To achieve a robust and powerful response with immunotherapeutic agents, both an adjuvant, to activate the innate immune system, and an antigen, to direct the immune response, must be delivered. Currently, it is not clear if both components need to be delivered to the same cell, and if temporal control of the two signals is required for maximum activation. Since it is difficult to modulate spatiotemporal delivery with most delivery systems, these questions have not been thoroughly investigated. However, the spherical nucleic acid (SNA) platform, which consists of a dense shell of oligonucleotides conjugated to a nanoparticle core, is ideal for this task due to its extremely modular architecture and unique properties (e.g.,  rapid cellular uptake and increased resistance to nuclease degradation) compared to  linear nucleic acids. SNAs composed of immunomodulatory oligonucleotides and tumor-specific antigens induce the immune system to clear tumors, and are thus promising as cancer vaccines. Since the mechanism through which the antigen and adjuvant are assembled into the SNA is easily modified, this can be used to control when and where the adjuvant and the antigen signals are delivered. Here, we incorporate both the adjuvant and antigen on the SNA via different encapsulation and conjugation schemes to study the spatiotemporal control of the two signals and its effect on tumor clearance. Hybridizing a peptide-oligonucleotide conjugate to the oligonucleotide shell of the SNA increased the speed of peptide presentation compared to either encapsulating the antigen or conjugating it to the surface of the nanoparticle with a lipid anchor. We found that this change in kinetics resulted in increased activation of the T cells <i>in vivo</i>, which in turn caused increased tumor cell clearance. Furthermore, we generalized this approach for the attachment of any peptide antigen by using universal linkers that utilize to the N-terminus. Since small changes to the peptide structure cause dramatic changes in the antigenicity of the peptide, we reasoned that traceless and reversible linkers would increase T cell activation. Indeed, we found that antigen-specific T cell activation could be increased an order of magnitude when peptide linkers with readily reversible and traceless chemistries (i.e., disulfide bonds) as opposed irreversible chemistries (i.e., thiol-maleimide conjugation) were used.<br/>

Structure-function relationships in the development of immunotherapeutic agents

256th National Meeting (2018)

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