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

Abstract

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. 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. Aberrant activations of both epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) signaling pathways have been implicated in driving tumor cell growth and proliferation in lung cancer (1Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Met, metastasis, motility and more.Nat. Rev. Mol. Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2160) Google Scholar, 2Liu X. Yao W. Newton R.C. Scherle P.A. 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Oncol. 2018; Full Text Full Text PDF PubMed Scopus Google the for novel to overcome resistance and to of both EGFR and a bispecific antibody a potential to overcome resistance and N. of EGFR and and in cell lung 2008; PubMed Scopus Google Scholar). of antibody targeting MET the of action on the of the antibody for the tumor are to the activity of kinase or hepatocyte growth factor a by the MET MET and signaling pathway activation F. A. C. The MET a in cancer PubMed Scopus Google Scholar). induce of MET may have agonistic activity B. D. the of with bispecific 2018; PubMed Scopus Google MET monoclonal have been L. W. J. V. et a and anti-MET and HGF-independent MET activation and tumor PubMed Scopus Google Scholar, A. M. C. N. A. T. A. C. N. L. A novel antibody with antitumor targeting both and ligand-independent J. PubMed Scopus Google Scholar). antibody with a anti-MET binding may MET M. X. J. M. A. Yang M. J. L. Su Y. et antibody and of action of a MET with activity a Natl. Acad. Sci. U. S. A. 2013; PubMed Scopus Google Scholar, H. B.C. M. M. T. I. E. J. A. and to 2013; PubMed Scopus Google Scholar). antibody with this have a M. A. of in c-MET lung Opin. Biol. 2011; PubMed Scopus Google Scholar, O'Byrne K. L. S. S. D. Yu W. Mok T. from the III of plus in or non-small-cell lung Clin. Oncol. PubMed Scopus Google Scholar, G. B. F. T. Orlov Yu W. et of in with in patients with advanced non-small-cell lung Clin. Oncol. 2013; 31: PubMed Scopus Google to to induce MET via by and targeting may of resistance via EGFR signaling. we on a molecule with a different and epitope to BsAbs EGFR and MET and have K.H. Lee J.M. The of and EGFR by a novel bispecific monoclonal the proliferation and of Oncol. PubMed Scopus Google Scholar, A. M. Tsai F. D. M. S. F. W. D. A study of a bispecific antibody targeting MET and in patients with advanced or metastatic 2018; PubMed Scopus Google Scholar, D. S. J. of inhibitors for targeted cancer 2015; 4: Google Scholar, J.M. Lee B. S. Lee Cho S. Lee J. et for a bispecific of and PubMed Scopus Google Scholar). of EGFR and MET we a novel BsAb the of action for EGFR and MET without receptor and The BsAb have two binding EGFR and the MET. the of the optimal bispecific we screened a panel of BsAbs in approach to the of amivantamab EGFR MET BsAb activity in EGFR NSCLC S.L. K. L. K. T. Martin J. J. et novel bispecific antibody targeting EGFR and EGFR lung PubMed Scopus Google Scholar). we a provide in the binding of and novel in vivo antitumor The was to generate a panel of MET parental with EGFR parental MET EGFR BsAbs in the A.F. de J. K. S. A. de J. of bispecific by Natl. Acad. Sci. U. S. A. 2013; PubMed Scopus Google The BsAb was by and by The antibody was a of BsAbs EGFR or MET binding to generate antibodies. 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A. 2013; PubMed Scopus Google Scholar). bispecific molecules MET binding of EGFR and MET on the cell result in MET and activation or of MET in BsAbs the MET were identified MET with with MET arms and with of to were from further EGFR were with MET to with EGFR Furthermore, molecules MET A induce MET BsAbs the EGFR and arms the for MET in the the of receptor via proliferation of cell lines with of EGFR and MET. 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K. between epidermal growth factor receptor and pathways in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. J. Lee K. A. J. G. Wang Y. J. J. J. et by EGFR and Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar). agonistic BsAbs EGFR activation in the absence of EGFR and EGFR we cell lines with the and EGFR In have low MET and EGFR EGFR was in EGFR was by the with and by BsAbs EGFR by BsAb MET and by the MET BsAb In to EGFR the EGFR epitope was the binding and binding to EGFR EGFR was by of the BsAbs in the absence of the lack of EGFR cross-phosphorylation in BsAbs the EGFR cell proliferation and EGFR in BsAbs with EGFR were BsAbs the MET were this and EGFR with MET BsAbs the MET and arms cell BsAbs MET A and arms were agonistic in the proliferation the was small with the MET the MET BsAb showed the optimal and with growth in a cell for of parental with low fucose Fc the BsAb The crystal structure of the MET Fab of amivantamab bound to MET was to the of MET signaling. 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Sci. U. S. A. 2013; PubMed Scopus Google Scholar, V. J. S. D. Gherardi E. of the receptor kinase in with the 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Yao X. D. C. structure of the HGF in with the Sema domain of the J. PubMed Scopus Google Scholar). The of to was toward with of to binding to the their with the The Sema to was and in the and in the Amivantamab antagonized signaling of MET by blocking binding of the of HGF to the MET Sema domain the HGF from binding to MET M. X. J. M. A. Yang M. J. L. Su Y. et antibody and of action of a MET with activity a Natl. Acad. Sci. U. S. A. 2013; PubMed Scopus Google Scholar). of the MET bound to amivantamab or HGF and M. X. J. M. A. Yang M. J. L. Su Y. et antibody and of action of a MET with activity a Natl. Acad. Sci. U. S. A. 2013; PubMed Scopus Google the anti-MET of amivantamab with the HGF the with HGF residues to to and to binding to MET. The amivantamab the binding of to MET. 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S. S.L. activity of EGFR bispecific antibody of lung cancer PubMed Scopus Google Scholar). The in and action of the selected lead were in in vivo Amivantamab showed superior in the HCC827-HGF with small molecule inhibitors of EGFR and with S.L. K. L. K. T. Martin J. J. et novel bispecific antibody targeting EGFR and EGFR lung PubMed Scopus Google Scholar). of the cell proliferation in of action may in The lead bispecific molecule receptor and S.L. K. L. K. T. Martin J. J. et novel bispecific antibody targeting EGFR and EGFR lung PubMed Scopus Google Scholar, S. L. K. B. J. M. K. S. S.L. Amivantamab Fc bispecific receptor and antitumor activity by PubMed Scopus Google Scholar, J. Lee K.H. S. M. J.C. et activity of amivantamab bispecific in of EGFR exon 10: Google Scholar). 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