Non-Clinical Characterization of Mocertatug Rezetecan, a B7-H4-Directed Antibody-Drug Conjugate

B7-H4 (B7 homolog 4 protein), also known as B7S1 (B7 superfamily member 1) or VTCN1 (V-set domain-containing T cell activation inhibitor 1), is an important immunoregulatory ligand in the B7-CD28 family. B7-H4 is overexpressed in various tumor tissues such as breast, ovarian, uterine, and lung cancers. B7-H4 has been described to both attenuate T cell function (e.g., proliferation, cytokine secretion and cell cycle) as well as promote tumor cell proliferation, invasion, and metastasis. Consistent with its described immunoregulatory and tumor promoting role, B7-H4 is associated with poor prognosis and negative clinicopathological features in patients with advanced tumors. Due to its overexpression in tumors and tumor-promoting functions, B7-H4 represents an attractive target for tumor-selective therapies like antibody-drug conjugates (ADCs). Mocertatug Rezetecan (Mo-Rez) is a novel ADC that combines a humanized anti-B7-H4 immunoglobulin G1 monoclonal antibody with an exatecan-derived topoisomerase I (TOPO1) inhibitor (SHR-9265, GSK5757810A, average DAR of 6). Here we describe various non-clinical characteristics of Mo-Rez, including biophysical, functional, and mechanistic attributes of the ADC. In vitro, Mo-Rez demonstrated concentration-dependent binding to B7-H4-expressing tumor cells, which resulted in time-dependent B7-H4 internalization and subsequent cellular cytotoxicity. Consistent with its TOPO1i payload characteristics, Mo-Rez also exhibited cell cycle arrest (S-phase) and bystander killing capability. In vivo, Mo-Rez exhibited significant and dose-dependent tumor growth inhibition (TGI) towards MX-1 (breast) and RL95-2 (endometrial) CDX models. Similar anti-tumor activity was observed across human PDX models of breast cancer, cholangiocarcinoma, cervical cancer, and ovarian cancer. Notably, Mo-Rez antitumor responses were observed in both homologous recombination deficient and proficient (HRD and HRP, respectively) ovarian cancer PDX models. Importantly, the strong antitumor activity in ovarian models align with recent clinical data for Mo-Rez in heavily pretreated platinum-resistant ovarian cancer (PROC, 48.5% ORR). Collectively, these findings support Mo-Rez as a promising cancer therapy and its rapidly progressing global clinical development (BEHOLD trials). Citation Format: Jeremy Waight, Yuanfeng Zhou, Danni Sun, Lu Zhang, Jon Chung, Michael Adam, Wenjin Zhou, Pengchao Qiu, Jifa Fan, Anna Strobl, Jaegil Kim, Aishwarya Bhaskar, Srujana Neelam, Geeta Sharma, Shannon McKearnan, Huifeng Niu, Takahiro Sato, Derek Poore, Alexander Cocks, Prajna Behera, Chris Hopson, Ken Hance, Richard Davidson. Non-clinical characterization of Mocertatug Rezetecan (GSK5733584), a novel B7-H4-directed antibody-drug conjugate [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 4575.