Immune protection against most intracellular pathogens requires T cell stimulation by Major Histocompatibility Complex (MHC) class I molecules present on the surface of first antigen presenting cells and subsequently on the infected cells. However, because exogenous proteins do not ordinarily enter the cytosol and access the MHC class I processing pathway, protein based vaccines that induce class I restricted T cell responses have proven difficult to design. Thus, extended research has aimed at facilitating the intracellular delivery of exogenous proteins using protein transduction domains (PTDs), which allow transport bioactive molecules into cells. Synthetic polymers, inspired by PTDs, provide a well-controlled platform to vary molecular architecture for structure activity relationship studies. Here, we use ring-opening metathesis, a facile and efficient polymerization technique, through which we can vary structural parameters to optimize non-covalently encapsulated cargos such as proteins, peptides, and siRNA. In this study, we investigated the ability of these PTD mimics to deliver OVA257-264 into whole blood along with their efficacy to stimulate a directed immune response toward the peptide sequence OVA257-264. We have detected that over 90% of CD14+ monocytes in our sample take up the peptide in less than 15 minutes with nominal cytokine response and high cell viability. Further studies aim to investigate the co-delivery of agonists to promote a specific immune response against OVA257-264 in vitro, allowing us to confirm that APCs process and present OVA257-264 in association with MHC class I molecules and stimulate an antigen specific response. Understanding the efficacy of these PTD mimics provides an important foundation for future applications of PTD technology in the field of peptide-based vaccines towards intracellular pathogens and immunomodulation of cancer.

Delivering antigen to monocytes using protein transduction domain mimics

253rd National Meeting (2017)

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