CXCR4 is involved in multiple functions of cancer cells and is a compelling target for monoclonal antibody-based therapeutics

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20013 Background: CXCR4 is over-expressed on > 75% of cancers and absent on most non-neoplastic cells. It is a G protein coupled receptor spanning the cell membrane with CXCL-12 as its ligand. It is uniquely involved in 3 vital aspects of cancer: 1) proliferation; 2) motility; and 3) metastasis. Our objective was to assess specific Abs as candidates for clinical development in preclinical models. Methods: Several human cancer cell lines were used to study whether either mAbs specific to the CXCR4 receptor or to CXCL12 could inhibit: 1) proliferation; 2) chemotaxis; and 3) invasion through a reconstituted basement membrane. The ability of anti-CXCR4 Ab to inhibit tumor growth in vivo was also tested. Female Nod/Scid mice were injected IP with 2 × 105 human Namalwa tumor cells with 10 mice per group. Mice were injected with: Group 1) 100μg irrelevant IgG2b isotype control Ab; Group 2) 100μg CX02 anti-CXCR4 Ab; and Group 3) 100 μg CX05 anti-CXCR4 Ab. All mice in each group received an injection of Ab at day 2, 8, 14 and 20. Mice were observed for tumor growth over the following 4–5 months. Results: We originally found that CXCR4 was over expressed in fresh surgical human Glioblastoma, then showing that it was also over expressed in multiple cancer types. Specific anti-CXCR4 monoclonal Abs, CX02 and CX05 as well as anti-CXCL12 Abs demonstrated the ability to block cell proliferation of a variety of human Glioblastoma tumor cells including GB1690, HTB16, and 5GB, but not the proliferation of cells that do not express CXCR4. CX02 and CX05 Abs bind to live tumor cells with high affinity and have an EC50 of 3.2 and 2.7 μg/ml respectively (effective concentration required to provide 50% maximal median fluorescence shift). Both Abs (10 μg/ml) also inhibited by over 90% the motility of HS Sultan cells as demonstrated by the standard chemotaxis assays. In addition, both Abs (10–40 μg/ml) also inhibited the ability of HS Sultan cells to penetrate Matrigel, a reconstituted basement membrane assay used to assess malignant potential of cancer cells. Finally, both Abs were successful in extensively prolonging survival of Nod/Scid mice injected with human Namalwa cells. Conclusions: CXCR4 represents a compelling target for mAb therapy; Phase I clinical trails are pending. [Table: see text]