Humanized Anti-CCR5 MoAb Blocks HIV Entry: Preclinical Trial

SAN DIEGO, California—Pro-genics Pharmaceuticals’ humanized monoclonal antibody (MoAb) PRO 140 has been shown to block HIV entry into immune system cells. The agent acts by binding to a portion of the CCR5 fusion coreceptor present on the outer membrane of immune system cells. William C. Olson, PhD, vice president of research and development at Progenics, Tarry-town, New York, presented the research at the 42nd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (abstract H-178).

The agent’s antiviral activity was examined using both whole-virus p24 assays and a novel fluorometric fusion assay. The virologic studies examined a broad range of wild-type and drug-resistant HIV-1 isolates and diverse primary target cell types.

The researchers found that PRO 140 actively blocked HIV-1 replication in target cells as diverse as T cells, macrophages, and dendritic cells. The agent was similarly effective in blocking infection of T cells by dendritic-cell-associated virus in trans. Viral replication was completely suppressed at PRO 140 levels that had little or no effect on CC-chemokine signaling through CCR5 and other normal immunologic activities.

The researchers also showed that PRO 140 is synergistic in combination with other investigational HIV-1 entry inhibitors, including Progenics’ PRO 542, which blocks the CD4 coreceptor by binding to gp 120, and Roche/Trimeris’ fusion inhibitor enfuvirtide (Fuzeon, T-20), which works by blocking the gp 41 protein. [See ONI October 2002, page 13, for a report on enfuvirtide.]

The parent mouse antibody was recently humanized to support repeated dosing in humans, and humanized PRO 140 is entering phase I clinical testing. "Humanized PRO 140 broadly and potently blocks HIV-1 entry through CCR5 without interfering with the receptor’s normal activity and should be advanced into human clinical testing," Dr. Olson concluded.