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.

Description

[0001]This application claims benefit of U.S. Provisional Application No. 60 / 702,064, filed Jul. 22, 2005; U.S. Provisional Application No. 60 / 701,889, filed Jul. 23, 2005; U.S. Provisional Application No. 60 / 711,528, filed Aug. 26, 2005; and U.S. Provisional Application No. 60 / 715,619, filed Sep. 9, 2005; the contents of each of which in its entirety is hereby incorporated by reference into this application.[0002]This invention was made with support under United States Government Grant Nos. AI046871 and AI066329 from the National Institute of Allergy and Infectious Diseases. Accordingly, the United States Government has certain rights in the subject invention.[0003]Throughout this application, various publications are referenced in parentheses by author name and date, or by a patent or patent publication number. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of each of these publications in its en...

AI Technical Summary

Benefits of technology

[0031]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 PRO140, 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 PRO140, (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 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.

[0033]This invention further provides a method for reducing the likelihood of a human subject's contracting an HIV-1 infection which comprises administering to the subject at a predefined interval effective fusion-inhibitory doses of a humanized antibody designated PRO140, or of an anti-CCR5 receptor 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 the subject's CD4+CCR5+ cells with a potency characterized by an IC90 of 10 μg / ml or less, (iii) coats the subject's CD4+CCR5+ cells 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 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 each administration of the antibody delivers to the subject from 0.1 mg per kg to 10 mg per kg of the subject's body weight, so as to thereby reduce the likelihood of the subject's contracting an HIV-1 infection.

[0036]The invention further provides a method for reducing the likelihood of a subject's contracting an HIV-1 infection comprising administering to the subject (a) an antibody which (i) binds to a CCR5 receptor on the surface of a CD4+ cell and (ii) inhibits fusion of HIV-1 to a CCR5+CD4+ cell, and (b) a non-antibody antagonist of a CCR5 receptor, in amounts effective to reduce the likelihood of the subject's contracting an HIV-1 infection.

Problems solved by technology

However, TAK-779 exhibited poor oral bioavailability (Baba et al., 2005) and local injection site irritation (Iizawa et al., 2003), and has been replaced in clinical development by a TAK-779 derivative, TAK-652 (Baba et al., 2005).

However, most of the above-mentioned coreceptors are not very efficient, are not normally coexpressed with CD4, and function only with certain strains of HIV-1, HIV-2 or SIV.

These similarities may conceivably limit the number of genuine treatment options afforded by small-molecule CCR5 antagonists.

However, no prior study has examined the combination of different classes of CCR5 coreceptor inhibitors, such as anti-CCR5 mAbs and non-antibody CCR5 antagonists.

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