Toll-like receptors (TLRs) are crucial for the detection of infections and activation of downstream signaling pathways that lead to the production of pro-inflammatory cytokines and interferons. Because of their strong immunostimulatory activity, TLRs are thought to be a "double-edged sword" for systemic treatment, even in the cancer field. To solve this, we have developed dextran-based TAM targeting activator conjugate (D-TAC) technology which successfully uses tumor-associated macrophages (TAMs) to deliver the TLR7 agonist DSP-0509. We have demonstrated that the anti-tumor effect of our best drug candidate 5DEX-0509R is dependent on the abundance of TAMs, which is consistent with their mechanism of action. In this study, we compared the anti-tumor effects of EIK1001 and 5DEX-0509R, and analyzed its unique immune reaction against tumors to evaluate whether 5DEX-0509R is suitable for further clinical study. 5DEX-0509R showed superior anti-tumor activity compared to EIK1001, an R848 sulfate currently in phase 2 trials, with comparable systemic cytokine profiles. 5DEX-0509R elicited unique CD4 T cell and B cell-dependent anti-tumor effects. We also found that 5DEX-0509R synergistically suppresses tumors with oxaliplatin by changing M2 macrophages that cause oxaliplatin to become resistant to antitumor M1 macrophages. In addition, 5DEX-0509R caused a rapid but not sustained cytokine elevation in both rats and dogs. We believe 5DEX-0509R is worth pursuing for clinical trials.
Keywords: B cells; Blood cytokines; Nanomedicine; TLR7 agonist; Tumor associated macrophages.
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