Methods for inhibiting hiv-1 replication involving the administration of an anti-ccr5 receptor monoclonal antibody and small molecule ccr5 receptor antagonist

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 - 104 . (canceled) 
     
     
         105 . A combined dosage regime comprising an anti-CCR5 receptor monoclonal antibody comprising (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) and a small molecule CCR5 receptor antagonist, wherein the small molecule CCR5 receptor antagonist binds a hydrophobic pocket within the transmembrane domains of a CCR5 receptor, and wherein the combined dosage regime permits one of an approximately four-fold to ten-fold dose reduction of the anti-CCR5 receptor monoclonal antibody and an approximately three-fold to sixteen-fold dose reduction of the non-antibody CCR5 receptor antagonist. 
     
     
         106 . The combined dosage regime of  claim 105 , wherein the anti-CCR5 receptor monoclonal antibody is a humanized, human, or chimeric antibody. 
     
     
         107 . The combined dosage regime of  claim 105 , wherein the anti-CCR5 receptor monoclonal antibody is PRO 140. 
     
     
         108 . The combined dosage regime of  claim 107 , wherein the PRO 140 comprises one of an intravenous infusion dosage form and a subcutaneous injection dosage form. 
     
     
         109 . The combined dosage regime of  claim 105 , wherein the small molecule CCR5 receptor antagonist comprises an oral dosage form. 
     
     
         110 . A method of potentiating HIV-1 inhibitory activity of a small molecule CCR5 receptor antagonist in an HIV-1-infected subject who has been administered, or will be administered, the small molecule CCR5 receptor antagonist in the treatment of the subject's HIV-1 infection, comprising administering to the subject an HIV-1 inhibitory amount of an anti-CCR5 receptor monoclonal antibody, wherein the amounts of the anti-CCR5 receptor monoclonal antibody and the small molecule CCR5 receptor antagonist combined, produces a synergistic antiviral effect on treating the HIV-1 infection, thereby potentiating the HIV-1 inhibitory activity of the small molecule CCR5 receptor antagonist, wherein the anti-CCR5 receptor monoclonal antibody is PRO 140, said PRO 140 comprising (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) and wherein the small molecule CCR5 receptor antagonist binds a hydrophobic pocket within the transmembrane domains of the CCR5 receptor. 
     
     
         111 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody is a humanized, human, or chimeric antibody. 
     
     
         112 . The method of  claim 110 , wherein the PRO 140 is administered via one or intravenous infusion and subcutaneous injection. 
     
     
         113 . The method of  claim 110 , wherein the small molecule CCR5 receptor antagonist is orally administered. 
     
     
         114 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody is administered concurrently with administration of the small molecule CCR5 receptor antagonist. 
     
     
         115 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody is administered prior to administration of the small molecule CCR5 receptor antagonist. 
     
     
         116 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody is administered subsequent to administration of the small molecule CCR5 receptor antagonist. 
     
     
         117 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody administered dose delivers between 75 mg and 600 mg of the anti-CCR5 receptor monoclonal antibody. 
     
     
         118 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody administered dose delivers one of 75 mg, 150 mg, 300 mg, and 600 mg of the anti-CCR5 receptor monoclonal antibody. 
     
     
         119 . The method of  claim 110 , wherein the non-antibody CCR5 receptor antagonist provides for an approximately four-fold to ten-fold dose reduction of the anti-CCR5 receptor monoclonal antibody. 
     
     
         120 . The method of  claim 110 , wherein the anti-CCR5 receptor monoclonal antibody provides for an approximately three-fold to sixteen-fold dose reduction of the non-antibody CCR5 receptor antagonist. 
     
     
         121 . The method of  claim 110 , wherein the synergistic antiviral effect comprises a reduction in HIV-1 viral load in the HIV-1-infected subject that is maintained for at least one week. 
     
     
         122 . The method of  claim 110 , wherein the synergistic antiviral effect comprises a reduction in HIV-1 viral load in the HIV-1-infected subject that is maintained for at least two weeks. 
     
     
         123 . The method of  claim 110 , wherein the synergistic antiviral effect comprises a reduction in HIV-1 viral load in the HIV-1-infected subject that is maintained for at least four weeks. 
     
     
         124 . The method of  claim 110 , wherein the synergistic antiviral effect comprises a reduction in HIV-1 viral load in the HIV-1-infected subject that is maintained for at least three months.