Click-to-Release for Controlled Immune Cell Activation: Tumor-Targeted Unmasking of an IL12 Prodrug.

ABSTRACT: Objectives: Immunotherapy utilizing immune-stimulating cytokines such as IL12 holds great promise for the treatment of cancer. However, clinical use of IL12 is hampered due to severe toxicity following systemic administration. We here present a novel treatment strategy in which IL12 is chemically silenced by conjugation to PEG masks that sterically hinder the receptor binding. Subsequently, the masks can be released on demand using a bioorthogonal click reaction, cleaving the linker connecting the masks, thereby restoring the native cytokine. This "click-to-release" approach is based on the highly selective Inverse electron-demand Diels-Alder (IEDDA) pyridazine elimination reaction between a tetrazine (Tz) and a trans-cyclooctene (TCO), optimized for fast reaction kinetics an

SUBMITTER: den Brok MH 

PROVIDER: S-EPMC12472795 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature