Methods for reducing viral load in HIV-1-infected patients

Abstract

This method provides a method for reducing HIV-1 viral load in an HIV-1-infected human subject which comprises administering to the subject at a predefined interval effective HIV-1 viral load-reducing doses of (a) a humanized antibody designated PRO 140, or of (b) an anti-CCR5 receptor monoclonal antibody. This invention also provides a method for inhibiting in a human subject the onset or progression of an HIV-1-associated disorder, the inhibition of which is effected by inhibiting fusion of HIV-1 to CCR5 + CD4 + target cells in the subject. This invention also provides a method for treating a subject infected with HIV-1 comprising administering to the subject (a) a monoclonal antibody which (i) binds to a CCR5 receptor on the surface of the subject's CD4 + cells and (ii) inhibits fusion of HIV-1 to the subject's CCR5 + CD4+ cells, and (b) a non-antibody CCR5 receptor antagonist, in amounts effective to treat the subject.

1 . A method for reducing HIV-1 viral load in an HIV-1-infected human subject which comprises administering to the subject at a predefined interval effective HIV-1 viral load-reducing doses of a humanized antibody designated PRO140, wherein PRO140 comprises (i) two light chains, each light chain comprising the expression product of the plasmid designated pVK:HuPRO140-VK (ATCC Deposit Designation PTA-4097), and (ii) two heavy chains, each heavy chain comprising the expression product of either the plasmid designated pVg4:HuPRO140 HG2-VH (ATCC Deposit Designation PTA-4098) or the plasmid designated pVg4:HuPRO140 (mut B+D+I)-VH (ATCC Deposit Designation PTA-4099), wherein the effective HIV-1 viral load-reducing dose comprises from 0.1 mg per kg to 10 mg per kg of the subject's body weight, so as to thereby reduce the subject's HIV-1 viral load. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the effective viral load-reducing dose is from 0.25 mg per kg to 7.5 mg per kg of the subject's body weight. 
     
     
         6 . The method of  claim 5 , wherein the dose is from 0.5 mg per kg to 5 mg per kg of the subject's body weight. 
     
     
         7 . The method of  claim 6 , wherein the dose is from 1 mg per kg to 3 mg per kg of the subject's body weight. 
     
     
         8 . The method of  claim 7 , wherein the dose is 2 mg per kg of the subject's body weight. 
     
     
         9 . The method of  claim 1 , the effective viral load-reducing dose is sufficient to achieve in the subject a serum concentration of the antibody of at least 400 ng/ml. 
     
     
         10 . The method of  claim 9 , wherein the doses administered at regular intervals are sufficient to achieve and maintain in the subject a serum concentration of the antibody of at least 1 μg/ml. 
     
     
         11 . The method of  claim 10 , wherein the doses are sufficient to achieve and maintain in the subject a serum concentration of the antibody of about 3 to about 12 μg/ml. 
     
     
         12 . The method of  claim 10 , wherein the doses are sufficient to achieve and maintain in the subject a serum concentration of the antibody of at least 5 μg/ml. 
     
     
         13 . The method of  claim 12 , wherein the doses are sufficient to achieve and maintain in the subject a serum concentration of the antibody of at least 10 μg/ml. 
     
     
         14 . The method of  claim 13 , wherein the doses are sufficient to achieve and maintain in the subject a serum concentration of the antibody of at least 25 μg/ml. 
     
     
         15 . The method of  claim 14 , wherein the doses are sufficient to achieve and maintain in the subject a serum concentration of the antibody of at least 50 μg/ml. 
     
     
         16 . The method of  claim 1 , wherein the predefined interval is at least once weekly. 
     
     
         17 . The method of  claim 16 , wherein the predefined interval is every two to four weeks. 
     
     
         18 . The method of  claim 17 , wherein the predefined interval is every two weeks. 
     
     
         19 . The method of  claim 17 , wherein the predefined interval is every four weeks. 
     
     
         20 . The method of  claim 16 , wherein the predefined interval is at least once monthly. 
     
     
         21 . The method of  claim 16 , wherein the predefined interval is every six weeks. 
     
     
         22 . The method of  claim 16 , wherein the predefined interval is every eight weeks. 
     
     
         23 . The method of  claim 1 , wherein the reduction of the subject's HIV-1 viral load is maintained for at least one week. 
     
     
         24 . The method of  claim 23 , wherein the reduction of the subject's HIV-1 viral load is maintained for at least two weeks. 
     
     
         25 . The method of  claim 24 , wherein the reduction of the subject's HIV-1 viral load is maintained for at least four weeks. 
     
