Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.

Autor:	Neijssen J; Genmab, Utrecht, The Netherlands., Cardoso RMF; Janssen Research & Development, Spring House, Pennsylvania, USA., Chevalier KM; Janssen Research & Development, Spring House, Pennsylvania, USA., Wiegman L; Genmab, Utrecht, The Netherlands., Valerius T; Section for Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany., Anderson GM; Janssen Research & Development, Spring House, Pennsylvania, USA., Moores SL; Janssen Research & Development, Spring House, Pennsylvania, USA., Schuurman J; Genmab, Utrecht, The Netherlands., Parren PWHI; Genmab, Utrecht, The Netherlands., Strohl WR; Janssen Research & Development, Spring House, Pennsylvania, USA., Chiu ML; Janssen Research & Development, Spring House, Pennsylvania, USA. Electronic address: markchiu03@gmail.com.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100641. Date of Electronic Publication: 2021 Apr 08.
DOI:	10.1016/j.jbc.2021.100641
Abstrakt:	A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain-Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling. Competing Interests: Conflict of interest Joost Neijssen, Luus Wiegman, and Janine Schuurman are employees of Genmab. Paul Parren was an employee of Genmab when this work was completed. Rosa M.F. Cardoso, Kristen Chevalier, and Sheri Moores are employees of Janssen Research & Development. Mark Chiu, Mark Anderson, and William Strohl were employees of Janssen Research & Development when this work was completed. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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