Background HER3 is a unique EGFR family member that plays a role in tumor progression, and its expression can act as a bypass mechanism for EGFR and HER2-targeted therapies, resulting in drug resistance. In addition to HER3, MET has also been reported as a bypass resistance mechanism to EGFR-TKI treatment. HER3 and MET are co-expressed at high prevalence in multiple tumor types, including gastric, colorectal, breast, and non-small-cell lung cancer (NSCLC). In addition, HER3 and MET are frequently overexpressed in liver metastases from patients with colorectal cancer, indicating that targeting both proteins may provide clinical benefit.
Methods To address this need, we generated fully human bispecific antibodies (BsAbs) targeting HER3 and MET with cross-species reactivity, using RenLite® mice, which contain the full human heavy chain variable domain with a common human kappa light chain to facilitate downstream bispecific antibody assembly. These BsAbs were then conjugated with a payload to generate HER3 and MET-targeting bispecific ADC (BCG022) candidates. We assessed the endocytic activity of unconjugated BCG022 in NUGC-4 cells. Following internalization, we next wanted to evaluate whether BCG022 could inhibit cell viability across several cancer cell lines. In vivo drug efficacies were screened in severely combined immunodeficient B-NDG mice inoculated with cell-derived gastric carcinoma xenografts, as well as patient-derived gastric and pancreatic xenograft models (PDX).
Results BCG022 BsAbs can bind a wide range of HER3/MET co-expressing cancer cell lines, including NSCLC, gastric, liver, colorectal, and pancreatic. These 1+1 structured BsAbs have demonstrated enhanced internalization compared to parental monoclonal antibodies in cancer cell lines. Lastly, BCG022 candidates demonstrated enhanced anti-tumor activity in vivo compared with benchmark and parental Ab-ADCs in PDX models.
Conclusions Collectively, these results suggest that BCG022 has the potential to be a novel therapeutic option for HER3 and MET co-expressing tumors.
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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