Synthetic Cathepsin B Sensitive Adjuvant‐Peptide Conjugates to Target Intracellular Toll‐Like Receptors 7 and 8

Therapeutic cancer vaccines have emerged as a promising approach to raise an immune response against tumors. These vaccines work by stimulating dendritic cells to present tumor‐associated antigens, thereby activating T cells that target cancer cells. To enhance immune responses, adjuvants targeting pattern recognition receptors are often used. Toll‐like receptor 7 (TLR7) and TLR8 agonists, which play key roles in initiating T Helper 1 (Th1) immunity, are central to this process. After screening a set of structurally different small molecule TLR7/8 agonists, resiquimod (R848) and a diaminoquinazoline were selected for the conception of cleavable adjuvant‐antigen conjugates. To this end, the ovalbumin derived T cell epitope containing SIINFEKL was covalently linked to the ligand through a cathepsin B‐sensitive linker, enabling controlled release of the adjuvant upon cleavage by intracellular cathepsin B, allowing controlled dendritic cell maturation and enhanced T cell activation.