     
         26 . The method of  claim 25 , wherein the reduction of the subject's HIV-1 viral load is maintained for at least three months. 
     
     
         27 . The method of  claim 1 , wherein the antibody is administered via intravenous infusion. 
     
     
         28 . The method of  claim 1 , wherein the antibody is administered via subcutaneous injection. 
     
     
         29 . The method of  claim 1 , wherein the subject's HIV-1 viral load is reduced by at least 50% following administration of the antibody. 
     
     
         30 . The method of  claim 29 , wherein the subject's HIV-1 viral load is reduced by at least 70% following administration of the antibody. 
     
     
         31 . The method of  claim 30 , wherein the subject's HIV-1 viral load is reduced by at least 90% following administration of the antibody. 
     
     
         32 . The method of  claim 1 , further comprising administering to the subject at least one anti-HIV-1 anti-retroviral agent. 
     
     
         33 . The method of  claim 32 , wherein the anti-HIV-1 anti-retroviral agent is a nonnucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor (PI), a fusion inhibitor, or any combination thereof. 
     
     
         34 . The method of  claim 1 , wherein the subject is treatment-naïve. 
     
     
         35 . The method of  claim 1 , wherein the subject is treatment-experienced. 
     
     
         36 . The method of  claim 1 , wherein (a) prior to administering the monoclonal antibody to the subject, the subject has received treatment with at least one anti-HIV-1 anti-retroviral agent, and (b) concurrent with administering the monoclonal antibody, the subject continues to receive treatment with the agent or agents, so as to enhance the reduction of HIV-1 viral load in the subject. subject. 
     
     
         37 . The method of  claim 36 , wherein the anti-HIV-1 anti-retroviral agent is a nonnucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor (PI), a fusion inhibitor, or any combination thereof. 
     
     
         38 - 43 . (canceled) 
     
     
         44 . The method of  claim 33 , wherein the fusion inhibitor is a non-antibody CCR5 antagonist. 
     
     
         45 - 66 . (canceled) 
     
     
         67 . The method of  claim 44 , wherein the non-antibody CCR5 receptor antagonist is a small organic molecule. 
     
     
         68 . The method of  claim 67 , wherein the CCR5 receptor antagonist is SCH-D, UK-427,857, TAK-779, TAK-652 or GW873140. 
     
     
         69 . The method of  claim 44 , wherein the CCR5 receptor antagonist is an agent that competes with (i) SCH-D's binding to the CCR5 receptor, (ii) UK-427,857's binding to the CCR5 receptor, (iii) TAK-779's binding to the CCR5 receptor, (iv) TAK-652's binding to the CCR5 receptor, or (v) GW873140's binding to the CCR5 receptor. 
     
     
         70 - 73 . (canceled) 
     
     
         74 . The method of  claim 67 , wherein the CCR5 receptor antagonist is administered a plurality of times and the effective amount per administration comprises from 0.5 mg to 2,500 mg. 
     
     
         75 . The method of  claim 74 , wherein the amount is from 5 mg to 1,250 mg. 
     
     
         76 . The method of  claim 74 , wherein the amount is from 5 mg to 15 mg of the antagonist to the subject. 
     
     
         77 . The method of  claim 76 , wherein the amount is from 50 mg to 1,250 mg of the antagonist to the subject. 
     
     
         78 . The method of  claim 77 , wherein the amount is from 200 mg to 800 mg of the antagonist to the subject. 
     
     
         79 . The method of  claim 78 , wherein the amount is from 300 mg to 600 mg of the antagonist. 
     
     
         80 . The method of  claim 67 , wherein the CCR5 receptor antagonist is administered orally once or twice per day. 
     
     
         81 . The method of  claim 68 , wherein the CCR5 receptor antagonist is administered orally three or fewer times per day. 
     
     
         82 - 104 . (canceled) 
     
     
         105 . The method of  claim 1 , wherein PRO140 comprises (i) two light chains, each light chain comprising the expression product of the plasmid designated pVK:HuPRO140-VK (ATCC Deposit Designation PTA-4097), and (ii) two heavy chains, each heavy chain comprising the expression product of the plasmid designated pVg4:HuPRO140 HG2-VH (ATCC Deposit Designation PTA-4098). 
     
     
         106 . The method of  claim 1 , wherein PRO140 comprises (i) two light chains, each light chain comprising the expression product of the plasmid designated pVK:HuPRO140-VK (ATCC Deposit Designation PTA-4097), and (ii) two heavy chains, each heavy chain comprising the expression product of the plasmid designated pVg4:HuPRO140 (mut B+D+I)-VH (ATCC Deposit Designation PTA-4099).