Abstract 1883: A novel T cell engager targeting BCMA and GPRC5D showed promising preclinical activity with low toxic risk for multiple myeloma treatment

Abstract Background: Multiple myeloma (MM) has become the second most hematological malignance. The patients are rarely cured and experience the recurrence or resistance. There is still an urgent need to develop potential therapeutic agents with better response. BCMA (B cell maturation antigen) and GPRC5D (G-protein-coupled receptor class 5 member D) are independently expressed in MM cells. The percentage of MM patients with single or co-expression of BCMA and GPRC5D is close to 90%, which means both are the ideal therapeutical targets. Methods/Results: Anti-GPRC5D and anti-BCMA antibodies with high binding affinity were respectively screened from hybridoma or alpaca phage library. Two antibodies were assembled to anti-CD3 antibody with low binding activity. Candidate molecule SCR-8572 was selected from dozens of triple-specific antibodies. The affinity of SCR-8572 to recombinant BCMA protein is 41.3pM. Binding EC50 to GPRC5D over-expressed cell is 2.4nM. SCR-8572 also showed very good binding activity with several MM cell lines, such as H929, RPMI-8226 and Molp-8, etc. The weak binding to CD3 can decrease the sink effect in peripheral blood. In vitro cytotoxicity of SCR-8572 against three MM cell lines with different expression levels was evaluated. It showed strong tumor-induced T cell activation but not non-specific activation, which resulted in the excellent tumor cytotoxicity. And the cytotoxicity was much stronger than that of BCMA-CD3 (Teclistamab analogue) and/or GPRC5D-CD3 (Talquetamab analogue) treatments. In the meanwhile, the cytokine release levels of IL-6 and TNFa are acceptable and similar with two TCE benchmarks. This predicted the low risk of CRS. We also conducted in vivo efficacy test in two MM Cell-derived-Xenograft mice models with PBMC reconstitution. SCR-8572 can eliminate the tumors and maintained tumor regression after drug withdrawal, while the tumor relapse occurred in Teclistamab and/or Talquetamb groups. The preliminary toxic effect of SCR-8572 was explored in cynomolgus by 10mpk followed by 30mpk intravenous injection with 21 days interval. The cynomolgus tolerated very well. Lymphocyte reduction was observed which indicated the lymphocyte redistribution. C Reaction Protein (CRP) level increased to 19-33mg/L and recovered to baseline in 7 days. IL-6 level increased to 116.3pg/ml in 24 hours after 10mpk injection and 52.5pg/ml in 2 hours after followed 30mpk injection. IFNγ, IL-2 and IL-10 levels were detected to be very low or below the limit of quantitation. Conclusion: We have developed a novel dual-targeted T cell engager for MM treatment, which showed strong tumor killing effect in in vitro and in vivo models with low CRS risk. The toleration of high dosage in cynomolgus suggested the good safety performance. Above all, the preclinical study illustrated SCR-8572 can be a promising therapeutic candidate in treatment of MM patients. Citation Format: Yayuan Fu, Shumei You, Menghao Wei, Bowei Yin, Qi Deng, Xiaokang Qin, Yun Zhang, Yanqiu Wang, Renhong Tang. A novel T cell engager targeting BCMA and GPRC5D showed promising preclinical activity with low toxic risk for multiple myeloma treatment [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 1883.