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.