1150 DM005, an EGFR × MET bispecific antibody-drug conjugate, showed robust anti-tumor activity in PDX models

• Published in: Journal for immunotherapy of cancer Vol. 11; no. Suppl 1; p. A1266
• Main Authors: Han, Yanfei, Dai, Wenjuan, Shang, Chengzhang, Li, Zhuolin, Han, Zhenyan, Li, Jun, Cui, Zixu, An, Gao, Hao, Wanjun, Liu, Yujie, Li, Hao, Liu, Baihong, Frank An, W, Guo, Chaoshe, Yang, Yi, Shen, Yuelei
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-11-2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Antibodies; Drug dosages; Flow cytometry; Immunotherapy; Kinases; Pancreatic cancer; Regular and Young Investigator Award Abstracts; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.1150

BackgroundBispecific antibodies (BsAb) that target dual tumor-associated antigens can invoke synergistic effects between two signaling pathways, increase target tissue specificity, and reduce systemic toxicity. Combining antibody-mediated specific targeting with potent killing from a cytotoxic payload, antibody-drug conjugates (ADC), especially bispecific ADCs (BsADC), have become powerful therapeutic strategies. EGFR and MET are oncogenic proteins that are co-expressed in a wide range of tumors. Moreover, MET amplification is largely associated with drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients.MethodsBiocytogen developed a fully human EGFR × MET BsADC using our proprietary common light chain RenLite® mouse platform and knobs-into-holes technology, evaluated internalization by flow cytometry and IncuCyte, and binding affinity potential by flow cytometry. In vivo drug efficacies were screened in severely combined immunodeficient B-NDG mice inoculated with NCI-H1975 and NCI-H292 cell-derived xenografts, as well as patient-derived NSCLC and pancreatic ductal adenocarcinoma (PDAC) xenograft models.ResultsThe BsAb showed enhanced internalization and binding affinity compared to parental monoclonal and monovalent antibodies in the EGFR/MET co-expressing NCI-H1975 cell lines. After conjugating the BsAb with monomethyl auristatin E (MMAE) via a protease-cleavable linker, the resulting BsADC, DM005, exhibited a remarkable and dose-dependent anti-tumor efficacy in NCI-H1975 and NCI-H292 cell line-derived xenograft models. Moreover, in multiple patient-derived xenografts of NSCLC and pancreatic ductal adenocarcinoma (PDAC), which co-express EGFR and MET, DM005 demonstrated superior and durable efficacy that outperformed benchmark antibodies at a lower dose (3 mg/kg).ConclusionsCollectively, these results suggest that DM005 can be an effective treatment option for EGFR and MET co-expressing tumors and overcome MET-driven EGFR-TKI resistance to improve patient outcomes.Ethics ApprovalAll animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Biocytogen Beijing Co., Ltd.