(M0930-10-66) Masking Strategies for Immune Checkpoint Inhibitors to Decouple Adverse Events in Cancer Treatment

Purpose: The purpose of this study was to investigate whether masking checkpoint antibodies with tumor microenvironment (TME)-responsive polymer chains could mitigate immune-related adverse events (irAEs) and selectively target tumors while reducing systemic exposure for patients.

Methods: The masking strategy in this research involved functionalizing immune checkpoint-blocking antibodies with a mildly acidic pH-cleavable poly(ethylene glycol) (PEG) shell. This shell prevented inflammatory side effects in normal tissues by minimizing antibody-cell interactions and inhibiting their binding ability and functionality at physiological pH. The conjugation of pH-sensitive PEG to specific checkpoint antibodies (anti-CD47, anti-CTLA-4, and anti-PD-1) was performed, and the effects were evaluated in mouse models.

Results: The conjugation of pH-sensitive PEG to anti-CD47 antibodies successfully prevented αCD47-induced anemia in tumor-bearing mice. Furthermore, when anti-CTLA-4 and anti-PD-1 antibodies were conjugated with pH-sensitive PEG, colitis induced by double checkpoint blockade was ameliorated. Notably, the protective PEG shell could be removed in response to the acidic TME, which restored the checkpoint antibody activities. This restoration led to effective tumor regression and long-term survival in the mouse model.

Conclusion: The study demonstrated that masking checkpoint antibodies with TME-responsive polymer chains can mitigate immune-related adverse events and selectively target tumors while reducing systemic exposure for patients. The results support the feasibility of this approach in antibody-based therapies to uncouple toxicity from efficacy, highlighting its translational potential in cancer immunotherapy.

Acknowledgements: This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT). (No. RS-2023-00256265)

Schematic illustration of masked antibody with PEG–CDM. PEG–CDM–antibody remains masked against off-target binding until PEG is dissociated in an acidic TME.

Colitis scoring for inflammation, crypt damage, extent, and overall colitis from H&E-stained colonic tissue sections.

MC38 and B16F10 tumor growth after treatment.