Tolerability and Antiviral Efficacy of CCR5 Monoclonal Antibody PRO 140

By Liz Highleyman

In order to enter human cells, HIV must attach to both the CD4 receptor and a co-receptor (either CCR5 or CXCR4) on the cell's surface. The first-ever CCR5 inhibitor, maraviroc (Selzentry), was approved by the FDA this week.

Another CCR5 inhibitor in the development pipeline works in a different manner. PRO 140 is a recombinant humanized monoclonal antibody that attaches to the part of the CCR5 receptor used by HIV, and thereby prevents the entry of CCR5-tropic virus.

Inhibition of virus entry of CCR5-utilizing (monocytotropic) and CXCR4-utilizing (T-cell tropic) HIV isolates by the natural ligands of the chemokine coreceptors CCR5 and CXCR4.

Past laboratory studies have shown that PRO 140 inhibits wild-type (non-mutated) and drug-resistant HIV in vitro, including strains resistant to small-molecule CCR5 antagonists such as maraviroc and vicriviroc. Single-dose PRO 140 demonstrated favorable tolerability and pharmacokinetic profiles in healthy HIV negative volunteers

At the recent 4th International AIDS Society Conference on HIV Treatment, Pathogenesis, and Prevention in Sydney, Australia (July 22-25, 2007), researchers presented data from the first study of PRO 140 in HIV positive individuals.

This randomized, double-blind, placebo-controlled study included 39 HIV positive subjects with exclusively CCR5-tropic virus, CD4 cell counts greater than 250 cells/mm3, HIV RNA greater than 5,000 copies/mL, and no antiretroviral therapy for at least 3 months. Participants were randomly assigned (10:3) to receive single intravenous infusions of PRO 140 monotherapy (0.5, 2, or 5 mg/kg) or placebo in sequential dose-ascending cohorts. Viral load, pharmacokinetic, and safety assessments were performed through day 59.

Results

• 10 days after dosing, mean maximum HIV RNA decreased by 0.58, 1.20 and 1.83 logs, respectively, in the 0.5 mg/kg, 2 mg/kg, and 5 mg/kg PRO 140 groups, compared with 0.39 logs in the placebo group.

• 1 of 10 subjects in the 0.5 mg/kg PRO 140 group, 6 of 10 in the 2 mg/kg group, and 10 of 10 in the 5 mg/kg group experienced a greater than 10-fold decrease in HIV RNA, compared with 0 of 9 in the placebo group.

• 2-3 weeks after dosing, HIV RNA remained a mean 1.0 log below baseline in the 5 mg/kg group.

• CD4 counts increased by a mean 129 cells/mm3 in the 5 mg/kg PRO 140 group.

• Antiviral effects were correlated with PRO 140 serum concentrations and CCR5 receptor occupancy as assessed by flow cytometry.

• PRO 140 was generally well tolerated.

• No drug-related serious adverse events or obvious patterns of toxicity were observed.

• 2 subjects showed evidence of HIV tropism switching from CCR5-tropic to CXCR4-tropic virus.

Conclusion

"Single-dose PRO 140 demonstrated favorable tolerability and potent, dose-dependent antiviral activity in HIV-infected individuals," the researchers concluded. "The study provides proof of concept for PRO 140 as a potent and long-acting antiretroviral agent."
Clinical trials of PRO 140 are continuing, and Progenics is testing a formulation that can be injected subcutaneously rather than infused intravenously.

University of Alabama, UAB Center for AIDS Research, Birmingham, AL; Drexel University, Philadelphia, PA; AIDS Research Consortium of Atlanta, GA; University of Miami, FL; Albany Medical Center, Albany, NY; University of Rochester, NY; University of Maryland, Baltimore, MD; University of Cincinnati, OH; Montefiore Medical Center and Einstein/Montefiore Center for AIDS Research, Bronx, NY; Jacobi Medical Center, Bronx, NY; Progenics Pharmaceuticals, Inc., Tarrytown, NY.

08/10/07

Reference
MS Saag, JM Jacobson, M Thompson, and others. Antiviral effects and tolerability of the CCR5 monoclonal antibody PRO 140: a proof of concept study in HIV-infected individuals. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract (late-breaker) WESS201.