Background:  The chemokine receptor CCR5 serves as a portal of entry for HIV-1, and blocking viral access to CCR5 inhibits HIV-1 replication in vitro and in man. PRO 140 is a humanized IgG4 CCR5 monoclonal antibody that broadly and potently blocks CCR5-mediated HIV-1 entry without CCR5 antagonism. PRO 140 is synergistic with and complementary to small-molecule CCR5 antagonists in development.

Methods:  A Phase 1, randomized, double-blind, placebo-controlled study was conducted to examine the safety, pharmacokinetics and pharmacodynamic effects of single-dose PRO 140 administered by intravenous infusion to healthy male subjects. Individuals were treated with 0.1, 0.5, 2.0, and 5.0 mg/kg PRO 140 in sequential, dose-rising cohorts of 5 subjects (4 active, 1 placebo) each and evaluated for 60 days post-treatment.

Results:  All 20 subjects received a full dose of study drug with no infusion-related toxicities observed. PRO 140 was generally well tolerated at all dose levels with no clinically meaningful drug-related side effects or changes in electrocardiograms during follow-up. Serum concentrations of PRO 140 increased proportionally with dose and decreased with a serum half-life of approximately 2 weeks. CCR5 lymphocytes were effectively coated with PRO 140 without cellular depletion. Surprisingly, CCR5 lymphocytes were coated for >60 days at 5 mg/kg PRO 140, and the study was extended to monitor these subjects for an additional 60 days. In preliminary bioanalytical testing, no significant change was observed in plasma levels of RANTES, and no anti-PRO 140 antibodies were observed.  

Conclusions:  PRO 140 demonstrated favorable tolerability, pharmacokinetic, and pharmacodynamic profiles in this initial study in humans, and the prolonged coating of CCR5 may presage durable antiviral effects in HIV-infected subjects. The findings support further development of PRO 140 as a novel and potentially long-acting therapy of HIV-1 infection.