Abstract 2965: SCR-A006, an innovative and potential best-in-class EGFR/cMet bispecific antibody-drug conjugate

Abstract Background: EGFR and cMet are widely co-expressed in solid tumors, and there is crosstalk between their signaling pathways, which is the general escape mechanism for each other in clinic. Although various drugs targeting EGFR and/or cMet have been approved or are in clinical development, primary and acquired resistance limits their prolonged efficacy. There still remains a large unmet need in solid tumor therapy. SCR-A006 is an antibody-drug conjugate (ADC) comprising a bispecific mAb targeting EGFR&cMET conjugated to a topoisomerase 1 inhibitor (TOP1i) via a cleavable and hydrophilic linker, which potentially benefits a broad population of solid tumor patients. Methods: Physiochemical and biological properties of SCR-A006 were evaluated. The binding affinity and cytotoxicity of SCR-A006 were investigated in vitro using cancer cell lines containing different target expression levels, tumor types (lung, head and neck, breast, gastric, colorectal and pancreas), as well as genomic landscapes. In vivo pharmacodynamic studies were conducted in several CDX and PDX models with different EGFR expression levels or mutations. Preclinical PK studies and tissue distributions were performed by intravenous injection of SCR-A006 at 5mg/kg single in WT mice and tumor cell xenograft mice. Results: SCR-A006 exhibited strong cytotoxicity against a broad range of tumor cell lines with higher potency than benchmark ADC, but did not enhance toxicity to normal cells, suggesting a larger therapeutic window. In vivo, SCR-A006 demonstrated dose-dependent tumor inhibition and was more effective than benchmark ADC in xenograft models regardless of tumor types and genetic profiles. SCR-A006 also showed good efficacy and was superior to benchmark ADC in amivantamab resistant xenograft models. Excitingly, we found complete response and prolonged efficacy in NSCLC PDX model. To figure out the mechanism of better efficacy compared to benchmark ADC, PK and cleavage efficiency in tumor or normal tissue from CDX model of SCR-A006 were carried out, which showed better tumor penetration and higher cleavable efficiency in tumor homogenate than benchmark ADC but very limited cleavage in normal tissue. SCR-A006 also displayed higher hydrophilicity and more excellent plasma stability than Benchmark ADC. All of above performance potentially resulted the better efficacy and good safety of SCR-A006. Conclusions: Taken together, these findings highlight the potential of SCR-A006 as a therapeutic candidate for broad treatment of solid tumors and with a larger therapeutic window than other EGFR/cMET BsADCs. IND enabling studies of SCR-A006 are currently underway, and planned to initiate clinical study in 2025. Citation Format: Yayuan Fu, Chaochao Cen, Lei Jiang, Xiaohua Yan, Chuanchuan Lu, Qian Wang, Ye Hong, Renhong Tang. SCR-A006, an innovative and potential best-in-class EGFR/cMet bispecific antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2965.