Abstract 659: Translational medicine studies of BR111, a biparatopic anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment

Abstract ROR1 is a type I transmembrane protein that belongs to the ROR family. It is a receptor for Wnt family signaling molecules Wnt5a, and plays a critical role in various cellular processes, such as cell proliferation, survival, and migration. Being an oncofetal protein, ROR1 exhibits limited expression in most normal tissues. However, it is abnormally expressed in various hematological and solid cancers, contributing to the development and progression of many types of cancer. Due to its overexpression in cancer, ROR1 presents as a highly attractive target for antibody-drug conjugate (ADC) therapy. The current clinical results of ROR1 ADCs have been promising in treating patients with relapsed and/or refractory (R/R) hematologic malignancies. BR111 is anti-ROR1 ADC that consists of a biparatopic antibody, stably conjugated to an antimitotic agent. The biparatopic antibodies demonstrate superior binding affinity to ROR1-expressing cancer cells compared to single epitope antibodies. Notably, our unique and innovative conjugation platform CysX™, not only prevents payload detachment during circulation and reducing the off-target toxicity, but also enables a uniformed drug-to-antibody ratio (DAR) of 4. Recent translational medicine studies showed that ROR1 is relatively highly expressed in the patients of many solid tumors including sarcoma, gastric cancer, TNBC, endometrial cancer, etc. And BR111 has demonstrated efficacy in in vitro and in vivo models of those indications. BR111 has also showed synergistic efficacy when combined with PD-1/L1 antibodies, SIRPα antibody and several chemotherapeutics. Studies have also shown that ROR1 levels increase while HER2 levels decrease in cell lines treated with DS-8201, and BR111 showed improved efficacy in DS-8201 resistant cell line as well as in combination with DS-8201. The promising outcome holds great potential as a therapeutic treatment for hematological and solid cancers, offering a better safety profile. BR111 has great potential in further clinical evaluations. Citation Format: Qinqin Zhuang, Yan Sun, Lilv Fan, Qianqian Tao, Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Lei Nie, Gang Chen, Haibin Wang. Translational medicine studies of BR111, a biparatopic anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment [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 659.