LAUSR

The FDA has granted Breakthrough Therapy Designation (BTD) for talquetamab, which targets both GPRC5D on multiple myeloma cells and CD3 on T-cells, for treating adult patients with relapsed or refractory multiple myeloma. Results showed that patients who received talquetamab experienced adverse events, including cytokine release syndrome (CRS), neutropenia, skin-related adverse events and dysgeusia. To allow preclinical in vivo evaluation of anti-human CD3/GPRC5D bispecific antibodies, we developed a BALB/c-hCD3EDG mouse model and a human GPRC5D-expressing A20 murine lymphoma cell line. The BALB/c-hCD3EDG cohort (6-8 weeks old) was subcutaneously inoculated with A20-hGPRC5D cells and then treated with anti-CD3/GPRC5D bispecific antibodies. As expected, anti-CD3/GPRC5D bispecific antibody treatment strongly inhibited the growth of A20-hGPRC5D tumors in BALB/c-hCD3EDG mice. To allow a comprehensive safety evaluation of anti-CD3/GPRC5D candidates, including the possibility of CRS and target organ toxicity, we engineered BALB/c-hCD3EDG mice that express hGPRC5D, denoted BALB/c-hCD3EDG/hGPRC5D. Human GPRC5D was detected in the liver, lung, thymus, adipose tissue, and thyroid. In vivo evaluation of anti-CD3/GPRC5D therapy in this mice is currently underway. In conclusion, BALB/c-hCD3EDG/hGPRC5D and BALB/c-hCD3EDG mice bearing A20-hGPRC5D tumors are suitable models for preclinical studies testing anti-CD3/GPRC5D bispecific antibodies. Citation Format: Xiaoliu Yang, Xinyuan Liang, Mingkun Zhang, Santi Suryani Chen, Zhiying Li, Erica Trujillo, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. A novel mouse model for preclinical efficacy evaluation of anti-CD3/GPRC5D bispecific antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5206.