MDX-1100, A FULLY HUMAN ANTI-CXCL10 (IP-10) ANTIBODY, IS A HIGH AFFINITY, NEUTRALIZING ANTIBODY THAT HAS ENTERED PHASE I CLINICAL TRIALS FOR THE TREATMENT OF ULCERATIVE COLITIS (UC).
P.-M. Cardarelli 1, S. Chang 1, S. Deshpande 1, H. Govindarajan 1, M. Kuhne 1, B. Preston 1, G. Vasudevan 1, A. Witte 1
1 Department Of Cell Biology & Pharmacology, Medarex, Sunnyvale, CA, USA
The chemokine, CXCL10 or interferon inducible protein-10 (IP-10) is a chemotactic cytokine for activated T cells and monocytes and plays an important role in migration of cells into sites of inflammation. The receptor for CXCL10, CXCR3, is expressed by activated T cells, eosinophils, NK, and endothelial cells. In addition to binding to CXCL10, CXCR3 has been shown to bind to two other chemokine ligands, CXCL9 (MIG) and CXCL11 (ITAC). Elevated levels of CXCL10 correlating with disease activity have been measured in colonic biopsies from patients with Ulcerative Colitis (UC). In preclinical animal models of IBD, antibodies against CXCL10 have been shown to modify disease progression. Medarex, Inc. has developed a fully human monoclonal antibody (MDX-1100) of IgG1 (kappa) isotype that binds selectively to CXCL10. This antibody binds to the ligand with high affinity and effectively competes for ligand binding to CXCR3 expressing cells. MDX-1100 blocks CXCL10 induced calcium flux and cell migration and with an estimated low IC50 in the nM range. The administration of MDX-1100 was well tolerated in cynomolgus monkey. To identify potential pharmacodynamic markers for CXCL10 activity, RNA was purified from stimulated human PBMCs and a gene chip analysis was performed. We identified cell surface receptors, intracellular and soluble markers that are CXCL10 responsive and confirmed the induction of a subset of these genes using quantitative RT-PCR. In summary, MDX-1100, an antibody that binds and neutralizes the activity of CXCL10 is predicted to reduce disease severity in patients with UC and thus a Phase I clinical trial has been initiated.
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