The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α V β 3 Integrin via Steric Hindrance - Archive ouverte HAL Access content directly
Journal Articles Structure Year : 2017

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α V β 3 Integrin via Steric Hindrance

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Abstract

The LM609 antibody specifically recognizes αVβ3 integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αVβ3-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αVβ3 integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αVβ3. Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the αV chain and the βI domain of the β3 chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool.

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pasteur-01632900 , version 1 (10-11-2017)

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Andrew Borst, Zachary M. James, William N. Zagotta, Mark Ginsberg, Félix A. Rey, et al.. The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α V β 3 Integrin via Steric Hindrance. Structure, 2017, 25 (11), pp.1732 - 1739.e5. ⟨10.1016/j.str.2017.09.007⟩. ⟨pasteur-01632900⟩

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