Abstract 4571: 515H7, a novel anti-CXCR4 antibody: In vitro efficacy on CXCR4-associated signaling pathways and in vivo anti-tumor activity

Chemokines are small, secreted peptides that control the migration of leukocytes along a chemical gradient of ligand, especially during immune and inflammatory reactions. They are divided into two major subfamilies, CC and CXC, based on the position of their NH2-terminal cysteine residues, and bind to G protein coupled receptors, whose two major sub families are designated CCR and CXCR. More than 50 human chemokines and 18 chemokine receptors have been discovered so far. Chemokine receptor CXCR4/[Stromal cell-derived factor (SDF)-1] axis plays a central role in various physiological and pathological processes, including cancer. CXCR4 is over-expressed in a large number of tumors: colon, breast, prostate, lung, ovary, pancreas. CXCR4/SDF-1 axis is directly implicated in migration, invasion leading to metastases, cell proliferation and angiogenesis. Moreover, CXCR4 overexpression correlated with poor prognosis in many types of cancer. A novel monoclonal antibody (Mab 515H7) was raised against the human CXCR4. It displayed efficacious antagonist properties for all major pathways associated with SDF-1-induced CXCR4 signaling in vitro. It was able to efficiently bind CXCR4 on both transfected cells and human tumor cell lines. It was found to strongly inhibit SDF-1 binding, Gα protein activation and beta-arrestin2 recruitment. It also blocked second messenger release (calcium, cAMP) and constrained by itself the formation of CXCR4 homodimers. It also inhibits SDF-1-induced cell migration in vitro. 515H7 Mab antitumor activities were also investigated in vivo using several human tumor models. We demonstrated that 515H7 Mab was able to significantly inhibit growth of xenograft tumors in mice. In addition to its effect on tumor growth, 515H7 Mab was also able to significantly improve mice survival in the lethal U937 model. The herewith data demonstrate that Mab 515H7 behaves as a potent and efficacious antagonist of all major CXCR4-controlled signaling pathways and suggest that targeting CXCR4 is a promising way for the treatment of tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4571. doi:10.1158/1538-7445.AM2011-4571