Lbl-076, a first-in-class GPRC5DxCD38xCD3 trispecific T cell engager (TCE) for the treatment of relapsed/refractory multiple myeloma

Abstract Background: Despite significant therapeutic advancements, multiple myeloma (MM) remains incurable. Most patients ultimately relapse and acquire drug resistance, particularly those refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. For these triple-class refractory patients, treatment options are limited, resulting in poor prognosis. High tumor heterogeneity, an immunosuppressive microenvironment, and cumulative therapy-related toxicities further complicate disease management. Therefore, novel therapeutic agents with novel mechanisms of action and improved safety profiles are urgently needed. CD38 is uniformly expressed on malignant plasma cells in the vast majority of MM patients. Although CD38 expression is downregulated during daratumumab treatment, it gradually rebounds to baseline within months after treatment cessation. GPRC5D is selectively overexpressed on MM cells, including patients relapsed or refractory to anti-CD38 therapies. Simultaneously targeting two tumor-associated antigens (TAAs) represents a promising therapeutic strategy to prevent antigen escape and extends therapeutic durability. We have therefore developed LBL-076, a novel GPRC5DxCD38xCD3 trispecific T cell engager. This molecule targets both GPRC5D and CD38 on MM cells, while recruiting and activating T cells. LBL-076 is designed to overcome immune evasion and antigen loss driven by tumor heterogeneity and to deliver potent sustained efficacy in relapsed/refractory MM (rrMM). Methods LBL-076 was developed using the LeadsbodyTM platform. It adopts a 2:1:1 trispecific antibody format, comprising two high-affinity Fab arms targeting GPRC5D, one VHH arm targeting CD38 with fine-tuned binding affinity and positioning, and a low-affinity scFv arm targeting CD3. This configuration achieves an optimal balance between efficacy and safety. The binding affinities of LBL-076 to antigens were determined using BLI technology. Functional activity was evaluated through cell-based assays, including T cell-dependent cellular cytotoxicity (TDCC) assays on MM cell lines co-cultured with PBMC. The anti-tumor activity of LBL-076 was investigated in multiple mouse models engrafted with myeloma cells expressing varying levels of GPRC5D and CD38. Results LBL-076 demonstrated potent TDCC activity against myeloma cells expressing varying levels of GPRC5D and CD38, accompanied by robust T cell activation and modest cytokine release. Critically, LBL-076 exhibited weak cytotoxicity against CD38-expressing immune cells, including activated T cells, B cells, NK cells, and monocytes, thereby mitigating the risk of on-target, off-tumor toxicity. In multiple mouse models engrafted with MM cells expressing various levels of GPRC5D and CD38, LBL-076 induced significant antitumor activity. Furthermore, no apparent off-tumor toxicity was observed, as indicated by normal clinical observations in treated mice. Conclusion LBL-076 is a first-in-class trispecific TCE to co-target GPRC5D, CD38 and CD3, designed to enhance cytotoxicity against MM cells. Its molecular architecture is rationally optimized: the GPRC5D arm carries precisely tuned valency, and the CD38 arm is positioned distally to maximize tumor-directed cytotoxicity while curbing CD38-mediated on-target, off-tumor toxicity. Simultaneous targeting of two validated TAAs by a single TCE, LBL-076 delivers enhanced cytotoxic potency across the full spectrum of GPRC5D and CD38 expression levels in both in vitro and in vivo models, indicating significant therapeutic potential to transform outcomes for MM patients relapsed or refractory to single-target therapies.