Background/Purpose: Melanoma cell adhesion molecule (MCAM; CD146) is expressed on the surface of Th17 cells, which have the capacity to produce IL-17 and a multitude of other cytokines.  The expression of MCAM and production of IL-17 are defining characteristics of Th17 cells. MCAM is hypothesized to be central to the pathogenesis of numerous autoimmune disorders, including psoriasis and psoriatic arthritis by modulating the adhesion and transmigration of Th17 cells through its interaction with vascular Laminin a4 (LAMA4). Unlike targeting an individual cytokine, PRX003, a monoclonal antibody designed to bind MCAM and block its interaction with LAMA4, might prevent the release of IL17 and other cytokines by limiting Th17 cell infiltration and subsequent pathogenic inflammation. The study objective was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PRX003 in healthy human subjects.

Methods: In a first-in-human, randomized, double-blind, placebo-controlled, Phase 1, single ascending dose-escalation study (NCT02458677) in healthy volunteers, PRX003 was administered by IV infusion over approximately 60 minutes. Five escalating dose cohorts received 0.3, 1.0, 3.0, 10, or 30 mg/kg of PRX003 or placebo (8 subjects/cohort in a 6:2 ratio) and were monitored for 24 hours and by periodic follow-up for 12 weeks. PD measurements included MCAM expression on circulating T-lymphocytes and serum soluble MCAM.

Results: After a single infusion, PRX003 was well tolerated at doses up to and including 30 mg/kg, the highest dose level tested. No PRX003-related serious or severe adverse events, no dose-limiting toxicities, no anti-drug antibodies or infusion-related reactions were reported. The most common treatment emergent adverse events (TEAEs), regardless of causality, were: headache (n=3, 10%), seasonal allergy (n=2, 6.7%), upper respiratory tract infection (n=2, 6.7%) and transient balance disorder (n=2, 6.7%). All TEAEs were mild to moderate. The PK of PRX003 were consistent with distribution to and saturation of MCAM with sustained exposures that fully saturated MCAM for >43 days at 30 mg/kg. Early and dose-proportional signs of demargination were observed.

This study supports the hypothesis that MCAM occupancy and down-regulation by PRX003 promotes demargination and sequestration of Th17 cells in the vascular space, limiting their extravasation.

Conclusion: These data collectively suggest that PRX003 may block MCAM-mediated extravasation of Th17 cells and support further examination of PRX003 in patients with inflammatory disease. A Phase 1b multiple ascending dose trial of PRX003 in patients with psoriasis (NCT02630901) is ongoing.