Integrins of the alphav family, such as alphavbeta3 and alphavbeta5, are implicated in tumor-induced angiogenesis; but their role in tumor growth has not been fully explored. CNTO 95 is a fully human antibody that recognizes the alphav family of integrins and is likely to be less immunogenic in humans compared to chimeric or humanized antibodies. CNTO 95 bound to purified alphavbeta3 and alphavbeta5 with a Kd of approximately 200 pM and to alphav integrin-expressing human cells with a Kd of 1-24 nM. In vitro, CNTO 95 inhibited human melanoma cell adhesion, migration and invasion at doses ranging 7-20 nM. In a rat aortic ring sprouting assay, CNTO 95 (approx. 70 nM) completely inhibited sprouting. Using a human melanoma xenograft model in nude mice wherein CNTO 95 recognized alphavbeta3 and alphavbeta5 on human tumor cells but not mouse angiogenic integrins, CNTO 95 (10 mg/kg, 3 times/week) inhibited growth of human melanoma tumors in nude mice by approximately 80% (p = 0.0005), suggesting that CNTO 95 inhibited human tumor growth independently of its antiangiogenic activity. In a nude rat human xenograft model where CNTO 95 binds and blocks both tumor and host integrins, this antibody (10 mg/kg once/week) reduced final tumor weight by >99% (p < 0.0001). Based on these preclinical data, a dose-escalating phase I clinical trial in cancer patients has been initiated. To our knowledge, CNTO 95 is the first fully human MAb to alphav integrins that has potent antitumor and antiangiogenic properties in in vivo preclinical models.

Proc Amer Assoc Cancer Res, Volume 45, 2004 2998 Increased expression and activity of urokinase and its receptor, uPAR, has been associated with tumor growth and metastasis, and blockage of the interaction between urokinase and uPAR by peptide antagonists or antisense methods has been demonstrated to decrease tumor growth, angiogenesis and metastasis. Using a monoclonal rat antibody against murine uPAR that interferes with the binding of uPA to its receptor, we found significant inhibition of bFGF-stimulated angiogenesis in a mouse subcutaneous Matrigel model. In vitro, antibody blockage of the uPA/uPAR interaction reduced the invasion of murine Lewis lung carcinoma cells through reconstituted basement membrane, as well as the adhesion of these cells to vitronectin. In an in vivo tumor model, nude mice bearing subcutaneous murine Lewis lung tumors were treated with anti-uPAR via i.p. injection three times weekly (10 mg/kg). Although primary tumor growth was not affected, the number of lung metastases was significantly reduced by antibody treatment, consistent with the involvement of uPA/uPAR in the early steps of the metastatic cascade. These observations suggest that blockage of the uPA/uPAR interaction by an antibody can inhibit multiple processes involved in tumor progression.