Journal Article
. 2019 Jul; 29(8):609-627.
doi: 10.1038/s41422-019-0184-1.

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

Yan Zhang 1 Xuexiang Du 2 Mingyue Liu 2 Fei Tang 2 Peng Zhang 2 Chunxia Ai 2 James K Fields 3 Eric J Sundberg 3 Olga S Latinovic 3 Martin Devenport 4 Pan Zheng 5 Yang Liu 6 
Affiliations
  • PMID: 31267017
  •     49 References
  •     30 citations

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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