机构：[1]Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[2]Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201.[3]Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.[4]State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.四川大学华西医院[5]Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing 100045, China.首都医科大学附属北京儿童医院[6]Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205.[7]Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[8]Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People's Republic of China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[9]OncoC4, Inc., Rockville, MD 20854.[10]Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20814.[11]Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[12]Calico Life Sciences, Limited Liability Company, South San Francisco, CA 94080
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.
基金：
This work was supported
by the Research Funding from the National Natural Science Foundation of China
to Y.Z. (No. 82071866, No.82271762, and No. 82241227), Natural Science
Foundation of Shanghai (22ZR1454800), National key research and development
project of Ministry of Science and Technology (2023YFC2411403), Nanjing
AcroImmune BioTech. Co., Ltd. (2023310031000221), and by the Division of
Intramural Research of National Institute of Allergy and Infectious Diseases, NIH.
Additionally, we would like to express our gratitude to Dr. Lieping Chen from Yale
for his insightful comments, which have significantly enhanced our manuscript.
Research grant from OncoC4, Inc.
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外文
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第一作者：
第一作者机构：[1]Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[10]Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20814.[11]Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[12]Calico Life Sciences, Limited Liability Company, South San Francisco, CA 94080
推荐引用方式(GB/T 7714)：
Zhang Meiyu,Li Jinmei,Yan Kepeng,et al.pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies[J].Proceedings Of The National Academy Of Sciences Of The United States Of America.2025,122(8):e2422731122.doi:10.1073/pnas.2422731122.
APA：
Zhang Meiyu,Li Jinmei,Yan Kepeng,Zhou Haoyue,Mei Song...&Zhang Yan.(2025).pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies.Proceedings Of The National Academy Of Sciences Of The United States Of America,122,(8)
MLA：
Zhang Meiyu,et al."pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies".Proceedings Of The National Academy Of Sciences Of The United States Of America 122..8(2025):e2422731122
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