Development of SDP0505: a first-in-class HER3 × c-Met bispecific ADC, demonstrates potent antitumor activity in EGFR TKI-resistant NSCLC, CRC, and beyond.

Background: Despite the success of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance remains an unmet need. Although human epidermal growth factor receptor 3 (HER3) and c-Met upregulation are key mechanisms of this resistance, the rationale for simultaneously targeting both to overcome this challenge remains unexplored. Methods: HER3 and c-Met expression were evaluated by immunohistochemistry in 270 clinical samples, including EGFR TKI-resistant NSCLC, lung adenocarcinoma (LUAD), gastric cancer, and colorectal cancer (CRC). The binding affinity of SDP0505 was measured by surface plasmon resonance and enzyme-linked immunosorbent assay, internalization was monitored using Incucyte, and Results: Immunohistochemical analyses revealed spatial colocalization of HER3 and c-Met in EGFR TKI-resistant NSCLC specimens. Furthermore, high co-expression was observed in 58% of EGFR-mutant LUAD and 95% of CRC cases. Consequently, SDP0505 was developed with optimal antigen-binding affinity and antibody format through comprehensive screening. In HER3/c-Met dual-positive cell lines, SDP0505 demonstrated enhanced cell binding and internalization over the in-house synthesized U3-1402 analog. Superior Conclusions: SDP0505 represents a novel HER3 × c-Met ADC with superior internalization and anti-tumor activity in preclinical models, especially in EGFR TKI-resistant PDX models. These results supported the initiation of a Phase I clinical trial in China.