Abstract

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CCR5 monoclonal antibody PRO 140 inhibited HIV-1 resistant to maraviroc, a small molecule CCR5 antagonist

Presented by Andre J. Marozsan, United States.

A.J. Marozsan1, T.J. Ketas1, W. Huang2, J. Toma2, J.M. Whitcomb2, C.J. Petropoulos2, P.J. Maddon1, W.C. Olson1


1Progenics Pharmaceuticals, Inc., Tarrytown, United States, 2Monogram Biosciences, South San Francisco, United States

Background: PRO 140 is a humanized monoclonal antibody that binds CCR5 and is designed to inhibit CCR5-tropic (R5) HIV-1 replication. In a phase 1b clinical study in subjects with only R5 HIV-1 detectable, a single 5 mg/kg intravenous infusion of PRO 140 reduced HIV-1 RNA levels by 1.83 log10 on average. PRO 140 and small-molecule antagonists, such as maraviroc, bind distinct sites on CCR5, and the differences in binding may confer different determinants of viral resistance. To test this hypothesis, viruses were selected for resistance to maraviroc and tested for susceptibility to PRO 140 in vitro.
Methods: The HIV-1 Case C 1/85 (CC1/85) isolate was cultured in CD8-depleted, stimulated peripheral blood mononuclear cells in the presence or absence of escalating concentrations of maraviroc. Cultures were passaged weekly with 25% of the culture being carried over from the previous passage. Cultures were continued until the virus replicated in 10 µM maraviroc for 3 consecutive weeks. HIV-1 envelope genes were cloned from the culture supernatants, sequenced, and tested for co-receptor usage and drug susceptibility using Trofile
ä and PhenoSenseä Entry assays, respectively.
Results: Maraviroc-resistant virus was isolated following 31 weeks of culture. The V3 region of this virus contained mutations (A316T, A319S, and I323V) that were previously associated with CC1/85 maraviroc resistance (Westby et al). Trofile
ä assay results showed that maraviroc-resistant and passage-control viruses continued to utilize CCR5 exclusively for entry. Maraviroc-resistant viruses displayed reduced maximal inhibition (48%) by maraviroc, but remained susceptible to inhibition by PRO 140 with a maximal inhibition (98%) and concentration (1.1-fold change IC50) similar to that of the parental isolate in the Phenosenseä Entry Assay.
Conclusions: Maraviroc-resistant viruses did not exhibit cross-resistance to PRO 140 in this study. The findings support the view that PRO 140 represents a CCR5 inhibitor class that is distinct from the small molecule drug, maraviroc.



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