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
  • 1. Divisions of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. [email protected].
  • 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. [email protected].
  • 8. OncoImmune, Inc, Rockville, MD, 20850, USA. [email protected].
  • 9. Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. [email protected].
  • 10. Divisions of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. [email protected].
  • 11. OncoImmune, Inc, Rockville, MD, 20850, USA. [email protected].
  • 12. Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD, 21201, USA. [email protected].
  • # 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.

Products