Abstract 5642: BCG040, a novel B7-H4-targeting biparatopic ADC, demonstrates superior preclinical efficacy in heterogeneous tumors.

Abstract B7-H4 (VTCN1) is overexpressed in many epithelial malignancies, particularly in ovarian, breast, biliary tract, and pancreatic cancers. These tumors are often resistant to both chemotherapy and immunotherapy, due to their aggressive nature and poor prognosis. Here, we present BCG040, a novel first-in-class, fully human IgG1κ biparatopic B7-H4 ADC. BCG040 binds to two non-overlapping B7-H4 epitopes and is conjugated to the potent topoisomerase I (TOP1) inhibitor BCPT02 (DAR≈8) via a hydrophilic protease-cleavable linker. In vitro, BCG040 showed nanomolar affinity for B7-H4, superior to Hu2F7 and SGN-B7H4V benchmark analogs, with fully human/cynomolgus cross-reactivity and no off-target binding to other B7 family members. BCG040 exhibited stronger binding and more rapid internalization than the two analogs in breast and ovarian cancer cells. In vivo, a single low dose of BCG040 showed durable tumor regressions (∼40 days) in breast cancer PDX models and significant efficacy in pancreatic cancer PDX models, outperforming other ADCs such as Hu2F7, SGN-B7H4V, or FPA150 (conjugated with MMAE or BCPT02). This potent efficacy was achieved without observable toxicity and was supported by a favorable pharmacokinetic (PK) profile. Furthermore, this drug demonstrates excellent developability. The enhanced therapeutic activity of BCG040 is attributed to its unique biparatopic design, which promotes receptor clustering and accelerated intracellular trafficking, leading to enhanced delivery of payload. Notably, BCPT02-containing ADCs exhibited potent antitumor activity in heterogeneous PDX tumors, whereas MMAE-based conjugates were ineffective. These findings underscore the potential of BCG040 as a promising therapeutic candidate for the treatment of pancreatic, biliary tract, ovarian, and breast cancers. Citation Format: Guan Wang, Peiran Li, Ying Zhu, Yanan Guo. BCG040, a novel B7-H4-targeting biparatopic ADC, demonstrates superior preclinical efficacy in heterogeneous tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5642.