Non-clinical characterization of GSK5764227, a novel B7-H3-directed antibody-drug conjugate (ADC)

B7-H3 (B7 homolog 3 protein), also known as CD276, is an important immunoregulatory ligand and member of the B7-CD28 family. Despite being widely expressed across tissues at the RNA level, the expression of B7-H3 protein is limited, where it can be found in cell-expressed and soluble forms. Notably, B7-H3 protein is found to be overexpressed in a variety of tumor tissues, including gastric, lung, prostate, kidney, oral, and bladder cancer, as well as osteosarcoma and hematologic malignant diseases - making B7-H3 an attractive target for tumor-selective approaches, such as antibody drug conjugates (ADCs). The expression of B7-H3 in tumor tissues is most prevalent on tumor epithelial and stromal cells (e.g., cancer associated fibroblasts and endothelial cells) but has also been described on tumor infiltrating dendritic cells (DCs), macrophages and monocytes. Consistent with its described immunoregulatory and tumor promoting role, B7-H3 is closely associated with poor prognosis and negative clinicopathological features, including metastasis, disease recurrence, and resistance to certain chemotherapeutics. GSK5764227 is a novel ADC developed by Shanghai Hansoh Biomedical Technology Co., Ltd that is comprised of a fully human anti-B7-H3 monoclonal antibody (mAb) conjugated to an exatecan-derived topoisomerase I (TOPO1) inhibitor (SHR-9265, GSK5757810A, average DAR of 4). Here we describe various non-clinical characteristics of GSK5764227, including biophysical, functional, and mechanistic attributes of the ADC. In vitro, GSK5764227 demonstrated binding to and internalization into B7-H3-expressing tumor cells, resulting in concentration-dependent tumor cell cytotoxicity. GSK5764227 also elicited cell cycle arrest (S-phase) and bystander killing capability. In vivo, GSK5764227 exhibited significant and dose-dependent tumor growth inhibition (TGI) towards multiple CDX models, including the small cell lung cancer (SCLC) tumor cell line NCI-H146. Similar anti-tumor activity was observed in human PDX models of SCLC. Importantly, the strong antitumor activity in SCLC models align with early phase clinical data (ARTEMIS-001), where GSK5764227 demonstrated >60% ORR in extensive stage SCLC patients [Wang, 2025]. Collectively, these non-clinical observations, in tandem with emerging clinical data, support GSK5764227 as a promising cancer therapy and its rapidly progressing global clinical development.