Although treatment advances over recent decades have significantly improved survival of patients with multiple myeloma, there is still an unmet medical need for more effective treatments. In this study, we identified G-protein-coupled receptor family C group 5 member D (GPRC5D) expression on the surface of malignant cells involved in multiple myeloma, but except for plasma cells and B cells, not at appreciable levels on normal hematopoietic cells and bone marrow progenitors , including hematopoietic stem cells. In addition, we constructed IgG-based anti-GPRC5D/CD3 bispecific T-cell-redirecting antibodies (GPRC5D TRAB), which suppressed the tumor growth of GPRC5D-positive myeloma cells through the activation of T cells in vitro and in vivo in xenograft models. Collectively, these findings suggest that GPRC5D is an antigen specific to multiple myeloma and a potential target of TRAB therapy.

Background: Although treatment advances over recent decades have significantly improved survival of patients with multiple myeloma, there is still an unmet medical need for more effective treatments. The orphan G protein-coupled receptor, class C group 5 member D (GPRC5D), was previously identified as expressed by mRNA in patients with multiple myeloma with only low expression detected in normal tissues, but confirmation of protein expression remained elusive. In this study, we determined the cell surface expression of GPRC5D on malignant and normal hematological cells. In addition, we evaluated the antitumor activity and mechanism of GPRC5D TRABs in in vitro and in vivo mouse models. Method & Results: We established specific monoclonal antibodies against human GPRC5D and identified its expression on the surface of malignant cells involved in multiple myeloma, but except for plasma cells and B cells, did not find it at appreciable levels on normal hematopoietic cells and bone marrow progenitors, including hematopoietic stem cells. To investigate whether GPRC5D could be therapeutic target, we generated IgG-based anti-GPRC5D/CD3 bispecific T-cell-redirecting antibodies (GPRC5D TRABs). GPRC5D TRABs induced T cell activation and the killing of a wide variety of GPRC5D expressing tumor cells in vitro. In mouse models with reconstituted human immune cells, GPRC5D TRABs showed strong antitumor efficacy against GPRC5D-positive tumors through the activation of T cells. Conclusion: These findings suggest that GPRC5D is an antigen specific to multiple myeloma and a potential target of TRAB therapy. Citation Format: Tatsushi Kodama, Yu Kochi, Waka Nakai, Hideaki Mizuno, Takeshi Baba, Kiyoshi Habu, Noriaki Sawada, Hiroyuki Tsunoda, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Yasuo Mori, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi. Anti -GPRC5D/CD3 T cell-redirecting bispecific antibody with potent in vitro and in vivo antitumor efficacy against multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1886.