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

Journal

Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423

Informations de publication

Date de publication:
08 Dec 2023
Historique:
received: 27 07 2023
accepted: 19 10 2023
revised: 18 10 2023
medline: 8 12 2023
pubmed: 8 12 2023
entrez: 7 12 2023
Statut: epublish

Résumé

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Identifiants

DOI: 10.1038/s41392-023-01686-z PMID: 38062078 PMC: PMC10703879
pubmed: 38062078
doi: 10.1038/s41392-023-01686-z
pii: 10.1038/s41392-023-01686-z
pmc: PMC10703879
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

445

Subventions

Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81900206
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82230006

Informations de copyright

© 2023. The Author(s).

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Auteurs

Yan Sun (Y)

Shanghai 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.

Xiu-Na Yang (XN)

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
ORCID: 0000-0003-3443-9815

Shuang-Shuang Yang (SS)

Shanghai 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.
ORCID: 0000-0002-8268-5343

Yi-Zhu Lyu (YZ)

Shanghai 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.
Department of Hematology, Second Hospital of Dalian Medical University, Dalian, 116023, China.

Bing Zhang (B)

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

Kai-Wen Liu (KW)

Shanghai 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.
ORCID: 0000-0002-2186-8031

Na Li (N)

National Facility for Protein Science Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China.

Jia-Chen Cui (JC)

Shanghai 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.

Guang-Xiang Huang (GX)

Shanghai 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.

Cheng-Lin Liu (CL)

Shanghai 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.
ORCID: 0009-0000-5322-8621

Jie Xu (J)

Shanghai 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.

Jian-Qing Mi (JQ)

Shanghai 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.

Zhu Chen (Z)

Shanghai 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.

Xiao-Hu Fan (XH)

Legend Biotech China, Nanjing, 211112, China. frankfanwondercel@gmail.com.
Wondercel Biotechnology, Shenzhen, 518052, China. frankfanwondercel@gmail.com.

Sai-Juan Chen (SJ)

Shanghai 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. sjchen@stn.sh.cn.
ORCID: 0000-0003-3789-1284

Shuo Chen (S)

Shanghai 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. shuochen@sjtu.edu.cn.
Shanghai Immune Therapy Institute, Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. shuochen@sjtu.edu.cn.

Classifications MeSH