Treffer: In vitro and in vivo characterization of nanolipoproteins (NLPs) conjugated with innate immune agonists: implications for host-based therapeutics (53.12)

Modulation of the innate immune system has the potential to provide transient, non-specific protection from a variety of infectious organisms. Activation of innate immunity is rapid and short-lived, therefore methods aimed at enhancing and prolonging the response will increase the effectiveness of innate immune targeting as a therapeutic measure. In order to enhance the stimulatory properties of innate immune agonists, we have employed a nanolipoprotein (NLP) platform. NLPs are discoidal, nanometer-sized particles comprised of self-assembled phospholipid membranes and apolipoproteins, analogous to reconstituted HDLs. NLPs have been successfully used in numerous biotechnology applications, including drug delivery and diagnostic imaging. Here, we show that two synthetic TLR ligands: monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotides (CpG ODNs) can be readily incorporated into NLPs. In addition, the delivery of agonist-conjugated NLPs significantly enhances immunostimulatory effects relative to agonists alone, at low doses, both in vitro and in vivo. Our data demonstrate that conjugation to NLPs promotes agonist trafficking to secondary lymphoid organs, increases cytokine production, and induces upregulation of immunoregulatory genes in peripheral organs. These data suggest that treatment with NLP:agonist conjugates may provide transient protection against lethal pathogen challenge, and experiments to determine their effectiveness at countering infection are ongoing.