The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α(V)β(3) Integrin via Steric Hindrance.
The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α(V)β(3) Integrin via Steric Hindrance.
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DOI：
10.1016/j.str.2017.09.007
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发表时间：
2017-11-07
期刊：
影响因子：
--
通讯作者：
Veesler D
中科院分区：
文献类型：
--
作者：
Borst AJ;James ZM;Zagotta WN;Ginsberg M;Rey FA;DiMaio F;Backovic M;Veesler D
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 radio-immunotherapy. 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 this 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. The LM609 antibody specifically recognizes αVβ3 integrin and has been employed in numerous clinical and academic research applications. In the manuscript, The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance, Borst AJ et al. shed light on the mode-of-action of a widely used integrin-targeting antibody.
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影响因子：
6.7
作者：
Krey T;d'Alayer J;Kikuti CM;Saulnier A;Damier-Piolle L;Petitpas I;Johansson DX;Tawar RG;Baron B;Robert B;England P;Persson MA;Martin A;Rey FA
通讯作者：
Rey FA
DOI：
10.1007/978-1-4939-3043-2_17
发表时间：
2016-01-01
期刊：
BACULOVIRUS AND INSECT CELL EXPRESSION PROTOCOLS, 3RD EDITION
影响因子：
--
作者：
Backovic, Marija;Krey, Thomas
通讯作者：
Krey, Thomas
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
DOI：
10.1073/pnas.84.18.6471
发表时间：
1987-09-01
影响因子：
11.1
作者：
CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
2.4
作者：
Backovic, Marija;Johansson, Daniel X.;Rey, Felix A.
通讯作者：
Rey, Felix A.