Immune potentiators represent a chemically diverse class of materials that can be used as direct immunotherapies or as adjuvants for vaccines. Synthetic small molecule Toll-like receptor agonists (TLRa) are some of the most promising immune potentiators for clinical application but are often limited by suboptimal pharmacokinetic characteristics. In this study, linear biocompatible polymers were used as chemically tunable scaffolds for controlling pharmacokinetics and modulating activity of TLRa. Combinatorial synthesis and <i>in vivo </i>structure-activity studies were used to evaluate how properties of Polymer-TLRa conjugates (Poly-TLRa) influence the magnitude and spatiotemporal characteristics of innate immune activation in mice. These studies identified that high densities of agonists attached to particle-forming polymers through hydrophilic linker groups are optimal for the capacity of Poly-TLRa to induce high magnitude and persistent innate immune activation in lymph nodes. Mechanistic studies using whole animal imaging and cellular level tracking identified that particle formation by Poly-TLRa strongly enhances the magnitude and duration (&gt;14 days) of innate immune activation in lymph nodes by restricting agonist distribution and promoting uptake by antigen presenting cells. Optimized particle-forming Poly-TLRa formulated with protein antigen were found to be effective for eliciting protective CD4 and CD8 T cell responses in two different infectious challenge models. In conclusion, polymer carriers of TLRa represent a versatile and effective platform for modulating both innate and adaptive immunity and warrant further investigation as direct immunotherapies and / or as a class of adjuvants for vaccines.

Programming immune responses with polymer carriers of Toll-like receptor (TLR) agonists

249th National Meeting (2015)

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