D5Pharma’s lead drug candidate is PEG-CCS13, a PEGylated single-stranded DNA aptamer that is a selective agonist for the inflammatory modulator, CD200R1, a glycoprotein receptor found on the surface of immune cells of myeloid lineage. CD200R1 acts as the receptor target for CD200-presenting cells during natural signalling processes that the body invokes to dampen the immune response. PEG-CCS13 is a synthetic agonist for this receptor, acting much like the natural CD200 ligand, and enabling immune reactions to be brought under control by a novel mechanism that is distinct from today's widely used anti-TNFα medicines.
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Aptamers that agonize CD200R1 dampen immune responses and thereby have the potential to suppress unwanted inflammation in conditions such as rheumatoid arthritis, Crohn's disease, psoriasis and other widespread indications. Read more about CD200 as an agonist here. Aptamers that antagonize CD200R1 unshackle immune cell regulation and have value in cancer immunotherapy.
The figure illustrates the immune modulating interaction between the Type 1 membrane glycoprotein, CD200, and its corresponding receptor, CD200R1. While CD200 is widely expressed on the surface of many cells (including immune cells), its cognate receptor, CD200R1, seems to be restricted to cells of the lymphoid and myeloid lineage. When the receptor is engaged with the ligand, it delivers immune inhibitory signals to modulate inflammatory responses by way of phosphorylation of proteins such as Dok2, which in turn recruits RasGAP (namely Ras GTPase activating protein). This latter protein converts the active GTP-bound family of proteins called Ras into their inactive GDP-bound state by stimulating Ras’ endogenous GTPase activity. While active, the Ras family of proteins serve to modulate a variety of functions, including upregulation of the immune response in inflammatory pathways through molecules such as cytokines.
CD200–CD200R1 signalling has been implicated in a number of immune related diseases such as allergic disorders, arthritis, infection, transplantation, and autoimmune disorders such as systemic lupus erythematosus and multiple sclerosis.
CD200R1 expressed on the surface of myeloid and lymphoid cells delivers immune inhibitory signals to dampen inflammatory responses when agonised by its natural ligand CD200. D5Pharma's small, synthetic PEGylated DNA aptamer, PEG-CCS13, can serve as a substitute agonist (see Appendix slide D) to stimulate this pathway and tune down the immune system in exactly the same manner as much larger, soluble protein analogues such as CD200Fc, the extracellular immunoglobulin-like domain of CD200. In a murine model of transplantation, bolus intravenous injection of this PEGylated aptamer enhanced survival of allogeneic skin grafts as effectively as a soluble CD200Fc.
Aptamers that recognize and bind the circulatory adipokine, TNFα, involved in the acute phase of systemic inflammation. Monoclonal antibody and protein fusion therapies such as infliximab and etanercept are widely used in the treatment of inflammatory diseases, but are currently only available at great expense to healthcare payors. D5Pharma's lead anti-TNFα therapy, PEG-VR11, is in the pre-clinical development phase. Read more here.
Aptamers that recognize and bind the tumour biomarker, carcinoembryonic antigen (CEA), found widely in cancers of the gastrointestinal tract. DNA aptamers N54 and N56 were shown to reduce tumour implantation in mice. Read more here.