2. Academic Validation
  3. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy

Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy

  • Cell Res. 2019 Aug;29(8):609-627. doi: 10.1038/s41422-019-0184-1.
Yan Zhang # 1,  Xuexiang Du # 2,  Mingyue Liu # 2,  Fei Tang 2,  Peng Zhang 2,  Chunxia Ai 2,  James K Fields 3 4,  Eric J Sundberg 3 5,  Olga S Latinovic 3 5,  Martin Devenport 6,  Pan Zheng 7 8 9,  Yang Liu 10 11 12
Affiliations

Affiliations

  • 1 Divisions of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. yzhang@ihv.umaryland.edu.
  • 2 Divisions of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA.
  • 3 Divisions of Basic Science Division, Institute of Human Virology, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA.
  • 4 Graduate Program in Molecular Microbiology and Immunology, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA.
  • 5 Department of Microbiology and Immunology, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA.
  • 6 OncoImmune, Inc, Rockville, MD, 20850, USA.
  • 7 Divisions of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. pzheng@ihv.umaryland.edu.
  • 8 OncoImmune, Inc, Rockville, MD, 20850, USA. pzheng@ihv.umaryland.edu.
  • 9 Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. pzheng@ihv.umaryland.edu.
  • 10 Divisions of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. yaliu@ihv.umaryland.edu.
  • 11 OncoImmune, Inc, Rockville, MD, 20850, USA. yaliu@ihv.umaryland.edu.
  • 12 Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. yaliu@ihv.umaryland.edu.
  • # Contributed equally.
PMID: 31267017 DOI: 10.1038/s41422-019-0184-1
Abstract

It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal Cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for Cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.

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