SAN DIEGO, CaliforniaPro-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.