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Supplemental Data from NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

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posted on 2023-03-31, 19:05 authored by Deborah H. Charych, Ute Hoch, John L. Langowski, Steve R. Lee, Murali K. Addepalli, Peter B. Kirk, Dawei Sheng, Xiaofeng Liu, Paul W. Sims, Laurie A. VanderVeen, Cherie F. Ali, Thomas K. Chang, Marina Konakova, Rhoneil L. Pena, Rupesh S. Kanhere, Yolanda M. Kirksey, Chunmei Ji, Yujun Wang, Jicai Huang, Theresa D. Sweeney, Seema S. Kantak, Stephen K. Doberstein
<p>Supplemental Materials and Methods. ELISA study materials; NKTR-214 chemistry; Mapping of PEGylation sites; Identification of active released IL-2 conjugates; Binding affinity to IL-2 receptors; In vivo immune cell phenotyping, In vivo immune cell phenotyping; In vivo T cell antigen staining; In vivo depletion of immune cells; Hematology parameters for evaluation of immune markers in non-human primates. Supplemental Figure Legends S1-S4. Supplemental Tables S1 and S2. Table S1: Fold change of affinity to IL-2αβ and IL-2β for NKTR-214 and its released active IL-2 conjugates compared to aldesleukin; Table S2: Activation of Primary Cynomulgus Monkey and Human T Cells in Response to IL-2 and the Active Metabolite of NKTR-214</p>

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    DOI - Is supplement to NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

ARTICLE ABSTRACT

Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti–CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.Results: In a murine melanoma tumor model, the ratio of tumor-killing CD8+ T cells to Foxp3+ regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti–CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates.Conclusions: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies. Clin Cancer Res; 22(3); 680–90. ©2016 AACR.

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    ChemotherapyCombination chemotherapyImmunologyCytokinesImmunotherapyCellular immunotherapy

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