Treg-depleting immunotherapy

Abstract Sonoval is expanding its successful biologic drug platform technology to develop second generation versions of the cancer therapeutic Ontak, with the potential to advance the field of regulatory T cells (Tregs)-depleting immunotherapy through a mechanism previously unique to Ontak alone. Sonova;’s therapeutics will target Tregs for treatment of major solid tumors, which afflict rt50,000 Americans per year, by transiently and potently depleting these CD25+ cells while being non-toxic to other cell types. Tregs contribute to cancer progression by suppressing anti-tumor immune responses Thus far, one of the lead second generation candidates has demonstrated 3-5-fold anti-tumor effect as monotherapy compared to no treatment, and in novel application, enhances check-point inhibitor (CPI) activity by up to 5-fold in murine models of solid tumors. For over a decade, Ontak was approved for treatment of cutaneous T-cell lymphoma, making it the first antibody fusion protein of non-monoclonal origin approved for use by the FDA. Ontak was also found to be effective in the treatment of several solid tumors by transient Treg depletion in the tumor microenvironment. Despite its clinical success Ontak suffered from two critical drawbacks: a 25% rate of vascular leak syndrome (VLS), and significant manufacturing inconsistencies that included variable levels of protein aggregates (up to 40%) and detergent contamination. These issues led to the drug being taken off the market in 2011. Sonoval’s second generation versions of Ontak, SON-211 and SON-301, both show reduced VLS and are potential lead drugs for development. Further, Sonoval holds IP on a novel production method that solves prior manufacturing problems and enables product to be made with 0% aggregation and no detergent. In preliminary experiments, compared to Ontak, SON-211 shows an improved safety profile; a lower dose response; and equipotent anti-tumor efficacy in 3 murine tumor models (melanoma, colon carcinoma, renal cell cancer). in these same models, SON-211 monotherapy is significantly potentiated by the addition of CPI, paving the path to novel sequential combination treatment regimens. Further, SON-211 has been show to deplete CD39+ activated Treg in the tumor microenvironment by 72%, and to increase levels of effector T cells in tumors, while not depleting resting Tregs in spleen. The purpose of this Fast Track project is to finalize lead compound identification (Phase I), and to meet safety, efficacy and manufacturing milestones (Phase II) needed to progress to IND approval. Phase I’s single Aim will be to evaluate SON-211 and SON-301 based on their levels of superiority to Ontak in safety (VLS testing), anti-tumor efficacy with and without CPI, and production efficiency of fermentation, at 5-liter scale. Phase II Aims include: 1) Determine optimal dosing regimen as anti-cancer monotherapy and as dual sequential immunotherapy with CPI; 2) Optimize production/purification; 3) Conduct pre-IND, pharmacokinetics studies of lead drug in rats; 4) Tumor repetitive dosing studies to evaluate tumor eradication and/or time to relapse in Murine tumor models.