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

Area of Science:

• Oncology
• Immunotherapy
• Biotechnology

Background:

• Monoclonal antibodies targeting immune checkpoints offer durable responses in cancer immunotherapy.
• Immune-related adverse events (irAEs) are a significant challenge, often requiring treatment discontinuation.
• Developing strategies to mitigate irAEs while maintaining therapeutic efficacy is crucial.

Purpose of the Study:

• To investigate a method for masking immune checkpoint antibodies with tumor microenvironment (TME)-responsive polymer chains.
• To mitigate irAEs and selectively target tumors by limiting systemic antibody exposure.
• To uncouple toxicity from efficacy in antibody-based cancer therapies.

Main Methods:

• Functionalization of immune checkpoint-blocking antibodies with a pH-cleavable poly(ethylene glycol) (PEG) shell.
• Conjugation of pH-sensitive PEG to anti-CD47, anti-CTLA-4, and anti-PD-1 antibodies.
• Evaluation of antibody-cell interactions, irAEs (anemia, colitis), tumor regression, and survival in mouse models.

Main Results:

• The PEG shell prevented antibody-cell interactions and functionality at physiological pH, mitigating αCD47-induced anemia.
• Conjugation to anti-CTLA-4 and anti-PD-1 antibodies ameliorated TME-induced colitis.
• Acidic TME triggered shell removal, restoring antibody activity, leading to effective tumor regression and long-term survival.

Conclusions:

• A broadly applicable strategy was devised to mask checkpoint antibodies with TME-responsive polymer chains.
• This approach effectively mitigates irAEs by limiting systemic exposure and selectively targets tumors.
• The findings demonstrate translational potential for safer and more effective antibody-based cancer immunotherapies.