Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET
| Autor: | Thomas Valerius, Paul W. H. I. Parren, Janine Schuurman, Joost J. Neijssen, William R. Strohl, Kristen M. Chevalier, Luus Wiegman, Cardoso Rosa Maria Fernandes, Mark L. Chiu, Sheri Moores, G. Mark Anderson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
TGF alpha Lung Neoplasms Sema domain non-small cell lung cancer (NSCLC) Apoptosis cFAE controlled Fab-arm exchange TKI tyrosine kinase inhibitor Biochemistry Epitope Tyrosine-kinase inhibitor Mice amivantamab NSCLC non–small cell lung cancer Carcinoma Non-Small-Cell Lung FACS fluorescence-activated cell sorting Antibodies Bispecific Drug Discovery Tumor Cells Cultured BsAb bispecific antibody EGFR exon 20 insertion Epidermal growth factor receptor Antibody-dependent cell-mediated cytotoxicity TGI tumor growth inhibition biology Chemistry bispecific anti-EGFR×MET antibody Proto-Oncogene Proteins c-met ErbB Receptors combinatorial screening Female MET amplification Research Article crystal structure medicine.drug_class Monoclonal antibody 03 medical and health sciences PDB Protein Data Bank non–small cell lung cancer (NSCLC) medicine Animals Humans TGFα transforming growth factor alpha mAb monoclonal antibody Molecular Biology Cell Proliferation ADCC antibody-dependent cellular cytotoxicity 030102 biochemistry & molecular biology MET mesenchymal–epithelial transition factor Cell Biology medicine.disease Xenograft Model Antitumor Assays EGFR epidermal growth factor receptor epitope mapping 030104 developmental biology Cancer research biology.protein HGF hepatocyte growth factor |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry, 296. ELSEVIER |
| Popis: | 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 nonsmall 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 crossphosphorylation 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 beta-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|