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  3. Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders

Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders

  • Nat Biomed Eng. 2024 Oct 17. doi: 10.1038/s41551-024-01258-8.
Zhen Xia 1 2 3 4 5,  Qihan Jin 1 2 5 6,  Zhilin Long 1 2 3 4 5,  Yexuan He 5,  Fuyi Liu 7,  Chengfang Sun 1 8,  Jinyang Liao 1 2 5 6,  Chun Wang 7,  Chentong Wang 1 2 5 6,  Jian Zheng 7,  Weixi Zhao 1 2 3 4 5,  Tianxin Zhang 1 2 5 6,  Jeremy N Rich 9,  Yongdeng Zhang 5,  Longxing Cao 10 11 12 13,  Qi Xie 14 15 16 17 18
Affiliations

Affiliations

  • 1 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
  • 2 Research Center for Industries of the Future, Westlake University, Hangzhou, China.
  • 3 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
  • 4 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.
  • 5 School of Life Sciences, Westlake University, Hangzhou, China.
  • 6 Artificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
  • 7 Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 8 School of Medicine, Zhejiang University, Hangzhou, China.
  • 9 University of Pittsburgh Medical Center Hillman Cancer Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 10 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. caolongxing@westlake.edu.cn.
  • 11 Research Center for Industries of the Future, Westlake University, Hangzhou, China. caolongxing@westlake.edu.cn.
  • 12 School of Life Sciences, Westlake University, Hangzhou, China. caolongxing@westlake.edu.cn.
  • 13 Artificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. caolongxing@westlake.edu.cn.
  • 14 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. xieqi@westlake.edu.cn.
  • 15 Research Center for Industries of the Future, Westlake University, Hangzhou, China. xieqi@westlake.edu.cn.
  • 16 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. xieqi@westlake.edu.cn.
  • 17 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. xieqi@westlake.edu.cn.
  • 18 School of Life Sciences, Westlake University, Hangzhou, China. xieqi@westlake.edu.cn.
PMID: 39420062 DOI: 10.1038/s41551-024-01258-8
Abstract

Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers.

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