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.

Spotlight on Amivantamab (JNJ-61186372) for EGFR Exon 20 Insertions Positive Non-Small Cell Lung Cancer

“…Tumor growth was inhibited 99.8% (p < 0.05) at day 34 with a durable response noted 8 weeks after amivantamab discontinuation. 27 Additionally, in xenograft models, the efficacy of amivantamab was superior to both cetuximab and poziotinib. 23…”

Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

“…These epitopes are the same target of mAbs pertuzumab and trastuzumab, respectively [ 32 ]. JNJ-61186372 (amivantamab), inhibits epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR; cMet) dimerization and phosphorylation, blocking signaling propagation to downstream effectors, while also promoting EGFR and MET downregulation [ 33 ]. Therefore, by dual-TAA targeting, the drug selectivity for cancer cells is enhanced, ideally reducing on target/off tumour toxicities.…”

“…Amivantamab (JNJ-61186372) is a fully-human anti-EGFR/cMET bsAb with immune cell directing activity [ 33 , 41 ]. While EGFR binding exploits some of the amino acids with the cetuximab binding loop (in the EGFR domain III), MET binding prevents the interaction with the hepatocyte growth factor (HGF) beta chain and subsequent downstream signaling [ 33 ]. Upon binding to its targets, amivantamab downregulates EGFR and MET membrane expression through their internalization, lysosomal degradation, and trogocytosis [ 42 ].…”

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

“…As of August 2021, three bispecific antibodies have been approved, the tandem single-chain variable fragment (Fv)-based CD19/CD3 Bispecific T-cell Engager (BiTE) blinatumomab developed by Amgen for the treatment of acute lymphocytic leukemia (ALL), 37 the heterodimeric ART-Ig-based coagulation factor IX/X bispecific IgG antibody emicizumab developed by Chugai and Roche for the treatment of hemophilia A, 7 , 8 , 10 and the heterodimeric DuoBody-based EGFR/c-Met bispecific IgG antibody amivantamab developed by Janssen for treatment of non-small cell lung cancer harboring EGFR exon 20 insertion mutations. 38–40 …”