Abstract 2878: Preclinical characterization of GLR1061, a B7H3-targeted ADC with a novel DNA topoisomerase I inhibitor, demonstrated superior bystander effect to overcome tumor heterogeneity

Abstract B7H3 (CD276) belongs to the B7 superfamily of immune checkpoint molecules. It is present at low levels in most normal tissues but is overexpressed in a variety of cancers, such as lung cancer, prostate cancer, breast cancer, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma. Notably, B7H3 overexpression has been found to be associated with a poor prognosis in a broad spectrum of malignant tumors, and it has become an attractive target for cancer therapy in recent years. B7H3-targeted antibody-drug conjugates (ADCs), such as DS7300, have shown positive clinical efficacy in small cell lung cancer, squamous non-small cell lung cancer, metastatic castration-resistant prostate cancer. GLR1061 is a B7H3 targeting ADC comprised of a humanized IgG1 monoclonal antibody, a cleavable linker and a novel DNA topoisomerase I inhibitor. Our independently developed topoisomerase I inhibitor had super strong cancer cell inhibition activity, which was 5 to 10 times stronger than DXd, and enhanced key advantages such as ADC bystander effect. Conjugated with B7-H3 antibody, which had superior binding and internalization, GLR1061 demonstrated more significant anti-tumor efficacy across various cancer types than DS7300 both in vitro and in vivo. In addition, in the CDX model of co-culture of antigen-positive and antigen-negative cells, GLR1061 exhibited much stronger bystander activity than DS7300, which was expected to overcome tumor heterogeneity and effectively eliminate cancer cells with different antigens expressions. In plasma stability studies, GLR1061 showed significantly lower free-payload release than DS7300 in different species (PBS, rat, monkey, and human). In a preclinical repeated-dose toxicology study in mice, GLR1061 showed good tolerability and reversible toxicity. Overall, GLR1061 demonstrated excellent specificity, efficacy, and safety as a next-generation therapy for the treatment of B7H3-positive tumors. Citation Format: Jiao Jiao, Yingjie Sun, Jiaxing Wang, Menghan Cui, Siyao Li, Wenjie Shao, Hairui Yuan, Haitong Sheng. Preclinical characterization of GLR1061, a B7H3-targeted ADC with a novel DNA topoisomerase I inhibitor, demonstrated superior bystander effect to overcome tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2878.