Reprogramming BCMA-Targeted CAR-T Cells through γ-Secretase Modulation Blocks Antigen Shedding and Extends CAR-T Longevity

Sharma, S.; Chauhan, V.; Bhat, Z. A.; Aich, J.; Madaan, D.; Gupta, S.; Rashmi, D.; Alam, R.; Dave, D.; Patel, P.; Chaudhary, N.; Singh, D. K.; Singh, V. P.; Husain, M.; Srivastava, A. K.; Mabalirajan, U.; Pendharkar, D.; Murugaiyan, N.; Ramalingam, S. p.; Kharya, G.; Verma, A. K.; Ahmad, T.

doi:10.64898/2026.01.20.700575

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bioRxiv · 10.64898/2026.01.20.700575

Reprogramming BCMA-Targeted CAR-T Cells through γ-Secretase Modulation Blocks Antigen Shedding and Extends CAR-T Longevity

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Abstract

B-cell maturation antigen (BCMA) shedding by {gamma}-secretase generates soluble BCMA (sBCMA), which diminishes membrane antigen density, and limits the durability of BCMA-directed immunotherapies in multiple myeloma (MM). Here, using AI-driven diffusion modeling, we identify peptide inhibitors that selectively block {gamma}-secretase-mediated BCMA cleavage, stabilizing membrane-bound BCMA (mBCMA) without compromising cellular viability. The lead peptide, P5, suppresses sBCMA and restores mBCMA in vitro and in xenograft models. To create sustained, cell-intrinsic inhibition, we engineered Shedding Deterrent Locked-in (SHEDLOCK) CAR-T cells that locally secrete {gamma}-secretase-modulatory peptides. SHEDLOCK-1 CAR-T cells secreting P5 exhibits enhanced cytotoxicity and persistence relative to conventional CAR-T cells. Building on this, SHEDLOCK-2 CAR-T cells were generated, which secrete a modified, naturally derived peptide (nxP) that directly engages the {gamma}-secretase catalytic site, concurrently preventing BCMA shedding, and surprisingly enhancing CAR-T cell longevity by preserving telomere integrity and metabolic fitness. In MM xenograft and patient-derived models, SHEDLOCK-2 CAR-T cells demonstrate durable antitumor activity with a favorable safety profile. Together, these findings establish SHEDLOCK as a next-generation CAR-T platform and provide a strong preclinical foundation for Phase I clinical evaluation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/700575v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@3cd38aorg.highwire.dtl.DTLVardef@164167borg.highwire.dtl.DTLVardef@1ffed21org.highwire.dtl.DTLVardef@1294d06_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sharma, S., Chauhan, V., Bhat, Z. A., Aich, J., Madaan, D., Gupta, S., Rashmi, D., Alam, R., Dave, D., Patel, P., Chaudhary, N., Singh, D. K., Singh, V. P., Husain, M., Srivastava, A. K., Mabalirajan, U., Pendharkar, D., Murugaiyan, N., Ramalingam, S. p., Kharya, G., Verma, A. K., Ahmad, T.. 2026-01-23. Reprogramming BCMA-Targeted CAR-T Cells through γ-Secretase Modulation Blocks Antigen Shedding and Extends CAR-T Longevity. https://doi.org/10.64898/2026.01.20.700575

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