Anti-Mcam Monoclonal Antibody PRX003 Inhibits the Unique Migratory Potential of Pathogenic IL-17–Producing T Cells
Sunday, March 6, 2016: 4:45 PM
Concourse Foyer (Convention Center)
Kenneth Flanagan, Stephen J. Tam, Lauri Li, Philip J. Dolan, Robin M. Barbour, Jeffrey N. Higaki, Yue Liu, Tarlochan Nijjar, Michael Skov, Wagner Zago, Ted A. Yednock, Gene F. Kinney, Dan Ness
Rationale: Melanoma cell adhesion molecule (MCAM) expression on a small subset of memory CD4+/CD8+ T cells defines their ability to secrete IL-17 and identifies the TH17 cell population critical in multiple autoimmune diseases. However, MCAM-expressing T cells also induce localized inflammation by secreting other cytokines after migration; this migratory potential is not targeted by existing therapeutics. Laminin α4 (LAMA4) is a vascular extracellular matrix molecule critical for T-cell transmigration across the blood-brain barrier though interaction with MCAM and, thus, provides a novel target for therapeutic intervention.

Methods: We characterized PRX003, a monoclonal antibody targeting an epitope on MCAM that is responsible for interactions with LAMA4 and that completely blocks laminin adhesion of MCAM-expressing cells in both in vitro and in vivo assays.

Results: PRX003 treatment resulted in complete loss of MCAM expression from the surfaces of circulating immune cells. MCAM inhibition in vivo inhibited T-cell infiltration into the central nervous system and culminated in slowing disease progression in multiple animal models, including experimental autoimmune encephalitis. In vivo toxicology in relevant animal species indicated that PRX003 is generally safe and well tolerated.

Conclusions: PRX003 was developed to inhibit only a small population of particularly pathogenic cells while sparing the vast majority of the immune system and preserving immune homeostasis. Given that this T-cell subpopulation appears critical to the immunopathogenesis of autoimmune diseases through its novel adhesion interaction, PRX003 may have highly selective effects. Clinical trials assessing the safety, pharmacokinetics, and mechanism of action of PRX003 are planned.