Targeting molecular pathways of tumor growth has recently become a major focus of anti-cancer treatments. The VEGF pathway has demonstrated significant mitogenic activity for arterial, venous, and lymphatic endothelial cells, induction of vascular permeability for extracellular remodeling, and activity as an endothelial cell growth factor. The proof of principle that targeting the VEGF pathway as an anti-cancer therapy was demonstrated by the phase III trial of the anti-VEGF monoclonal antibody bevacizumab versus placebo in combination with chemotherapy for metastatic colorectal cancer. In this trial the addition of bevacizumab to chemotherapy showed a statistically significant improvement in overall survival for these subjects (11). Since this trial, the addition of bevacizumab to chemotherapy has been shown to be beneficial in non-small cell lung cancer subjects and metastatic breast cancer subjects (9, 12).

Integrins have been shown to be essential components of angiogenesis. One of the best-characterized integrins in tumor-induced angiogenesis is αvβ3. Angiogenesis dramatically up-regulates integrin αvβ3 expression by endothelial cells (13). Integrin αvβ3 has been linked to cell migration and invasion (14), and cell survival (15). Inhibition of αvβ3 results in apoptosis of endothelial cells (16) and inhibition of microvascular network formation (17). The signaling pathways activated by αvβ3 and VEGF act synergistically in the formation of microvascular networks (17). Both αvβ3 and VEGF activate Src, Ras, PI3K, and Erk cascades (18). CNTO 95 is a fully humanized monoclonal antibody that blocks integrin αvβ3 with high affinity.

The combination of different targeted therapies has the potential of providing a more complete inhibition of angiogenesis. It is our hypothesis that the combination of CNTO 95 and bevacizumab will be a safe and potentially efficacious anti-angiogenesis strategy for the treatment of adult solid tumors. This combination may have utility directly or may prove useful when subsequently combined with other anti-angiogenic agents or standard chemotherapy regimens. We also hypothesize that our clinical dermal wound angiogenesis assay will help quantify and characterize the anti-angiogenic contribution of each agent in this combination.

Bevacizumab (Avastin) is a humanized monoclonal antibody to VEGF. VEGF is known to play a pivotal role in tumor angiogenesis and is a significant mitogenic stimulus for arterial, venous and lymphatic endothelial cells. The addition of bevacizumab to chemotherapy has been shown to increase overall response rate, duration of response and survival for patients with metastatic colon cancer (4) and is beneficial in first line non-small cell lung cancer and metastatic breast cancer \[1, 2\], and second line metastatic colorectal cancer (7). VEGF signals through phosphotidylinositol 3-kinase (PI3K) and Akt as well as through the extracellular regulated kinase (ERK 1/2), a mitogen activated protein kinase (MAPK). VEGF's multiple biologic actions may be mediated by different pathways. Erikkson demonstrated that VEGF induced hyperpermeability was highly dependent on activation of the AKT pathway, while the angiogenic effect was largely unaffected by blocking this pathway and likely depended on ERK activation \[3\].

CNTO 95 is a fully human mAb immunoglobulin G (IgG) of the gamma isotype and kappa light chain that has been shown to have antiangiogenic and antitumor properties. Results of in vitro studies demonstrate that CNTO 95 is an anti-αv integrin antibody that binds and blocks integrin ανβ3 with high affinity. CNTO 95 has also been shown to bind to integrins ανβ1, ανβ5, and ανβ6. No cross-reactivity of CNTO 95 to glycoprotein IIb/IIIa, ανβ1 or platelets has been observed. By binding and blocking the ανβ3 and ανβ5 integrins, CNTO 95 can inhibit cell adhesion, migration, proliferation, and invasion of both tumor and endothelial cells in vitro. It is known that CNTO 95 binds to other αν integrins. However, the clinical implications of binding to these integrins are unknown.