JZP898，一种条件性激活的干扰素 α，在同基因小鼠模型中产生疗效并实现强劲的 TME 参与

Interferon alpha (IFNalpha) is a cytokine belonging to type I IFNs that exert pleiotropic effects on cell functions. IFNalpha induces antitumor activity and has been extensively applied in clinical oncology. However, use of IFNalpha has historically been restricted in clinical practice largely due to systemic toxicity and limited clinical activity compared to currently approved immunotherapies. JZP898, a conditionally activated IFNalpha, has the potential to minimize the toxicity associated with systemic IFNalpha therapy, preferentially releasing IFNalpha to tumors and thereby expanding its clinical utility in treating cancer. Cleavage of a proprietary linker by tumor associated proteases controls the release of active IFNalpha into the tumor microenvironment. Here we describe the preclinical tumor activity, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of JZP898 using a mouse specific analog of JZP898 (JZP898S). Targeted release of IFNalpha by JZP898S in syngeneic mouse tumor models increased tumor exposure relative to peripheral circulation, translating into greater achievable efficacy, both as a single agent and in combination with CPIs. JZP898S-induced antitumor activity correlated with immune cell activation in the TME and increased cytokine levels in the periphery; elevated peripheral cytokine levels correlated with increased JZP898S exposure. We observed increased number of activated cytotoxic T-cells and decreased number of regulatory cells within the TME. This effect on immune cells in the TME was extended a week beyond the last dose suggesting increased and sustained IFNalpha effects due to the conditional release of IFNalpha over time. Predictably, an IFNalpha gene expression profile was detected in treated tumors in a time and dose dependent manner and demonstrated a PK/PD relationship. From this data, we derived a JZP898-specific gene expression signature in tumors treated with JZP898S. These data support the utility and effectiveness of JZP898 as a novel mechanism to drive IFNalpha exposure in the TME and impact tumor growth while potentially attenuating IFNalpha associated tolerability and supports exploring the combinatorial effects with checkpoint inhibitors (CPIs).