882 BCG040, a novel B7-H4-targeting biparatopic ADC, demonstrates superior preclinical efficacy in heterogeneous tumors
Year: 2026
Type: conference-abstract
Abstract: Background B7-H4 (VTCN1) is highly overexpressed in many aggressive epithelial malignancies, including ovarian, breast, biliary tract, and pancreatic cancers. Due to their resistant nature, these tumors are often refractory to standard chemotherapy and immunotherapy, resulting in poor clinical outcomes.Methods We developed BCG040, a novel, first-in-class, fully human IgG1κ biparatopic antibody-drug conjugate (ADC) targeting two non-overlapping B7-H4 epitopes. It is conjugated to a potent topoisomerase I (TOP1) inhibitor, BCPT02 (DAR≈8), via a hydrophilic protease-cleavable linker. BCG040 was evaluated in vitro for binding affinity, cross-reactivity, and internalization kinetics. Its in vivo antitumor efficacy, pharmacokinetics (PK), developability, and toxicity were assessed in breast and pancreatic patient-derived xenograft (PDX) models against benchmark analogs (Hu2F7, SGN-B7H4V, and FPA150).Results Superior in vitro Profile: BCG040 demonstrated superior nanomolar affinity for B7-H4 compared to Hu2F7 and SGN-B7H4V analogs. It showed robust human/cynomolgus cross-reactivity, zero off-target binding to other B7 family members, and significantly faster internalization and receptor clustering.Robust in vivo Efficacy: A single low dose of BCG040 induced durable tumor regressions (~40 days) in breast cancer PDX models and exceptional efficacy in pancreatic cancer PDX models, consistently outperforming all benchmark competitors.Payload-Dependent Antitumor Activity: BCPT02-containing ADCs achieved potent antitumor activity in heterogeneous PDX tumors where MMAE-based conjugates completely failed.Safety & Developability: BCG040 exhibited a favorable PK profile, excellent developability, and strong potency with no observable toxicity.Conclusions The enhanced therapeutic activity of BCG040 is driven by its unique biparatopic design, which accelerates intracellular trafficking and optimizes payload delivery. These findings position BCG040 as a highly promising therapeutic candidate for the treatment of advanced pancreatic, biliary tract, ovarian, and breast cancers.
Authors: Peiran Li, Ying Zhu, Yanan Guo, Icy Niu
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: W7225169310