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<p>There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2<sup>+</sup> AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2<sup>+</sup> AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.</p>

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T cell receptor mimic CAR T cells targeting cathepsin G signal peptide

  • 期刊论文

  • 发表日期：

    2025年5月28日

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  • Jun Yan,
  • Chunhua Shi,
  • Guojun Yang,
  • Ze Tian,
  • Hiroki Torikai,
  • Pariya Sukhumalchandra,
  • Shaohua Peng,
  • Edward Chang,
  • Meng Cui,
  • Celine Kerros,
  • Anne Philips,
  • Na Qiao,
  • Mao Zhang,
  • Timothy E. Lofton,
  • Jason K. Allen,
  • Michelle A. Gonzalez,
  • Sathvik Patchametla,
  • Anna Sergeeva,
  • Lisa St. John,
  • Helen He,
  • Dongxing Zha,
  • Jeffrey Molldrem,
  • Gheath Alatrash

摘要

There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2+ AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2+ AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.