Immunomodulating Activities of the TLR7 Selective Agonist 851, a Novel Drug Candidate for Treatment of High-risk Human Papillomavirus Infection (B182)

Abstract

Abstract TLR agonists have been used in treating diseases including infections, cancer and as vaccine adjuvants. Aldara™ (imiquimod 5% cream) is the first TLR7 agonist approved in the US, and is indicated for the treatment of genital warts caused by human papillomavirus (HPV). Aldara was not well-tolerated when delivered vaginally; therefore a 2nd generation analog, 851, that retained the ability to stimulate cytokine production upon vaginal application was selected for development to treat high-risk cervical HPV infection. In human PBMC and purified plasmacytoid DC cultures, 851 stimulated a >10 fold increase in type I IFN, and indirectly activated human NK cells to express CD69 (8-fold) at concentrations of ≥10μM. In the rat, intravaginal application of 851 gel (0.01% and 0.1% w/v) led to local tissue production of TNF-α and MCP-1 without evidence of systemic cytokine induction. Increases in vaginal levels of TNF-α (9-fold) and MCP-1 (81-fold) were seen with the top strength of 851 tested (0.1%). Vaginal application of 851 results in the influx of NK cells, T cells and macrophages and an efflux of DC from the vaginal tissue. The ability of 851 to induce local cytokine production leading to influx and efflux of various immune cell populations could result in elimination of virally-infected cells from the cervix and vaginal tract including cells infected with high-risk HPV that are known to lead to cervical cancer.