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<p>Successfully extending immunotherapies to solid tumors involves addressing several key challenges, importantly the “antigen dilemma”, the expression of a solid tumor target antigen on the normal tissue of tumor origin. Claudin 18.2 (CLDN18.2) has emerged as an important target for upper gastrointestinal (GI) cancer therapies (such as Zolbetuximab, a naked antibody, recently approved; or CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy with promising clinical data). However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041. Here, we describe clinical Zolbetuximab treatment associated cases of gastric erosive lesions. We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy.</p>

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Modeling and addressing on-target/off-tumor toxicity of claudin 18.2 targeted immunotherapies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月1日

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  • Elizabeth J. Carstens,
  • Kazuki Takahashi,
  • Naoya Sakamoto,
  • Martina De Vizio,
  • Micaela Morgado,
  • Shahryar Khoshtinat Nikkhoi,
  • Abhishek Mangipudi,
  • Canh Hiep Nguyen,
  • Tate Weltzin,
  • Izuma Nakayama,
  • Qiang Lv,
  • Jue Zeng,
  • Cui Nie,
  • Changjing Deng,
  • Xiaoxiao Wang,
  • Lile Liu,
  • Samuel J. Klempner,
  • Anusuya Ramasubramanian,
  • Jonathan A. Nowak,
  • Andrew J. Aguirre,
  • Kohei Shitara,
  • Eric L. Smith

摘要

Successfully extending immunotherapies to solid tumors involves addressing several key challenges, importantly the “antigen dilemma”, the expression of a solid tumor target antigen on the normal tissue of tumor origin. Claudin 18.2 (CLDN18.2) has emerged as an important target for upper gastrointestinal (GI) cancer therapies (such as Zolbetuximab, a naked antibody, recently approved; or CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy with promising clinical data). However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041. Here, we describe clinical Zolbetuximab treatment associated cases of gastric erosive lesions. We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy.