Targeting Tumor-Associated\nMacrophages with the Immune-Activating\nNanomedicine for Achieving Strong Antitumor Activity with Rapid Clearance\nfrom the Body

Toll-like receptors (TLRs) are a class of pattern recognition\nreceptors\n(PRRs) crucial for the detection of infections and activation of downstream\nsignaling pathways that lead to the production of pro-inflammatory\ncytokines and interferons. The TLR pathway is an attractive actively\nstudied target pathway. Because of their strong immunostimulatory\nactivity, TLRs are thought to be a “double-edged sword”\nfor systemic treatment, even in the cancer field. To solve this, we\nhave developed dextran-based TAM targeting activating conjugate (D-TAC)\ntechnology, which successfully uses tumor-associated macrophages (TAMs)\nto deliver the TLR7 agonist DSP-0509. We used low molecular weight\ndextran to target CD206 high M2-type macrophages, activate them, and\ninduce a change in phenotype to antitumor M1-type macrophages with\nrapid clearance from the body and astonishing antitumor activity.\nWe also demonstrated that the antitumor effect of our best drug candidate\n5DEX-0509R is dependent on the abundance of TAMs, which is consistent\nwith their mechanism of action. We believe that 5DEX-0509R generated\nby D-TAC technology can be a clinically applicable immunotherapy targeting\nthe TLR signaling pathway.