Abstract 1742: Activatable Fc-IL-15 and anti-PD1 -IL-15 fusion molecules with extended half-life
Authors: Yu chunxiao , Shanebeck Kurt , Zhang Shiwen , Ruiz Jeanine , Chuang Ray , Yuan Yuanxia , Wen Yong , Streamland Tobin , Li Lu , Li Ming , Cunanan Lynwel , Xu Mouzhong , Lee Hung-yen , Lu Jeff , Liu Liqin , Lu Yuefeng 
Published: July 2021

Abstract
Introduction: Cytokines are potent molecules, yet their broad application as therapeutics has been significantly hampered by several limitations. First, cytokines typically have very short half-lives in vivo due to “PK sink”, leading to limited exposure and poor efficacy yet dose-dependent systemic toxicities. Secondly, “homing” of cytokines to the disease sites is often challenging even when the cytokines were fused to disease specific targeting antibodies, because the cytokine molecules dominantly control the destinations of the fusion molecules. In addition, cytokines can activate counter-regulatory pathways thus impair their potential efficacy. To fully harness the therapeutic potentials of cytokine molecules, AskGene created a novel cytokine prodrug platform (Smartkine®), wherein cytokine molecules can avoid the “PK sink” at systemic level and be activated at a disease site. ASKG215β and ASKG215γ are the first two programs from the prodrug platform.
Methods: The in vitro activities of ASKG215β and ASKG215γ were evaluated in NK92 cell proliferation assay and primary T cell proliferation assay. The PK/PD properties and safety profiles of ASKG215β and ASKG215γ were assessed in non-human primates (NHPs) following three weekly IV injections at 1 mg/kg for ASKG215β and 2 mg/kg for ASKG215γ. The in vivo immune activities were evaluated in a GvHD model with human PBMC-engrafted NSG mice. The anti-tumor activities are currently being tested in human PBMC-engrafted tumor xenograft models.
Results: Both ASKG215β and ASKG215γ showed significantly enhanced activity in vitro after protease-dependent activation. In NHPs, ASKG215β and ASKG215γ demonstrated prolonged and antibody-like PK profiles, which were well maintained throughout the study. More importantly both molecules were well tolerated in cynomolgus monkeys with acceptable safety profiles, with no cytokine release syndrome (CRS) observed, and no immune reaction at injection sites reported. Some immune cell activation and expansion were detected in the circulation potentially due to low levels of non-specific activation in the circulation. At high dosages, both molecules showed immune-stimulating activities in the GvHD model, including Interferon γ release and proliferations of CD8+ T cells and NK cells, potentially due non-specific activation in mice serum. The anti-tumor efficacy of in human PBMC-engrafted tumor xenograft models are expected to be presented at the conference.
Conclusions: We established a novel cytokine prodrug platform. The early programs ASKG215β and ASKG215γ showed extended antibody-like PK in NHPs with acceptable safety profiles. To our knowledge this is the first report showing that IL-15 fusion molecules were able to avoid the “PK sink” usually associated IL-15 molecules. This would enable the targeted delivery of cytokine molecules to a disease site.
Citation Format: chunxiao Yu, Kurt Shanebeck, Shiwen Zhang, Jeanine Ruiz, Ray Chuang, Yuanxia Yuan, Yong Wen, Tobin Streamland, Lu Li, Ming Li, Lynwel Cunanan, Mouzhong Xu, Hung-yen Lee, Jeff Lu, Liqin Liu, Yuefeng Lu. Activatable Fc-IL-15 and anti-PD1 -IL-15 fusion molecules with extended half-life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1742.