BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma

Simple Summary In recent years, BCMA-targeted therapies have significantly improved the limited efficacy of conventional therapies for multiple myeloma (MM), yet many patients still relapse. GPRC5D, an MM-specific target that is independent of BCMA expression, has emerged as a potential therapeutic intervention for MM. Additionally, T-cell-mediated therapies have shown promise in treating MM. Consequently, we have developed and analyzed the properties of BR109, an anti-GPRC5D x anti-CD3 T-cell-engaging bispecific antibody (TCB). Both in vitro cell assays and xenograft tumor models in mice showed that BR109 has high antitumor efficacy, supporting its clinical progress as a promising approach to multiple myeloma therapy.Abstract At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D x anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3 epsilon. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.