Scholarlink

<p>Antibody–drug conjugates (ADCs) have been remarkably successful in treating solid and hematological malignancies. Generation of ADCs for T cell cancers is challenging because the ADCs must selectively target cancerous T cells while sparing some normal T cells necessary for immune function. T cells express one of two <i>TRBC</i> alleles: <i>TRBC1</i> or <i>TRBC2</i>. Normal T cells are composed of about 40% <i>TRBC1</i>-expressing and 60% <i>TRBC2</i>-expressing cells. In contrast, T cell malignancies are characterized by the clonal expression of either <i>TRBC1</i> or <i>TRBC2</i>. Selective targeting of <i>TRBC1</i> or <i>TRBC2</i> enables the killing of cancer cells but preserves about 60–40% of the normal T cells. To enable such a therapy for cancers expressing <i>TRBC2</i>, here we developed a high-affinity anti-TRBC2 antibody. An ADC generated with this antibody and a pyrrolobenzodiazepine dimer payload showed specific killing of TRBC2<sup>+</sup> cancers in vitro and in mouse models. The anti-TRBC2 ADC provides a promising, off-the-shelf therapy for patients with T cell cancers.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

TRBC2-targeting antibody–drug conjugates for the treatment of T cell cancers

  • 期刊论文

  • 发表日期：

    2025年12月22日

查看全文
  • Jiaxin Ge,
  • Joshua Urban,
  • Sarah R. DiNapoli,
  • Bum Seok Lee,
  • Taha Ahmedna,
  • Tushar D. Nichakawade,
  • Brian J. Mog,
  • Steve Lu,
  • Xuyang Li,
  • Nikita Marcou,
  • Stephanie Glavaris,
  • Jacqueline Douglass,
  • Jin Liu,
  • Maximilian F. Konig,
  • Evangeline Watson,
  • Maria Popoli,
  • J. David Peske,
  • Sima Rozati,
  • Cole H. Sterling,
  • Nina Wagner-Johnston,
  • Richard F. Ambinder,
  • Kathy Gabrielson,
  • Charles G. Mullighan,
  • Nickolas Papadopoulos,
  • Chetan Bettegowda,
  • Drew M. Pardoll,
  • Shibin Zhou,
  • Surojit Sur,
  • Kenneth W. Kinzler,
  • Bert Vogelstein,
  • Suman Paul

摘要

Antibody–drug conjugates (ADCs) have been remarkably successful in treating solid and hematological malignancies. Generation of ADCs for T cell cancers is challenging because the ADCs must selectively target cancerous T cells while sparing some normal T cells necessary for immune function. T cells express one of two TRBC alleles: TRBC1 or TRBC2. Normal T cells are composed of about 40% TRBC1-expressing and 60% TRBC2-expressing cells. In contrast, T cell malignancies are characterized by the clonal expression of either TRBC1 or TRBC2. Selective targeting of TRBC1 or TRBC2 enables the killing of cancer cells but preserves about 60–40% of the normal T cells. To enable such a therapy for cancers expressing TRBC2, here we developed a high-affinity anti-TRBC2 antibody. An ADC generated with this antibody and a pyrrolobenzodiazepine dimer payload showed specific killing of TRBC2+ cancers in vitro and in mouse models. The anti-TRBC2 ADC provides a promising, off-the-shelf therapy for patients with T cell cancers.