Abstract LB279: SDP01873, a novel HER3×c-Met bispecific antibody-drug conjugate (ADC) targeting EGFR tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and beyond

Abstract Background: Both HER3 and c-Met play a crucial role in regulating resistance to EGFR TKIs in NSCLC through upregulation of the expression of HER3 and/or c-Met post TKI treatment, suggesting that dual targeting of the two targets may effectively treat patients resistant to EGFR TKIs. Beyond NSCLC, HER3 and c-Met are highly co-expressed in other cancer types such as CRC and gastric cancer (GC), which suggests that dual targeting HER3 and c-Met might provide a better therapeutic strategy. Herein, we presented a novel HER3×c-Met bispecific ADC, SDP01873, which exhibited excellent in vitro activity and superior efficacy in xenograft models. Methods: We used a site-specific conjugation technology to conjugate SDP01873 using a topoisomerase I inhibitor via an enzyme-cleavable linker. The in vitro binding affinity of SDP01873 against HER3 and c-Met proteins was measured by surface plasmon resonance (SPR) and enzyme-linked immunosorbent (ELISA) assay. The internalization activity was monitored by Incucyte after being labeled with pH-sensitive dye. The in vitro cell killing activity against various cell lines was performed by CellTiter Glo assay. The in vivo anti-tumor activities were investigated in both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Results: The in vitro binding assay showed that SDP01873 could bind to both human HER3 and c-Met proteins simultaneously, and exerted potent and comparable affinity to both targets. SDP01873 showed higher internalization activity than the HER3 ADC, U3-1402 analog (synthesized in-house), indicating an augment to internalization activity through dual targeting. SDP01873 exhibited strong cell killing activity against tumor cell lines with different levels of HER3 and c-Met expression, with IC50 values ranging from 0.39 to 69.52 nM. In vivo pharmacology studies manifested that SDP01873 significantly outperformed the U3-1402 analog in terms of antitumor efficacy. SDP01873 displayed tumor growth inhibitions (TGIs) of 91% and 97% in the NCI-H441 CDX and the EGFR-TKI resistant PDX model, respectively, while the U3-1402 analog at the same dose (3 mg/kg) only achieved TGIs of 48% and 76%, respectively. In the CRC PDX model, SDP01873 also significantly inhibited tumor growth (TGI=88%). Meanwhile, SDP01873 was well-tolerated in all the CDX and PDX models, indicating a favorable safety profile in the clinic. Conclusion: SDP01873 represents a novel HER3×c-Met ADC with superior internalization activity and higher anti-tumor activity in preclinical models of NSCLC and CRC, and efficacy in PDX models resistant to EGFR TKI was also observed. The promising preclinical data support its advancing into clinical testing, and an Investigational New Drug (IND) application to NMPA has been approved in 2024. Citation Format: Limin Wang, Xing Sun, Changyong Yang, Dan Li, Yali Hu, Simeng Chen, Wei Zhang, Cheng Liao. SDP01873, a novel HER3×c-Met bispecific antibody-drug conjugate (ADC) targeting EGFR tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB279.