Functionally Masked Antibody to Uncouple Immune-Related Toxicities in Checkpoint Blockade Cancer Therapy

Of the existing immunotherapy drugs in oncology, monoclonalantibodiestargeting the immune checkpoint axis are preferred because of thedurable responses observed in selected patients. However, the associatedimmune-related adverse events (irAEs), causing uncommon fatal events,often require specialized management and medication discontinuation.The study aim was to investigate our hypothesis that masking checkpointantibodies with tumor microenvironment (TME)-responsive polymer chainscan mitigate irAEs and selectively target tumors by limiting systemicexposure to patients. We devised a broadly applicable strategy thatfunctionalizes immune checkpoint-blocking antibodies with a mildlyacidic pH-cleavable poly-(ethylene glycol) (PEG) shell to prevent inflammatoryside effects in normal tissues. Conjugation of pH-sensitive PEG toanti-CD47 antibodies (alpha CD47) minimized antibody-cellinteractions by inhibiting their binding ability and functionalityat physiological pH, leading to prevention of alpha CD47-inducedanemia in tumor-bearing mice. When conjugated to anti-CTLA-4 and anti-PD-1antibodies, double checkpoint blockade-induced colitis was also ameliorated.Notably, removal of the protective shell in response to an acidicTME restored the checkpoint antibody activities, accompanied by effectivetumor regression and long-term survival in the mouse model. Our resultssupport a feasible strategy for antibody-based therapies to uncoupletoxicity from efficacy and show the translational potential for cancerimmunotherapy.

Automated summary

This study investigates the use of tumor microenvironment-responsive polymer chains to mask immune checkpoint antibodies, which can mitigate immune-related adverse events (irAEs) and selectively target tumors. The results support a strategy to separate toxicity from efficacy in antibody-based therapies and demonstrate the translational potential for cancer immunotherapy.