6I04

Crystal structure of Sema domain of the Met receptor in complex with FAB

6I04 の概要

• エントリーDOI: 10.2210/pdb6i04/pdb
• 分子名称: Hepatocyte growth factor receptor, Fab heavy chain, Fab light chain (3 entities in total)
• 機能のキーワード: immune system, met, sema domain
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 219995.70

構造登録者

Casaletto, J.B.,Geddie, M.L.,Abu-Yousif, A.O.,Masson, K.,Fulgham, A.,Boudot, A.,Maiwald, T.,Kearns, J.D.,Kohli, N.,Su, S.,Razlog, M.,Raue, A.,Kalra, A.,Hakansson, M.,Logan, D.T.,Welin, M.,Chattopadhyay, S.,Harms, B.D.,Nielsen, U.B.,Schoeberl, B.,Lugovskoy, A.A.,MacBeath, G. (登録日: 2018-10-25, 公開日: 2019-03-13, 最終更新日: 2024-10-16)

主引用文献

Casaletto, J.B.,Geddie, M.L.,Abu-Yousif, A.O.,Masson, K.,Fulgham, A.,Boudot, A.,Maiwald, T.,Kearns, J.D.,Kohli, N.,Su, S.,Razlog, M.,Raue, A.,Kalra, A.,Hakansson, M.,Logan, D.T.,Welin, M.,Chattopadhyay, S.,Harms, B.D.,Nielsen, U.B.,Schoeberl, B.,Lugovskoy, A.A.,MacBeath, G.
MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM.
Proc.Natl.Acad.Sci.USA, 116:7533-7542, 2019

PubMed Abstract: Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.

PubMed: 30898885
DOI: 10.1073/pnas.1819085116

実験手法

X-RAY DIFFRACTION (3.1 Å)