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

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.

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

“…In line with the idea to optimize the "on target" aspect of checkpoint blockade, Zhang et al designed and modified the pH-sensitivity of an anti-CTLA-4 antibody. 258 Because of the acidic Fig. 4 Shared transcriptional signature of inflammatory Th1 and Th17 cells and exhausted T cells.…”

Degradation of CTLA-4 balances toxicity and efficacy

“…The notorious side effects of anti-CTLA-4 limit its use in the clinic, but what causes the severe side effects remains largely unclear. Zhang et al [1] elucidated antibody-induced CTLA-4 lysosomal degradation as a new mechanism accounting for the severe immunotherapy-related adverse effects and limited efficacy of anti-CTLA-4 therapy.…”

“…In a recent paper published in Cell Research, Zhang et al [1] demonstrate that antibody-induced CTLA-4 lysosomal degradation leads to irAEs and compromised efficacy. By comparing four different clones of anti-human CTLA-4 antibodies, the authors observed that irAE-prone Ipilimumab and TremeIgG1 down-regulated the CTLA-4 proteins but not for the non-irAE-prone antibodies (HL12 or HL32).…”

“…The mechanisms of how anti-CTLA-4 works in clinics are still under debate and most of the studies focused on how anti-CTLA-4 antibodies affected the function of effector and Tregs. Zhang et al [1] proved that clinically used anti-CTLA4 caused CTLA-4 degradation and irAE in human-CTLA-4 transgenic mice, but modulated pH-sensitive anti-CTLA4 antibodies reduced CTLA-4 degradation and relieved irAE. This result is consistent with previous studies showing CTLA-4-deficient mice developed severe autoimmune diseases.…”

“…Increasing the ADCC effect of anti-CTLA-4 will increase the efficacy of anti-CTLA-4 treatment [10]. Zhang et al [1] showed that increasing the recycling of CTLA-4 by pH-sensitive antibodies lead to more Treg-cell depletion and improved therapeutic effects. First, pH-sensitive antibodies increased the recycling of CTLA-4.…”