A Series of Function Blocking Antibodies against the αvβ3 Integrin Bind Allosteric to the Ligand Binding Site and Induce Ligand Dissociation

Abstract

The αvβ3 integrin plays a critical role in bone resorption, angiogenesis, and tumor cell invasion. A blockade of this receptor has therapeutic potential in osteoporosis, vascular restenosis, and cancer. In this report, we characterize the mechanism by which six monoclonal antibodies inhibit the function of αvβ3. All six antibodies interact with a common site that is partially comprised of residues 164–202 within the β3 subunit. This domain is physically separate from the RGD binding site, and appears to regulate ligand binding allosterically. Thus, the blocking antibodies function, in part, by inducing the dissociation of ligand from αvβ3. Although this family of antibodies is able to virtually abolish αvβ3-mediated cell adhesion, they only block about one-half of soluble ligand binding to the integrin. This observation is consistent with the idea that two functionally distinct populations of αvβ3 are present on the cell surface. The unique mechanism of action of these antibodies provides new insight in the structure-function relationships of αvβ3, and also suggest that such antibodies are likely to behave differently than RGD mimetics if used as drugs.

Key Words:

• Integrin
• RGD. Antibody
• αvβ3