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

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 and Eric L. Smith ()
Additional contact information
Elizabeth J. Carstens: Dana-Farber Cancer Institute
Kazuki Takahashi: Dana-Farber Cancer Institute
Naoya Sakamoto: National Cancer Center Hospital East
Martina De Vizio: Dana-Farber Cancer Institute
Micaela Morgado: Dana-Farber Cancer Institute
Shahryar Khoshtinat Nikkhoi: Dana-Farber Cancer Institute
Abhishek Mangipudi: Dana-Farber Cancer Institute
Canh Hiep Nguyen: Dana-Farber Cancer Institute
Tate Weltzin: Dana-Farber Cancer Institute
Izuma Nakayama: National Cancer Center Hospital East
Qiang Lv: Nona Biosciences (Suzhou) Co., Ltd
Jue Zeng: Nona Biosciences (Suzhou) Co., Ltd
Cui Nie: Nona Biosciences (Suzhou) Co., Ltd
Changjing Deng: Nona Biosciences (Suzhou) Co., Ltd
Xiaoxiao Wang: Nona Biosciences (Suzhou) Co., Ltd
Lile Liu: Nona Biosciences (Suzhou) Co., Ltd
Samuel J. Klempner: Massachusetts General Hospital
Anusuya Ramasubramanian: Dana-Farber Cancer Institute
Jonathan A. Nowak: Brigham and Women’s Hospital
Andrew J. Aguirre: Dana-Farber Cancer Institute
Kohei Shitara: National Cancer Center Hospital East
Eric L. Smith: Dana-Farber Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65148-6

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