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1150 DM005, an EGFR × MET bispecific antibody-drug conjugate, showed robust anti-tumor activity in PDX models
  1. Yanfei Han1,
  2. Wenjuan Dai2,
  3. Chengzhang Shang1,
  4. Zhuolin Li1,
  5. Zhenyan Han1,
  6. Jun Li1,
  7. Zixu Cui1,
  8. Gao An1,
  9. Wanjun Hao1,
  10. Yujie Liu1,
  11. Hao Li1,
  12. Baihong Liu1,
  13. W Frank An1,
  14. Chaoshe Guo1,
  15. Yi Yang1 and
  16. Yuelei Shen1
  1. 1Biocytogen Pharmaceuticals (Beijing) Co., Ltd., Beijing, China
  2. 2Doma Biopharmaceutical (Suzhou) Co., Ltd., Suzhou, Jiangsu, China
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Bispecific 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.

Methods Biocytogen 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.

Results The 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).

Conclusions Collectively, 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 Approval All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Biocytogen Beijing Co., Ltd.

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