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Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

Yan Sun1, Xiu-Na Yang2, Shuang-Shuang Yang1

  • 1Shanghai Institute of Hematology, National Research Center for Translational Medicine, State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Signal Transduction and Targeted Therapy
|December 7, 2023
PubMed

Insights

Cell-surface antigen-induced multimerization (AIM) enhances chimeric antigen receptor (CAR) therapies. This study shows AIM amplifies T cell-mediated cytotoxicity against multiple myeloma by multimerizing BCMA-targeted CARs.

Area of Science:

  • Immunology
  • Structural Biology
  • Biochemistry

Background:

  • Receptor dimerization/oligomerization is crucial for cellular communication and signal transduction.
  • Cell-surface antigen-induced multimerization (AIM) is a known mechanism but underexplored in chimeric antigen receptor (CAR) engineering.
  • T cell-based therapies, particularly for multiple myeloma, can benefit from enhanced activation mechanisms.

Purpose of the Study:

  • To elucidate the structural and functional model of antigen-induced multimerization in CAR engineering.
  • To investigate the role of BCMA-induced multimerization of ciltacabtagene autoleucel (cilta-cel) CAR in enhancing T cell-mediated cytotoxicity.
  • To provide a framework for utilizing the AIM approach in designing next-generation CARs.

Main Methods:

  • Co-development of ciltacabtagene autoleucel (cilta-cel) CAR with tandem BCMA-targeted nanobodies.
  • Crystallographic analysis of BCMA-nanobody complexes.
  • Analytical ultracentrifugation and small-angle X-ray scattering to characterize molecular interactions.

Main Results:

  • Atomic details of BCMA-nanobody hetero-multimerization were revealed.
  • Interdependent BCMA apposition and CAR juxtaposition in solution were characterized.
  • BCMA-induced nanobody CAR multimerization significantly enhanced T cell cytotoxicity, immune synapse formation, and cytokine release against myeloma cells.

Conclusions:

  • BCMA-induced cilta-cel CAR multimerization amplifies T cell-mediated cytotoxicity against multiple myeloma.
  • The study provides a structural and functional model for antigen-induced multimerization in CARs.
  • The AIM approach offers a promising strategy for next-generation CAR design.

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