883 A novel CDH17/HER3 bispecific ADC demonstrates superior preclinical efficacy in colorectal cancer
Year: 2026
Type: conference-abstract
Abstract: Background Colorectal cancer (CRC) presents a significant unmet clinical need for novel targeted therapies. CDH17 is highly and specifically expressed in gastrointestinal tumors, notably CRC. Concurrently, HER3 expression is frequently observed in CRC. We hypothesized that co-targeting CDH17 and HER3 would synergistically enhance tumor-specific binding and cellular internalization compared to monospecific targeting. Here, we developed a novel common light-chain 1+1 CDH17/HER3 bispecific antibody-drug conjugate (BsADC) and evaluated its therapeutic potential.Methods The novel CDH17/HER3 BsADC was constructed utilizing a common light-chain 1+1 structural format. To comprehensively evaluate its anti-tumor activity, the bispecific antibody was conjugated with two distinct payloads: a microtubule inhibitor (vcMMAE) and a novel DNA topoisomerase I (TOP1) inhibitor linker-payload (BLD1102). Target binding synergy and cellular internalization were evaluated in vitro. In vivo efficacy was assessed in CRC models. Specifically, the BLD1102-conjugated BsADC was evaluated in one cell line-derived xenograft (CDX) model and two independent patient-derived xenograft (PDX) models, with efficacy directly compared against parental molecules and a clinical-stage benchmark agent.Results In vitro assays confirmed that the CDH17/HER3 bispecific antibody leverages the high specificity of CDH17 and the synergistic presence of HER3 to achieve enhanced dual-antigen binding and significantly accelerated cellular internalization into CRC cells. In vivo, the BsADC exhibited potent anti-tumor activity when conjugated with either the vcMMAE or BLD1102 payload. Focusing on the BLD1102 conjugate, the BsADC induced remarkable and sustained tumor regression in the CRC CDX model and the two clinically relevant CRC PDX models. Crucially, the CDH17/HER3-BLD1102 BsADC significantly outperformed its respective parental molecules and demonstrated definitively superior therapeutic efficacy compared to the selected clinical-stage benchmark agent.Conclusions The novel CDH17/HER3 BsADC exploits target synergy to achieve exceptional preclinical efficacy. Its definitive superiority over both parental molecules and a clinical-stage benchmark strongly supports its development as a highly promising, next-generation targeted therapy for colorectal cancer.
Institution: Beijing Biocytogen (China)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225158538