Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 431, Issue 10, Pages 2020-2039Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2019.03.024
Keywords
MET; protein engineering; X-ray crystallography; DARPins; biparatopic
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Funding
- Schweizerischer Nationalfonds (Switzerland) [3100306_166676]
- German Science Foundation [NI694/6-1]
- Associazione Italiana contro Leucemie-Linfomi e Mieloma (AIL) Trentino
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MET, the product of the c-METproto-oncogene, and its ligand hepatocyte growth factor/scatter factor (HGF/SF) control survival, proliferation and migration during development and tissue regeneration. HGF/SF-MET signaling is equally crucial for growth and metastasis of a variety of human tumors, but resistance to small-molecule inhibitors of MET kinase develops rapidly and therapeutic antibody targeting remains challenging. We made use of the designed ankyrin repeat protein (DARPin) technology to develop an alternative approach for inhibiting MET. We generated a collection of MET-binding DARPins covering epitopes in the extracellular MET domains and created comprehensive sets of bi-paratopic fusion proteins. This new class of molecules efficiently inhibited MET kinase activity and downstream signaling, caused receptor downregulation and strongly inhibited the proliferation of MET-dependent gastric carcinoma cells carrying MET locus amplifications. MET-specific bi-paratopic DARPins may represent a novel and potent strategy for therapeutic targeting of MET and other receptors, and this study has elucidated their mode of action. (C) 2019 Elsevier Ltd. All rights reserved.
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