Abstract 7323: LBL-043, a novel LILRB4xCD3 T cell engager, for the treatment of relapsed/refractory multiple myeloma

Abstract Background: Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by abnormal increase of monoclonal immunoglobulins. Despite newly developed novel therapeutic agents have greatly improved the outcome of MM patients in the past decades, MM is still an incurable hematological malignancy. Several CD3 bispecific immunotherapies that harness T cells against MM are at various stages of preclinical and clinical development, but most of them are hampered by the refractory and resistant mechanisms. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint inhibitory receptor, which is highly expressed on monocytic blasts of AML and myeloid-derived suppressive cells. Most recently it is discovered also highly expressed in MM, in particular rrMM(relapsed/refractory MM). It does not express on hematopoietic stem cells and progenitor cells, therefore make it a promising target for hematological malignancies. Herein a novel T cell engager targeting LILRB4, LBL-043, is developed to specifically kill LILRB4 expressing MM cells. Methods: LBL-043 is a bispecific antibody targeting LILRB4 and CD3, designed using proprietary LeadsBodyTM platform, which is a 2:1 format with two VHH arms targeting LILRB4 with high affinity and one scFv arm targeting CD3 with fine-tuned affinity. The binding affinity of LBL-043 was determined with Fortebio and flow cytometry, and the function activity was measured using reporter gene and TDCC assays on MM cell lines. The anti-tumor activity was investigated in B-NDG/hu-PBMC reconstructed mice implanted with NCI-H929. In addition, the potential toxicity profile of LBL-043 was examined in a non-GLP dose range finding (DRF) study in cynomolgus monkeys via IV infusion, once a week for a total of 4 doses. Results: The binding affinity of LBL-043 to LILRB4 and CD3 protein was 0.724 nM and 35.7 nM, respectively. In CD3 reporter gene assays, LBL-043 could activate the NFAT signaling only in the presence of LILRB4+ cells. And LBL-043 was shown a potent TDCC activity in different LILRB4 expression level MM cells. In NCI-H929 CDX mouse model, LBL-043 was shown significant anti-tumor activity. DRF Study in Drug Toxicology Assessments demonstrated that LBL-043 has good safety profile in cynomolgus monkeys. There were no LBL-043 related changes of cardiac parameters, clinical chemistry, hematology, urinalysis, organ weight and gross pathology (except for decreased size of thymus). Conclusion: LBL-043, a novel bispecific antibody targeting CD3 and LILRB4, redirecs T cells to effectively kill MM cells by simultaneously binding MM cells and T cells. It is also shown a great anti-tumor efficacy in NCI-H929 CDX mouse model. DRF of LBL-043 (0.2∼10 mg/kg) in cynomolgus monkeys was well tolerated, and HNSTD was 10 mg/kg. These data for the first time show LBL-043 as a promising therapeutic bispecific antibody for the treatment of MM patients. Citation Format: Yujia Dang, Xiao Huang, Yurong Qin, Xiaoya Liu, Min Chen, Duqing Jiang, Guojin Wu, Mi Ye, Jianming Sun, Hong Ling, Shoupeng Lai, Xiaoqiang Kang, Jordan Zhu. LBL-043, a novel LILRB4xCD3 T cell engager, for the treatment of relapsed/refractory 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 7323.