US2007026441A1PendingUtilityA1

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

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Assignee: OLSON WILLIAM CPriority: Jul 22, 2005Filed: Jul 21, 2006Published: Feb 1, 2007
Est. expiryJul 22, 2025(expired)· nominal 20-yr term from priority
Inventors:William OlsonPaul J. MaddonDaniel C. PevearRobert J. IsraelJose D. Murga
A61K 2039/55511C07K 2317/24A61K 39/39A61K 2039/505A61K 31/46A61K 31/4178A61K 31/551C07K 2317/76A61P 31/18A61K 31/506C07K 16/2866A61K 39/39541A61K 31/7072A61K 31/496A61P 43/00C12Q 1/701A61K 38/195A61K 38/1709A61K 39/3955A61K 31/351A61K 39/395
62
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Claims

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.

Claims

exact text as granted — not AI-modified
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) a humanized antibody designated PRO 140, or of (b) an anti-CCR5 receptor monoclonal antibody which (i) binds to CD4+ CCR5+ cells in the subject and inhibits fusion of HIV- 1  with such cells, (ii) inhibits HIV-1 fusion with CD4+ CCR5+ cells with a potency equal or greater than that of PRO 140, (iii) coats CD4+ CCR5+ cells in the subject without reducing the number of such cells in the subject, and/or (iv) binds to the subject's CD4+ CCR5+ cells without inducing an increase in the subject's plasma concentration of circulating β-chemokines, wherein PRO 140 comprises (i) two light chains, each light chain comprising the expression product of the plasmid designated pVK:HuPRO140-VK (ATCC Deposit Designation PTA4097), 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 . The method of  claim 1 , wherein the anti-CCR5 receptor monoclonal antibody binds to the same CCR5 epitope as that to which PRO 140 binds.  
     
     
         3 . The method of  claim 1 , wherein the anti-CCR5 receptor monoclonal antibody is a humanized, human, or chimeric antibody.  
     
     
         4 . The method of  claim 1 , wherein the antibody administered to the subject is the antibody designated PRO 140.  
     
     
         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 . (canceled)  
     
     
         31 . (canceled)  
     
     
         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 normucleoside 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.  
     
     
         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 - 41 . (canceled)  
     
     
         42 . A method for reducing HIV-1 viral load in an HIV-1-infected human subject who has developed resistance to a form of anti-HIV-1 therapy, which method 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 which (i) binds to CD4+ CCR5+ cells in the subject and inhibits fusion of HIV-1 with such cells, (ii) inhibits HIV-1 fusion with CD4+ CCR5+ cells with a potency equal or greater than that of PRO 140, (iii) coats CD4+ CCR5+ cells in the subject without reducing the number of such cells in the subject, and/or (iv) binds to the subject's CD4+ CCR5+ cells without inducing an increase in the subject's plasma concentration of circulating β-chemokines, wherein PRO 140 comprises (i) two light chains, each light chain comprising the expression product of the plasmid designated pVK:HuPRO140-VK (ATCC Deposit Designation PTA4097), and (ii) two heavy chains, each heavy chain comprising the expression product of either the plasmid designated pVg4:HuPRO140 HG2-VH (ATCC Deposit Designation PTA4098) or the plasmid designated pVg4:HuPRO140 (mut B+D+I)-VH (ATCC Deposit Designation PTA4099), 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.  
     
     
         43 - 46 . (canceled)  
     
     
         47 . 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.  
     
     
         48 - 90 . (canceled)  
     
     
         90 . A method of potentiating HIV-1 inhibitory activity of (i) an anti-CCR5 receptor monoclonal antibody or (ii) a non-antibody CCR5 receptor antagonist in the treatment of HIV-1 infection in a subject, comprising: administering to the subject an HIV-1 inhibitory activity potentiating amount of the anti-CCR5 receptor monoclonal antibody in combination with an HIV-1 inhibitory activity potentiating amount of a non-antibody CCR5 receptor antagonist, wherein the combination produces a synergistic effect on inhibiting HIV-1 infection, thereby potentiating the inhibitory activity of (i) the anti-CCR5 receptor monoclonal antibody or (ii) the non-antibody CCR5 receptor antagonist.  
     
     
         91 - 104 . (canceled)

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