In vivo efficacy, safety and PK/PD analysis of SYN101, a first in class, immune cell targeted TGFb therapy for cancer patients

NCI SBIR Phase II Summary The immune checkpoint inhibitors (ICI) block a single immuno-suppressive pathway in cancer patients. However, across all cancers, less than 30% of patients respond to ICI therapies, due to additional brakes on the immune system, which limit efficacy. The immuno-suppressive cytokine, TGF− is one of those “brakes” that drives checkpoint resistance in multiple solid tumors such as colorectal, bladder, prostate, head and neck cancers and melanoma. Levels of TGF− increase as the cancer becomes more aggressive, driving a worse patient prognosis. In addition to maintaining tissue health and homeostasis, TGF− is a validated tumor promoting cytokine with has multiple roles in cancer development, including immune suppression, increasing angiogenesis and driving metastasis. Despite long standing interest in TGF− blockade as a cancer therapy, clinical development has been hampered for two main reasons: 1) significant host (i.e., cardiac) toxicity and 2) the potential to convert indolent early stage tumors into more aggressive ones. However, in preclinical studies, blockade of the TGF− pathway only in T cells is sufficient for tumor clearance in vivo. Thus, a therapy that eliminates TGF− signaling solely in immune cells would drive tumor clearance, while avoiding the adverse events demonstrated by systemic TGF− therapies. With both a Phase I SBIR grant and venture funding, we have generated SYN101, a proprietary immune cell targeted TGF- therapeutic (SYN101) that selectively reverses TGF- mediated immune suppression, while sparing host tissue toxicity. We have demonstrated that monotherapy SYN101 drives tumor clearance and survival in syngeneic mouse tumor models, with corresponding immune cell activation markers in the blood and tumor microenvironment. Moreover, SYN101 does not cause cardiac toxicity at efficacious doses in vivo. In this Phase II SBIR application, we will perform additional in vivo efficacy, safety and PK studies with our SYN101 development candidate, which will lead to IND enabling studies. In Aim 1, we will test efficacy of human SYN101 in humanized mouse tumor models, along with corresponding lymphocyte PD markers in the blood and tumor microenvironment. Using CyTOF analysis, we will define the comprehensive immune response driven by SN101 in vivo, as a step towards identifying biomarkers of TGF- target engagement in clinical trials. In Aim 2, we will test the safety and toxicity of SYN101 in Sprague Dawley rats, the industry standard for systemic TGF- inhibitor toxicity. In addition, we will perform PK studies, to round out the full preclinical data package. While we do not anticipate significant toxicity from SYN101, these studies will derisk the platform, establish efficacy and safety, and support entry into IND enabling. Virtually every advanced tumor has elevated TGF− levels, such that a safer, more efficacious targeted TGF- therapy would be beneficial for a significant portion of cancer patients. SYN101 will provide new therapeutic options for refractory cancer patients and will safely reverse immune suppression to improve patient response rates.