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Session 58 Poster Session Entry Inhibitors Session Time: 4:30-6:30 pm Room 4E-F

403-T. The CCR5 Co-Receptor Inhibitor PRO 140 Effectively Controls Established HIV-1 Infection in Vivo M. Franti1, K. Nagashima2, P. Maddon1, D. R. Burton2, W. Olson2, and P. Poignard*1 1Scripps Res. Inst., La Jolla, CA and 2Progenics Pharmaceuticals, Inc., Tarrytown, NY Background: The increasing incidence of multidrug-resistant HIV-1 mandates the search for novel classes of antiretroviral agents. CCR5 is a requisite fusion co-receptor for primary HIV-1 isolates and provides a promising target for antiviral therapy. PRO 140 is an anti-CCR5 monoclonal antibody that potently inhibits HIV-1 entry and replication at concentrations that do not affect CCR5's chemokine receptor activity in vitro. In the present study, we evaluated the therapeutic potential of PRO 140 in vivo using a therapeutic animal model of HIV-1 infection. Methods: CB-17 SCID mice were reconstituted with normal human PBMC and infected with the R5 isolate HIV-1JR-CSF. When viral steady state was reached, the animals were treated intraperitoneally with PRO 140 or control antibody and monitored for viral burden using the Roche Amplicor assay. Initial studies examined a single 1-mg dose of PRO 140. In multi-dose studies, PRO 140 was administered once every 3 days for 3 weeks at doses ranging from 0.1-1.0 mg. In a separate experiment, flow cytometry was used to examine the potential for lymphocyte depletion following PRO 140 injection. Results: Both single-dose and multi-dose PRO 140 reduced viral loads to undetectable levels in all treated animals, and the viral load reductions ranged to 1.8 log10. A transitory control of viral replication was observed following single injection of PRO 140 while multiple injections led to a prolonged control with no evidence of viral rebound during therapy. Dose-dependent differences were observed in the kinetics of the PRO 140-mediated reductions in viral load. Flow cytometry analysis showed that treatment with PRO 140 did not lead to lymphocyte depletion, confirming that impact on viral replication in vivo was solely due to CCR5-blockage. Conclusions: PRO 140 is highly effective in controlling established HIV-1 infection in the hu-PBL-SCID mouse model of HIV-1 infection. These findings provide in vivo proof-of-concept for PRO 140 therapy in particular and for CCR5-inhibitors therapy in general.

©2002 9th Conference on Retroviruses and Opportunistic Infections