Immunotherapy to deplete key Treg subsets in solid tumors

Abstract Solid tumors such as non-small cell lung cancer and melanoma afflict more than 250,000 Americans per year. While immunotherapies such as checkpoint inhibitors (CPIs) have improved cancer cure rates, they are only effective in 20-40% of patients; hence there is a significant unmet need to improve solid tumor treatment outcomes. Regulatory T (Treg) cells, classically defined as CD4+CD25+FoxP3+ T cells, are a key target for cancer immunotherapies since they inhibit anti-tumor T effector responses, promote tumor progression, and correlate with poor treatment outcomes. Reducing tumor-associated Tregs would enhance innate anti-tumor immune responses and would also be likely to improve the activity of CPI immunotherapies. Indeed, a Treg-depleting immunotherapy, Ontak® which targets the CD25 molecule (abundant on Tregs) was on the market from 1999- 2011, but critical drawbacks, including 25% rate of vascular leak syndrome (VLS) and significant manufacturing inconsistencies, led to its removal from the market. A “cleaner” version of Ontak with additional purification steps, Remitoro, was approved for human use in Japan in March 2021, but still shows high levels of VLS. The need for safe, effective anti-cancer agents targeting Treg cells remains. To address this need and advance the field of Treg-depleting immunotherapy, Sonoval is developing a second-generation version of Ontak, called SON-211. By modifying a key VLS-inducing domain of Ontak, Sonoval has virtually eliminated VLS in SON- 211, while full its cytotoxic potency against Tregs is retained. Sonoval also holds IP on a novel production method that solves prior manufacturing problems. In Phase I equivalent results, SON-211 demonstrated potent anti-tumor efficacy as a monotherapy, and showed significant anti-tumor synergy when used together with a CPI in murine models of solid tumors (melanoma, colon carcinoma, renal cell carcinoma). Recently, our team member, Dr. Drew Pardoll, showed that the most highly immunosuppressive Treg subset in human tumors (OX40hi GITRhi) strongly expresses CD25 (the direct target of SON-211 and Ontak), while another Tregs subset (Tbet IFNG) has paradoxical antitumor effects and very weakly expresses CD25. These data suggest that SON-211—by targeting CD25—may selectively eliminate the “bad” OX40hi GITRhi Treg subset and preserve the beneficial Tbet IFNG Treg subset. Building from this strong and highly encouraging preliminary data, Sonoval will leverage these key new findings to characterize the ability of SON-211 to selectively “re-balance” Treg subsets in tumors towards a potent inflammatory anti-tumor population. Specific Aims of this Direct to Phase II project are to: 1) Determine the effect of SON-211 monotherapy vs. no therapy on the balance of Treg subsets in the TME; 2) Compare the effect of dual therapy with SON-211 plus an Anti-PD1 CPI on the Treg subsets; 3) Optimize expression of SON-211 for production/purification.; 4) Demonstrate an ability to manufacture SON-211 at scale; and 5) Perform pre-IND, dose-finding and toxicology studies of SON-211 in Sprague Dawley rats.