RT journal article
T1 Dual targeting of BCMA and SLAMF7 with the CARtein system: chimeric antigen receptors with intein-mediated splicing elicit specific T cell activation against multiple myeloma
A1 Moares Fernández, Noelia del Carmen
A1 González García, Pablo
A1 Yi-He, Wenjie
A1 Muñoz Miranda, Juan Pedro
A1 Gabucio López, Antonio
A1 Luna-Espejo, Rosa
A1 Ocaña-Cuesta, Javier
A1 Fernandez-Cisnal, Ricardo
A1 Fernández-Ponce, Cecilia
A1 García-Cózar, Francisco
A2 BiomedicinaBiotecnología y Salud Pública
K1 chimeric antigen receptor
K1 multiple myeloma
K1 inteins
K1 protein splicing
K1 B-cell maturation antigen
K1 SLAMF7
K1 modular CAR
K1 immunotherapy
AB Introduction: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy against multiple myeloma (MM). However, several barriers continue to limit the overall effectiveness of this approach, such as high production costs, prolonged manufacturing timelines, safety issues, and the potential for tumor antigen escape due to selective therapeutic pressure. To overcome these challenges, innovative CAR T strategies, such as engineering modular CAR systems, are being explored. These systems utilize adaptor molecules to enable multi-antigen targeting, thereby enhancing specificity, safety, and overall efficiency of CAR T-cell therapy. Notably, CAR T-cells directed against BCMA and SLAMF7 antigens have generated strong and robust antitumor responses in MM therapy. Methods: To address the limitations of conventional CAR T therapy, we developed a novel modular CAR platform targeted against BCMA and SLAMF7. This was achieved using a split intein-mediated protein splicing mechanism, which allows specific covalent peptide bonds to form between CAR modules. This strategy maintains an almost seamless CAR structure, preserving its overall integrity and functionality. The design of the intein-spliced CAR system (termed "CARtein") was further optimized through advanced protein structure prediction software. Results: Cells expressing the spliced CARtein constructs, engineered to target BCMA, SLAMF7, or both antigens simultaneously, demonstrated robust and highly specific activation in response to their respective antigens. Discussion: These results suggest that the CARtein platform is a promising, versatile, and highly specific approach for the modular design and engineering of CARs, enabling multi-antigen targeting while maintaining structural and functional integrity. This modular strategy addresses key limitations of conventional CAR T-cell therapy and may improve both the safety and effectiveness of future MM treatments.
PB FRONTIERS MEDIA SA
SN 1664-3224
YR 2025
FD 2025-07
LK http://hdl.handle.net/10498/37970
UL http://hdl.handle.net/10498/37970
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 08-nov-2026