|Neha Vapiwala, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
Integrins are a large family of proteins located in the surface membrane of normal human cells. They play a role in many important cellular functions, including cell migration and survival. Integrins serve as key mediators between the cell and its outside world. Different integrins have different shapes, also known as conformalities or configurations, and the shape helps determine the specific substances to which that integrin can bind and respond. The binding substances are referred to as ligands, and many integrin ligands (such as fibronectin) are located in the environment immediately surrounding the cell, called the "extracellular matrix".
CNTO 95 is a fully human antibody against integrin avb3 (also anti-avb5) that has been shown to block new blood vessel growth in rat studies. It also appears to have a direct anti-tumor effect on melanoma cells both in the petri dish and in animal studies. There is currently a phase I safety study underway in patients with a variety of diagnoses, including ovarian, colorectal, and ureteric. CNTO 95 appears to be well-tolerated thus far.
MEDI-522 is another fully human antibody that has been shown to cause programmed death in endothelial cells. Acceptable safety has been shown in two phase I trials of patients with a variety of solid tumors, with doses of up to 4 mg/kg a week for 6 weeks.
Volociximab (M200) is a chimeric (82% human) antibody that blocks a5b1 at its fibronectin binding site. By inhibiting fibronectin binding to a5b1, cell migration and new blood vessel growth are sabotaged. This agent appears to be well tolerated in safety studies at doses of up to 15 mg/kg a week. There is no established maximum tolerated dose, as no dose-limiting toxicities were seen. Current phase II studies, each with about 40 patients, are testing volociximab given 10 mg/kg intravenously every two weeks. The agent is administered with concurrent chemotherapy (metastatic melanoma and pancreatic cancer), with another targeted therapy (erlotinib in non-small cell lung cancer), or alone (renal cell carcinoma).