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Abstract



Antiviral synergy between the CCR5 mAb PRO 140 and small-molecule CCR5 antagonists

Murga J.1, Olson W.1, Pevear D.1

Introduction: PRO 140 is a humanized monoclonal antibody (mAb) to CCR5, which serves as the major fusion coreceptor for HIV-1. Currently in Phase 1 human testing, PRO 140 broadly and potently inhibits R5 HIV-1 without CCR5 antagonism. In the present studies, we examined the in vitro inhibitory interactions between PRO 140 and small-molecule CCR5 antagonists, including SCH-C, SCH-D and TAK-779, as well as with the only approved entry inhibitor, T-20 (Fuzeon). The studies could have utility in the design of clinical trials that examine combinations of entry inhibitors.
Methods: In order to study the combination effects of inhibitors on HIV-1 entry, we have utilized a fluorescence resonance energy transfer (RET) assay that measures the fusion of effector HeLa cells expressing HIV-1 JR-FL env glycoproteins to target HeLa cells expressing CD4 and CCR5 (Litwin et al., J. Virol. 70:6437). This assay faithfully recapitulates each stage of the HIV-1 entry process. Confirmatory assays examined inhibition of single-cycle, luciferase-encoding HIV-1 pseudoviruses complemented with env from additional HIV-1 isolates. Inhibition data were analyzed for cooperativity using the Combination Index method.
Results: PRO 140 exhibited potent and reproducible synergy with small-molecule CCR5 antagonists and with T-20. Synergies routinely translated into 5- to 10-fold dose reductions, suggesting significant improvement in inhibitory potency for the drug combinations. In contrast, purely additive effects were observed for combinations of small-molecule CCR5 antagonists. The findings may reflect the patterns of CCR5 recognition: Whereas small-molecule CCR5 antagonists bind a common hydrophobic pocket defined by the transmembrane regions of CCR5, PRO 140 recognizes an extracellular epitope that spans multiple hydrophilic domains.
Conclusions: PRO 140 inhibits HIV-1 entry synergistically with small-molecule CCR5 antagonists and with T-20. The findings support the use of PRO 140 in combination with other HIV-1 entry inhibitors and suggest that PRO 140 represents a distinct CCR5 inhibitor subclass.





The 3rd IAS Conference on HIV Pathogenesis and Treatment
Abstract no. TuOa0206


Suggested Citation
"MurgaJ., et al. Antiviral synergy between the CCR5 mAb PRO 140 and small-molecule CCR5 antagonists. Oral Abstract Sessions: The 3rd IAS Conference on HIV Pathogenesis and Treatment: Abstract no. TuOa0206"