Abstract 1817: WTX-613, (JZP898) a selectively activated IFNα INDUKINE™ molecule, reprograms the tumor microenvironment and generates robust anti-tumor immunity as a monotherapy and in combination with checkpoint inhibitors
Authors: Nirschl Christopher J. , Brodkin Heather R. , Domonkos Celesztina , Economides Kyriakos , Hicklin Daniel J. , Ismail Nesreen , Seidel-Dugan Cynthia , Steiner Philipp , Steuert Zoe , Winston William M. , Salmeron Andres 
Published: April 2023

Abstract
A member of the type-I IFN family, IFNα was also one of the first cytokines tested in the clinic as a therapy for cancer patients, leading to the approval of its use in chronic myelogenous leukemia, lymphoma, and malignant melanoma. Mechanistically, IFNα directly inhibits tumor cell proliferation and induces apoptosis, while simultaneously activating various innate and adaptive immune cell populations. Unfortunately, clinical use of IFNα has been hindered by the adverse events associated with its systemic administration, demonstrating the need for novel approaches to utilize this cytokine in the clinic. WTX-613 is a conditionally activated IFNα prodrug, or INDUKINE™ molecule, which has two identical half-life extension (HLE) domains tethered to IFNα2b via a proprietary tumor protease-sensitive linker. Following systemic administration, WTX-613 circulates as an inactive prodrug that is unable to bind to IFNα receptors in normal tissues due to the steric hinderance of the HLE domains complexed with albumin. However, when WTX-613 enters the tumor, proteases found in the tumor microenvironment (TME) cleave the protease-sensitive linkers, releasing fully active IFNα2b selectively in the tumor. Since human IFNα is not active in mice, a surrogate INDUKINE™ molecule containing mouse IFNα1 (mWTX-613/WW0610) was created. mWTX-613 treatment generated robust anti-tumor immunity in several murine syngeneic tumor models. In the MC38 model, mWTX-613 treatment was more efficacious than equimolar amounts of the recombinant cytokine (mIFNα1) and was accompanied by an increase in the therapeutic window. Mechanistically, systemic treatment with mWTX-613 resulted in prolonged peripheral exposure extending over a week beyond the time of the final dose. mWTX-613 treatment also resulted in a significant increase in the CD8/Treg ratio, and a robust increase in MHC I and MHC II expression by various professional antigen presenting cell populations. In addition, mWTX-613 treatment resulted in a clear and prolonged activation of both tumor infiltrating CD8+ T cells and NK cells. Transcriptionally, systemic treatment with mWTX-613 resulted in prolonged IFNα signaling within the TME, as demonstrated by significant enrichment in multiple Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with an anti-viral immune response. Finally, the combination of mWTX-613 treatment with various checkpoint inhibitor molecules resulted in improved anti-tumor efficacy in syngeneic models. Together, these data support the advancement of this innovative IFNα therapy into clinical testing.
Citation Format: Christopher J. Nirschl, Heather R. Brodkin, Celesztina Domonkos, Kyriakos Economides, Daniel J. Hicklin, Nesreen Ismail, Cynthia Seidel-Dugan, Philipp Steiner, Zoe Steuert, William M. Winston, Andres Salmeron. WTX-613, (JZP898) a selectively activated IFNα INDUKINE™ molecule, reprograms the tumor microenvironment and generates robust anti-tumor immunity as a monotherapy and in combination with checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1817.