CreTAC-2

CreTAC-2 is a charge-reversal proteolysis-targeting chimera (CreTAC) designed for the tissue-specific degradation of the Stimulator of Interferon Genes (STING) protein. Developed by researchers at Zhejiang University, it is intended for the treatment of rheumatoid arthritis (RA). The drug utilizes a multilevel, pH-responsive polymer platform that remains electroneutral at physiological pH (7.4) to minimize systemic toxicity but undergoes charge inversion (protonation) in the acidic microenvironment of arthritic joints (pH 6.5). This mechanism facilitates a significant increase in tissue accumulation, pH-gated cellular internalization, and enhanced cytoplasmic affinity for STING. In preclinical models of collagen-induced arthritis, CreTAC-2 demonstrated the ability to suppress synovitis and bone erosion more effectively than methotrexate, without the associated hematological toxicity.