pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies

Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-02-18
DOI
https://doi.org/10.1073/pnas.2422731122
Citations
3
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
4.08

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article

pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies

Benyu Wang, Kepeng Yan, James K. Fields, Pan Zheng et al.
3 citations
Proceedings of the National Academy of Sciences
Monoclonal and Polyclonal Antibodies Research
4.08
article

pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies

Benyu Wang, Kepeng Yan, James K. Fields, Pan Zheng, Haoyue Zhou, Michael J. Lenardo, Xuexiang Du, Lei Ye, Yang Liu, Peng Zhang, Yan Zhang, Dongyang Li, Jin Li, Mingyue Liu, Meiyu Zhang, Song Mei
article en
3 citations

Abstract

Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy.

Proceedings of the National Academy of SciencesVol. 122(8)
University of Maryland, Baltimore (US), Shandong University (CN), Shanghai Jiao Tong University (CN), Capital Medical University (CN), Sichuan University (CN), National Health and Family Planning Commission (CN), Ruijin Hospital (CN), Center for Children (US), Oncoceutics (United States) (US), Institute of Immunology (HR), National Institute of Allergy and Infectious Diseases (US), Beijing Children’s Hospital (CN)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Natural Science Foundation of China
Good health and well-being
Openalex Percentile: Top 8%
Monoclonal and Polyclonal Antibodies Research
4.08
DOIOpen Access PDFOpenAlex
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