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).
The Journal of Immunology, 2007, 178: 131.20.
Michelle Kuhne1, Benjamin Preston1, Steven Wallace1, Sharline Chen1, Geetha Vasudevan2, Alison Witte1 and Pina Cardarelli1
1 Cell Biology and Pharmacology, 2 Scientific Computing, Medarex, Inc., 1324 Chesapeake Terrace, Sunnyvale, CA, 94089
Abstract
The chemokine, CXCL10 or interferon {gamma} 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. CXCL10 levels are elevated in ulcerative colitis (UC) amongst other inflammatory diseases. In preclinical animal models of UC, antibodies against CXCL10 have been shown to modify disease progression. Medarex, Inc. has developed a fully human monoclonal antibody (MDX-1100) 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 with an estimated IC50 in the low nM range. In order to identify potential pharmacodynamic markers for CXCL10 activity, gene chip analysis was performed with RNA purified from CXCL10-stimulated human PBMCs. 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. |
