim 1 , wherein the light chain of the type II anti-CD20 antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. 
     
     
         40 . The method of  claim 1 , wherein the type II anti-CD20 antibody is obinutuzumab. 
     
     
         41 . The method of  claim 1 , wherein the individual is a human. 
     
     
         42 . A kit for treating or delaying progression of lupus nephritis in an individual that has lupus, comprising:
 (a) a container comprising a type II anti-CD20 antibody, wherein the type II anti-CD20 antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:1, HVR-H2 sequence of SEQ ID NO:2, and HVR-H3 sequence of SEQ ID NO:3, and a light chain comprising HVR-L1 sequence of SEQ ID NO:4, HVR-L2 sequence of SEQ ID NO:5, and HVR-L3 sequence of SEQ ID NO:6; and   (b) a package insert with instructions for treating or delaying progression of lupus nephritis in an individual, wherein the instructions indicate that at least a first antibody exposure to a type II anti-CD20 antibody and a second antibody exposure to the type II anti-CD20 antibody are administered to the individual, the second antibody exposure not being provided until from about 18 weeks to about 26 weeks after the first antibody exposure; wherein the first antibody exposure comprises one or two doses of the type II anti-CD20 antibody, the first antibody exposure comprising a total exposure of between about 1800 mg and about 2200 mg of the type II anti-CD20 antibody; and wherein the second antibody exposure comprises one or two doses of the type II anti-CD20 antibody, the second antibody exposure comprising a total exposure of between about 1800 mg and about 2200 mg of the type II anti-CD20 antibody.   
     
     
         43 . The kit of  claim 42 , further comprising a container comprising:
 (c) a second medicament, wherein the type II anti-CD20 antibody is a first medicament; and   (d) instructions on the package insert for administering the second medicament to the subject.   
     
     
         44 . The kit of  claim 43 , wherein the second medicament is an immunosuppressive agent, a glucocorticoid, a corticosteroid, an anti-malarial agent, a cytotoxic agent, an integrin antagonist, a cytokine antagonist, or a hormone. 
     
     
         45 . A kit for treating or delaying progression of lupus nephritis in an individual that has lupus, comprising:
 (a) a container comprising a type II anti-CD20 antibody, wherein the type II anti-CD20 antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:1, HVR-H2 sequence of SEQ ID NO:2, and HVR-H3 sequence of SEQ ID NO:3, and a light chain comprising HVR-L1 sequence of SEQ ID NO:4, HVR-L2 sequence of SEQ ID NO:5, and HVR-L3 sequence of SEQ ID NO:6; and   (b) a package insert with instructions for treating or delaying progression of class III or class IV lupus nephritis in an individual.   
     
     
         46 . The kit of  claim 45 , further comprising a container comprising:
 (c) a second medicament, wherein the type II anti-CD20 antibody is a first medicament; and   (d) instructions on the package insert for administering the second medicament to the subject.   
     
     
         47 . The kit of  claim 46 , wherein the second medicament is an immunosuppressive agent, a glucocorticoid, a corticosteroid, an anti-malarial agent, a cytotoxic agent, an integrin antagonist, a cytokine antagonist, or a hormone. 
     
     
         48 . A method for treating or delaying progression of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) in an individual, comprising administering to the individual an effective amount of an anti-CD20 antibody, wherein the antibody comprises a heavy chain variable region comprising an HVR-H1 sequence of SEQ ID NO:1, an HVR-H2 sequence of SEQ ID NO:2, and an HVR-H3 sequence of SEQ ID NO:3, and a light chain variable region comprising an HVR-L1 sequence of SEQ ID NO:4, an HVR-L2 sequence of SEQ ID NO:5, and an HVR-L3 sequence of SEQ ID NO:6. 
     
     
         49 . The method of  claim 48 , wherein the antibody is administered intravenously. 
     
     
         50 . The method of  claim 48 , wherein the method results in a depletion of circulating peripheral B cells in the individual. 
     
     
         51 . The method of  claim 50 , wherein the circulating peripheral B cells are CD19+ B cells. 
     
     
         52 . The method of  claim 48 , wherein the antibody is a humanized or human antibody. 
     
     
         53 . The method of  claim 48 , wherein the antibody is afucosylated. 
     
     
         54 . The method of  claim 48 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:7. 
     
     
         55 . The method of  claim 48 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:8. 
     
     
         56 . The method of  claim 48 , wherein the antibody is obinutuzumab. 
     
     
         57 . The method of  claim 48 , wherein the antibody comprises a modified Fc region. 
     
     
         58 . The method of  claim 57 , wherein the Fc region comprises a modification for attenuating effector function. 
     
     
         59 . The method of  claim 57 , wherein the Fc region is a human IgG1 Fc region. 
     
     
         60 . The method of  claim 59 , wherein the Fc region comprises L234A, L235A and P329G amino acid substitutions, numbering according to EU index. 
     
     
         61 . The method of  claim 48 , wherein the individual is a human.