Abstract LB129: VTS105: A novel and potent BCMA/GPRC5D/CD3 trispecific T cell engager (TCE) for the treatment of hematologic malignancies and autoimmune diseases

Abstract Multiple myeloma (MM) is a genetically complex and heterogeneous malignancy with a poor survival rate. Despite therapeutic advancements, MM remains incurable, and patients ultimately succumb to relapsed disease. Recently approved T cell engagers targeting BCMA (e.g., Teclistamab) and GPRC5D (e.g., Talquetamab) have demonstrated clinical responses; however, high relapse rates persist due to suboptimal complete response (CR) rates and minimal residual disease (MRD). Additionally, BCMA mutations and antigen escape diminish the clinical benefits of BCMA-targeted therapies, including TCEs and CAR-T cells (chimeric antigen receptor T cells). Consequently, broader tumor-associated antigen coverage is urgently needed to address the unmet medical need for effective tumor cell elimination and prevention of resistance due to antigen loss. Here, we present VTS105, a trispecific antibody featuring a proprietary CD3 arm and the capability to target both BCMA and GPRC5D, which are co-expressed or individually expressed on heterogeneous MM cancer cells. VTS105 exhibits potent human PBMC-mediated tumor cell killing across various heterogeneous MM cell lines, outperforming competitors such as JNJ-79635322, IBI3003, and SCR-8572. VTS105 maintains high killing potency against BCMA low MM cells, effectively addressing drug resistance associated with BCMA escape following frontline BCMA-targeted therapies. In CDX models with varying BCMA and GPRC5D expression levels, VTS105 induces complete tumor remission, even at low or very low doses, demonstrating superior efficacy compared to JNJ-79635322. VTS105 activates T cells exclusively in a BCMA- and/or GPRC5D-dependent manner, indicating a promising safety profile. This innovative approach has the potential to significantly improve progression-free survival (PFS) and reduce relapse rates in MM clinical development. In addition, BCMA and GPRC5D expression are upregulated in Systemic Lupus Erythematosus (SLE), particularly in patients with Lupus Nephritis (LN). This suggests that VTS105 can also serve as a promising therapeutic option for SLE treatment. Evaluations in this indication are currently underway. Currently VTS105 is advancing into CMC and toxicology studies, with an Investigational New Drug (IND) filing planned for the second half of 2026. Citation Format: Wei (Vivian) Wang, Bo Peng, Man Xu, Xuekun Zhang, Jing Li. VTS105: A novel and potent BCMA/GPRC5D/CD3 trispecific T cell engager (TCE) for the treatment of hematologic malignancies and autoimmune diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB129.