OP0205 Clinical and Preclinical Assessment of The Anti-MCAM Monoclonal Antibody PRX003, A Potential Novel Treatment for Th17-Mediated Inflammatory Diseases. (15th July 2016)

• Record Type: Journal Article
• Authors: Koller, M.; Flanagan, K.; Skov, M.; Goldblum, R.; Griffith, S.G.; Barbour, R.M.; Ehsani-Chimeh, N.; Marinkovich, M.P.; Zago, W.; Yednock, T.A.; Kinney, G.G.; Ness, D.
• Is Part Of: Annals of the rheumatic diseases. Volume 75(2016)Supplement 2
• Page Start: 134
• Page End: 134
• Publication Date: 2016-07-15
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2016-eular.3570
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Melanoma cell adhesion molecule (MCAM; CD146) is expressed on the surfaces of a small population of T cells that have the capacity to produce a multitude of cytokines; further, expression of MCAM is a defining characteristic of TH17 cells. As such, MCAM is hypothesized to be central to the pathogenesis of numerous autoimmune disorders, including psoriasis and psoriatic arthritis. Laminin α4 (LAMA4), the primary MCAM ligand, promotes T-cell transmigration into sites of inflammation. Thus, inhibition of MCAM/LAMA4 binding may limit cell infiltration and subsequent pathogenic inflammation. PRX003, a monoclonal antibody designed to bind an MCAM epitope critical for LAMA4 interactions, blocks adhesion of MCAM-expressing cells to LAMA4 rather than targeting an individual cytokine, thus preventing the infiltration of cells responsible for disease pathogenesis. Objectives: Study objectives were twofold: (1) to demonstrate preclinical proof of concept for anti-MCAM antibodies in mice overexpressing RAC1, an aggressive transgenic model of psoriasis and (2) to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PRX003 in healthy human subjects. Methods: The effects of anti-MCAM antibodies (murine homolog of PRX003) on the MCAM expression of circulating immune cells and on disease progression were assessed in RAC1 mice treated 3×/week with anti-MCAM antibodies (0.1 or 10 mg/kg) or isotype control from postnatal day 7 (when disease progression is evident) through postnatal day 34. In a first-in-human, randomized, double-blind, placebo-controlled, phase 1, single ascending dose-escalation study (NCT02458677 ), PRX003 was administered by intravenous 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 (6 subjects randomized to PRX003 and 2 to placebo per cohort) and were subsequently monitored in an inpatient unit for 24 hours and by periodic follow-up for 12 weeks. PD measurements in humans included MCAM expression on circulating T-lymphocytes and serum soluble MCAM. Results: Anti-MCAM antibodies demonstrated target-mediated binding to circulating immune cells after administration to RAC1 transgenic mice. Furthermore, anti-MCAM antibody-treated mice experienced marked reductions in MCAM expression levels on circulating cells, resulting in diminished (by 40% to 60%) psoriatic disease progression, as evidenced by less erythema, scaling, and skin thickness than were observed in RAC1 transgenic mice treated with an isotype control antibody. PRX003 may thus have a beneficial impact on inflammatory diseases in humans. Data on the safety, tolerability, serum PRX003 PK, and immunogenicity of PRX003 in healthy human subjects, including PK/PD modeling of markers of target engagement, will be presented for the first time. Conclusions: The results of these studies and of previously published reports support further examination of PRX003 in patients with inflammatory disease. A phase 1 multiple ascending dose trial of PRX003 in patients with plaque psoriasis (NCT02630901 ) is planned. Disclosure of Interest: M. Koller Shareholder of: Prothena, Employee of: Prothena, K. Flanagan Shareholder of: Prothena, Employee of: Prothena, M. Skov Shareholder of: Prothena, Employee of: Prothena, R. Goldblum Consultant for: Prothena, Vascular BIogenics Limited, Sophiris, S. Griffith Consultant for: Prothena, R. Barbour Shareholder of: Prothena, Employee of: Prothena, N. Ehsani-Chimeh: None declared, M. Marinkovich: None declared, W. Zago Shareholder of: Prothena, Employee of: Prothena, T. Yednock Shareholder of: Prothena, Consultant for: Prothena, G. Kinney Shareholder of: Prothena, Consultant for: Janssen, Employee of: Prothena, D. Ness Employee of: Prothena