pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Meiyu Zhang
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
Jinmei Li
NHC Key Laboratory of Biotechnology for Microbial Drugs, State Key Laboratory of Bioactive Substance & Function of Natural Medicines, Institute of Medicinal Biotechnology
Kepeng Yan
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
Haoyue Zhou
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
Song Mei
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
Benyu Wang
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
Dongyang Li
Department of Materials Science and Engineering
Xuexiang Du
Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine
Mingyue Liu
Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine
Peng Zhang
James K. Fields
Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine
Lei Ye
Innovative Centre for Flexible Devices (iFLEX), Max Planck-NTU Joint Lab for Artificial Senses, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Republic of Singapore
Pan Zheng
Key Laboratory of Superlight Materials & Surface Technology of Ministry of Education, College of Material Sciences and Chemical Engineering, Harbin Engineering University, Harbin 150001, P. R. China
Yang Liu
Michael J. Lenardo
Yan Zhang