Anti-tumor activity and safety of SYN429, a synthetic type I IFN.

Abstract

e14561 Background: Immune checkpoint inhibitors (ICIs) are effective for some types of cancer; however, a large population of patients fail to respond or develop resistance. Therefore, there remains an unmet need for patients that don’t respond to ICIs. Type I interferon (IFN) signaling is central to antitumor immunity through activation of antigen-presenting cells (APCs), promotion of T cell priming and effector function, and induction of PD-L1 that sensitizes tumors to anti–PD-1/PD-L1 therapy. Type I IFNs have demonstrated efficacy in the clinic and are approved in multiple cancers; however, the utility of type I IFNs is limited by toxicity. To address these limitations, we developed synthetic interferons (SYNs) designed to improve the anti-tumor properties of type I IFN while improving safety. SYN molecules are partial agonists composed of bispecific antibody domains that engage IFNAR1 and IFNAR2, enabling tunable activation of the IFN pathway with distinct biological outcomes. Methods: STAT phosphorylation in human peripheral blood mononuclear cells (PBMCs) was assessed by flow cytometry. Mixed lymphocyte reactions (MLR) were performed using primary monocyte-derived dendritic cells and T cells. Antitumor efficacy was evaluated using syngeneic mouse tumor models. Results: In preclinical studies, the SYN429 molecule activated the type I IFN pathway to mediate anti-tumor activity while showing reduced induction of CRS-associated inflammatory cytokines and reduced anti-proliferative activity compared to IFN-α in vitro. This is consistent with the profile of SYNs which show an improved safety profile compared to IFN-α in vitro and in vivo. The lead SYN429 molecule increased PD-L1 and HLA expression on tumor cells in a dose-dependent manner in vitro. SYN429 enhanced T cell activation in MLR assays with greater potency compared to IFN-α, and the observed SYN429-dependent T cell activation was further increased by combination with ICIs. In the MLR assays, SYN429 induced IFN-γ production without inducing cytokines associated with CRS, including IL-6 and TNF-α. In addition, SYN429 promoted activation of APCs, as indicated by upregulation of CD80 as well as other activation markers. In syngeneic mouse tumor models, SYN429 demonstrated anti-tumor activity as a monotherapy that was comparable to ICIs, while SYN429/ICI combinations profoundly enhanced tumor growth inhibition. Mice that achieved complete tumor regression rejected subsequent tumor re-challenge, indicating induction of durable, protective antitumor immunity. Conclusions: These findings demonstrate that SYN429 exhibits potent anti-tumor immunity as a monotherapy and shows potential synergy in combination with immune checkpoint blockade in preclinical models. SYN429 represents a promising therapeutic approach that harnesses the type I IFN pathway to drive new biology for improved efficacy and safety.