Abstract 5454: DB-1325, a BCMA-targeting antibody-drug conjugate with a Duality Unique Payload, exhibits promising efficacy and safety in preclinical multiple myeloma treatment

Introduction: B cell maturation antigen (BCMA) overexpression has been found on the surface of the malignant plasma cells in the bone marrow of multiple myeloma (MM) patients. In recent years, innovative medicines targeting BCMA such as antibody-drug conjugates (ADC), T-cell engager and CAR-T have made great progress in the treatment of MM patients. Among them, belantamab mafodotin has been approved by FDA. However, a significant fraction of patients does not respond, or respond for a short period of time, to belantamab mafodotin. Thus, there remains unmet medical needs for BCMA-targeting ADC with novel mode of actions. DB-1325 is a novel BCMA-targeting ADC comprised of belantamab and PDUP5, a Duality Unique Payload (DUP) inhibiting mRNA translation, conjugated through a cleavable linker. Methods: A proprietary inhibitor of mRNA translation PDUP5 was discovery through a campaign of medicinal chemical design and screening. A cleavable linker was designed to be attached to PDUP5, resulting in LPDUP5. Belantamab was conjugated with LPDUP5 to yield DB-1325. The therapeutic profile of DB-1325, including in vitro and in vivo efficacy, and its safety profile was assessed in preclinical models. Results: PDUP5 exhibited sub-nanomolar to nanomolar potency in in vitro cell killing test on various MM cell lines. DB-1325 (belantamab-LPDUP5) showed robust in vitro anti-proliferation activity in multiple BCMA-expressing cell models (e.g. NCI-H929, KMS-11, MM1S, MOLP8) with activity similar to belantamab mafodotin. In addition, we observed robust efficacy of DB-1325 in several in vivo xenograft models following a single dose treatment. In NCI-H929 CDX model, treatment with DB1325 demonstrated anti-tumor activity superior to belantamab mafodotin when given at an equivalent dose. Furthermore, DB-1325 was well-tolerated at a preliminary toxicology assessment using monkeys, with favorable toxicokinetic profile. Conclusions: DB-1325 is a novel and promising therapy for MM and currently in preclinical development as a first-in-class ADC with mRNA translation inhibitions as its major mode of action. Citation Format: Shengchao Lin, Bing Li, Yu Zhang, Jun Yao, Rong Shi, Yang Qiu, Haiqing Hua. DB-1325, a BCMA-targeting antibody-drug conjugate with a Duality Unique Payload, exhibits promising efficacy and safety in preclinical multiple myeloma treatment [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 5454.