Anti-denatured collagen antibody D93: An extra-cellular matrix approach to treatment of solid tumors and metastasis

Proc Amer Assoc Cancer Res, Volume 47, 2006 236 The extracellular matrix (ECM) is an interconnected molecular network comprised mostly of collagen, which provides mechanical support for cells and tissues and regulates processes such as adhesion, migration, invasion, cell-cycle progression, proliferation, and survival. Structural remodeling of collagen by proteolytic enzymes secreted by tumor and endothelial cells during angiogenesis results in the exposure of cryptic sites that may play a role in angiogenesis and cell growth. Monoclonal antibodies that bind to cryptic sites on denatured (dn) collagen have been generated. Prior reports have demonstrated that the humanized anti-dn collagen monoclonal antibody D93 specifically binds to dn collagen and significantly inhibits tumor growth in M21 melanoma and MDA-MB-231 breast cancer models. Here we report studies in the MDA-MB-435 human breast orthotopic staged murine model, where D93 (5 mg/kg, b.i.w., i.v.) inhibited tumor growth up to 52%; increasing the total weekly dose did not further inhibit tumor growth. When D93 was combined with Taxol, greater inhibition of tumor growth was observed than with either treatment alone. Immunohistochemical evaluation of tumors and organs collected from D93 treated mice demonstrated that D93 targets to tumor vasculature. In an initial study using the human pancreatic BxPC3-GFP orthotopic staged murine model, D93 significantly inhibited tumor growth as well as metastasis to the lymph nodes by 50% and to the abdominal cavity (diaphragm) by 86%, compared to vehicle-treated animals. In non-human primates, the pharmacokinetic half-life of D93 was ∼10 days, and no significant toxicity was noted after administration of multiple doses of D93 based on gross observation, ECG, serum chemistry profiles and urine analyses. Conclusion: D93 significantly inhibits tumor growth in preclinical models of human melanoma, breast, or pancreatic cancer. In the MDA-MB-435 breast cancer model, tumor inhibitory effect of D93 is enhanced when in combination with Taxol beyond D93 and Taxol treatments alone. D93 also reduced metastasis to the abdominal cavity and lymph nodes in a pancreatic model. The specificity of D93 binding to cryptic sites exposed on collagen during angiogenesis and tumor growth may contribute to the selective localization of D93 in tumor vasculature of treated animals. D93 appears to be well tolerated in mice or non-human primates.