Our drug discovery and development efforts have revolved around developing SNAs based on two classes of oligonucleotides: immunomodulatory (which includes immunostimulatory and immunoregulatory effects) and antisense molecules. Immunostimulatory oligonucleotides are short strings of nucleotides containing motifs that activate disease-fighting innate immune signaling networks, including pathways that: (1) initiate antigen presentation and co-stimulation, (2) activate innate immune cells such as NK cells, macrophages, and dendritic cells, and (3) induce the production of therapeutically relevant pro-inflammatory cytokines, through interactions with certain receptors within the cell. SNAs are attractive as novel therapeutics for cancer immunotherapy because they exhibit a suite of useful properties leading to profound, lengthened and multi-faceted disease-fighting innate immune responses, as shown in multiple preclinical animal models. Traditional immunostimulatory oligonucleotide-based approaches have failed to substantially provoke this kind of response in humans. We believe that this dramatically enhanced potency, particularly in human cells, will be therapeutically enabling for cancer immunotherapeutics.
The gene regulation approach called antisense represents the "third way" of pharmaceutical development - an alternative to small molecule and antibody based drugs. While the first two classes of molecules have been very successful at producing therapeutics, they are both limited by the types of targets they can address. For instance, small molecules often work by binding to a catalytically active site on a protein and inhibiting its function. Unfortunately, not all protein targets of therapeutic interest have these kinds of addressable sites. As for antibodies, they are usually limited to binding to extracellular and circulating proteins, which limits the number of targets they may address - it has been estimated that up to 80% of all encoded proteins are intracellular. In the antisense process, single-stranded DNA binds to messenger RNA (mRNA) and prevents its translation into protein by either inducing the destruction of the mRNA molecule or by preventing the binding of the cellular machinery needed to make the protein. Antisense represents a powerful approach for developing new and specific therapies for previously "undruggable" targets, i.e. those targets that are not addressable with small molecules or antibodies. SNA constructs maintain the advantages of antisense oligonucleotides while increasing their cellular uptake and stratum corneum penetration, allowing the SNA constructs to regulate gene expression in the skin. We believe that this is a greatly enabling development that leads to new therapeutic opportunities.
We believe that the SNA provides the following advantages for therapeutic development.
SNA constructs allow for more optimal timing and delivery of signals to innate immune cells, enabling more effective long-term adaptive immunity. In order for a class of immune cells, called antigen presenting cells, to drive optimal long term immunological memory, they need to be presented with an antigen and an immunostimulatory signal at the same time. SNA constructs can act as scaffolds that present both immunostimulatory oligonucleotides and antigens on their external surface, which we believe increases their efficacy when compared to systems that encapsulate or otherwise shield the immunological payload from the cellular receptors that initiate innate-to-adaptive immune responses.