Abstract
Abstract Multiple myeloma (MM) comprised 0.9% of all new cancer cases and 1.2% of cancer death in 2020 and is the second most common hematological neoplasm in adults. Primary refractory to treatment and relapse resulted in a high death rate of MM patients. Bispecific antibodies (BsAbs) are attracting candidate drugs against multiple myeloma by targeting CD3 on T cells and MM specific cell surface markers such as B cell maturation antigen (BCMA), CD38, and G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D). In the current study, we developed a humanized antibody targeting GPRC5D (clone number G-02-9D7). The antibody was derived from hybridoma of mouse immunized with GPRC5D overexpressed mouse cell line. Compared to the GPRC5D antibody in clinical (JNJ-64407564), this antibody has a higher affinity to 293T cells overexpressing GPRC5D (EC50=1.9nM vs. 3nM), MM cell lines, and MM patient samples. In addition, this antibody did not bind to GPRC5A, B, and C and had weaker non-specific binding to human serum albumin than JNJ-64407564. Bispecific antibody derived from the GRPC5D antibody and CD3 antibody (clone number: sp34) induced specific cytotoxicity of MM cells in the presence of T cells from PBMC. This bispecific antibody stimulated the release of cytokines from T cells such as INF-γ, IL-2, IL-8, and TNF-α. In NCI-H929 prophylactic xenograft mouse model with PBMC transplantation, tumor growth could be prevented by administration weekly with this bispecific antibody as low as 0.1ug per mouse. In the presence of T cells, the bispecific antibody also resulted in complete remission of established MM.1S tumor in xenografted NSG mouse with the injection of 1ug antibody weekly. At last, MM patient bone marrow samples cultured in vitro with this bispecific antibody increased cell death of the CD138+ population. In summary, the GPRC5D antibody could efficiently target Multiple myeloma tumor cells. Citation Format: Feng He, Kefei Wu, Jiabei Liang, Jianhui Li, Hao Peng, Guojin Wu, Jinying Ning. A therapeutic antibody against G-protein-coupled receptor class 5 member D to treat multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5299.
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