Abstract 2135: QLS4131, a proprietary T cell engager targeting both BCMA and GPRC5D for the treatment of multiple myeloma

Abstract Multiple myeloma (MM) is a genetically complex and heterogeneous malignancy with poor prognosis. Despite recent advances in the development of new therapeutics, clinical management of MM remains a big challenge largely due to quick emergence of drug resistance. Thus, novel therapies which can cause deeper response or overcome drug resistance are highly desired. It has been found that both BCMA and GPRC5D are overexpressed in MM in a manner of either co-expression or mono-expression. In fact, T cell engagers (TCE) targeting either BCMA or GPRC5D alone have been approved by FDA for MM treatment. Hence, TCE target both BCMA and GPRC5D have a great potential to demonstrate superior efficacy and overcome resistance to TCE only targeting a single antigen. QLS4131 demonstrated a higher affinity for MM tumor cell lines when compared to JNJ-79635322, which is a clinical stage TCE targeting both BCMA and GPRC5D developed by Janssen Research & Development. QLS4131 was capable of effectively depleting both dual (BCMA and GPRC5D) and single (BCMA or GPRC5D) target-expressing cells, and its cytotoxicity was substantially more potent than JNJ-79635322. Meanwhile, the level of IL-6 cytokine release was comparable to that of JNJ-79635322. Additionally, QLS4131 maintained robust TDCC activity even in the presence of 2.5 µg/mL soluble BCMA. The single-dose PK evaluation revealed linear pharmacokinetic characteristics with a half-life (T1/2) of approximately 120 hours, it also demonstrated high bioavailability (79.83%) when SC dosing. In in vivo pharmacology studies, QLS4131 could inhibit tumor growth in a dose-dependent manner and even induce tumor regression and exhibited superior antitumor efficacy related to JNJ-79635322. QLS4131 was well tolerated in a cyno monkey QW x 4 GLP toxicity study. Skin and nail toxicity (related to the GPRC5D target) was not observed. The HNSTD was 2 mpk for both intravenous and subcutaneous injections. In conclusion, the excellent efficacy, favorable PK, and safety profile support the potential of QLS4131 as a novel therapeutic agent to address the significant unmet needs in multiple myeloma. A Phase 1 dose-escalating study of QLS4131 in multiple myeloma is currently underway (NCT06500507). Citation Format: Liuqing Yang, Hongliang Qian, Juan Luo, Ke Liu, Ling Zhang, Shuyong Zhao, Hua Ying, Weikang Tao. QLS4131, a proprietary T cell engager targeting both BCMA and GPRC5D for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2135.