2. Academic Validation
  3. The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance

  • Structure. 2017 Nov 7;25(11):1732-1739.e5. doi: 10.1016/j.str.2017.09.007.
Andrew J Borst 1,  Zachary M James 2,  William N Zagotta 2,  Mark Ginsberg 3,  Felix A Rey 4,  Frank DiMaio 1,  Marija Backovic 5,  David Veesler 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • 2 Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
  • 3 Department of Hematology and Oncology, University of California at San Diego, La Jolla, CA 92093-0726, USA.
  • 4 Unité de Virologie Structurale, Institut Pasteur, Paris, France; CNRS UMR 3569 Virologie, Paris, France.
  • 5 Unité de Virologie Structurale, Institut Pasteur, Paris, France; CNRS UMR 3569 Virologie, Paris, France. Electronic address: marija@pasteur.fr.
  • 6 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: dveesler@uw.edu.
PMID: 29033288 DOI: 10.1016/j.str.2017.09.007
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.

Keywords

LM609 antibody; abegrin; alpha V beta 3 integrin; etaracizumab; integrins; single-particle electron microscopy; vitaxin.

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