Investigating anti-CTLA-4 Abs with pH-sensitive binding, Zhang, Li, and Yan et al. found that only some pH-sensitive ipilimumab variants enhanced the therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0, maintained colocalization with CTLA-4 at the late endosomes and lysosomes, resulting in lysosomal degradation of CTLA-4 and no advantage over Ipi. In contrast, Ipi25 dissociated from CTLA-4 at pH 6.0, the pH of the early endosome (EE), allowing for CTLA-4 recycling, and resulting in enhanced Treg depletion, increased tumor regression, longer survival, and less severe irAEs. Similar EE pH 6.0 dissociation was observed with Tremelimumab.
Contributed by Lauren Hitchings
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.
Author Info: (1) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (2) Department of Immunol
Author Info: (1) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (2) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (3) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (4) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (5) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (6) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (7) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (8) Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China. (9) Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. (10) Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing 100045, China. (11) Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205. (12) 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. 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. (13) Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. OncoC4, Inc., Rockville, MD 20854. (14) Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. OncoC4, Inc., Rockville, MD 20854. (15) 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. (16) Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
