APRIL-driven BCMA/TACI dual-targeted ligand–drug conjugates for selective and potent therapy of multiple myeloma

B-cell maturation antigen (BCMA) is highly expressed on malignant plasma cells and has emerged as an ideal therapeutic target in multiple myeloma (MM). However, the efficacy of BCMA-targeted therapies is often limited by antigen downregulation and tumor escape. Here, we report the design of a dual-targeted ligand–drug conjugate (LDC) leveraging a proliferation-inducing ligand (APRIL), the natural ligand for both BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). This dual-targeting strategy enables enhanced binding breadth and mitigates antigen-loss-mediated resistance. Compared to conventional antibodies, APRIL-based fusion proteins (APRILFc) exhibited markedly faster internalization in MM cells (∼25% within 30 min), facilitating efficient intracellular drug delivery. LDCs conjugated with monomethyl auristatin E (MMAE) or SN-38 demonstrated potent cytotoxicity across diverse MM cell lines, outperforming corresponding antibody–drug conjugates (ADCs). Notably, LDCs maintained strong antitumor activity in BCMA-knockout models, highlighting their capacity to overcome BCMA escape. In both subcutaneous and intratibial MM mouse models, LDC-MMAE significantly suppressed tumor growth, including in the context of BCMA shedding. These findings establish APRIL-based LDCs as a promising, mechanistically distinct modality for MM therapy, capable of addressing key limitations of current BCMA-targeted approaches. We engineer a ligand‒drug conjugate (LDC) leveraging natural APRIL ligand for dual BCMA/TACI targeting exhibit accelerated internalization and superior cytotoxicity over anti-BCMA ADCs. This mechanistically distinct strategy addresses key limitations of current BCMA-targeted approaches.