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

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Deborah H. Charych , Ute Hoch , John L. Langowski , Steve R. Lee , Murali K. Addepalli , Peter Kirk , Dawei Sheng , Xiaofeng Liu , Paul W. Sims , Laurie A. VanderVeen , Cherie F. Ali , Thomas K. H. Chang , Marina Konakova , Rhoneil L. Pena , Rupesh S. Kanhere , Yolanda Kirksey , Chunmei Ji , Yujun Wang , Jicai Huang , Theresa D. Sweeney , Seema Kantak , Stephen K. Doberstein ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/1078-0432.c.6524552

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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Aldesleukin Cytokine Interleukin 2 Prodrug Pharmacology Chemistry Cancer research Molecular biology Medicine Immunology Biology

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/1078-0432.c.6524552
OA Status: gold
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OpenAlex ID: https://openalex.org/W4361816726

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DOI: https://doi.org/10.1158/1078-0432.c.6524552

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Title: 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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Language: en

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Publication year: 2023

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Publication date: 2023-03-31

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Authors: Deborah H. Charych, Ute Hoch, John L. Langowski, Steve R. Lee, Murali K. Addepalli, Peter Kirk, Dawei Sheng, Xiaofeng Liu, Paul W. Sims, Laurie A. VanderVeen, Cherie F. Ali, Thomas K. H. Chang, Marina Konakova, Rhoneil L. Pena, Rupesh S. Kanhere, Yolanda Kirksey, Chunmei Ji, Yujun Wang, Jicai Huang, Theresa D. Sweeney, Seema Kantak, Stephen K. Doberstein

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Concepts: Aldesleukin, Cytokine, Interleukin 2, Prodrug, Pharmacology, Chemistry, Cancer research, Molecular biology, Medicine, Immunology, Biology

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abstract_inverted_index.antibody.	212
abstract_inverted_index.effective	7
abstract_inverted_index.evaluated	84, 124
abstract_inverted_index.non-human	126, 218
abstract_inverted_index.patients;	22
abstract_inverted_index.potential	41
abstract_inverted_index.resistant	204
abstract_inverted_index.responses	17
abstract_inverted_index.retaining	50
abstract_inverted_index.tolerated	216
abstract_inverted_index.treatment	39
abstract_inverted_index.activation	159
abstract_inverted_index.conjugated	48, 62, 186
abstract_inverted_index.conjugates	96
abstract_inverted_index.evaluation	224
abstract_inverted_index.metastatic	10
abstract_inverted_index.molecules.	175
abstract_inverted_index.regulatory	143
abstract_inverted_index.releasable	65
abstract_inverted_index.repertoire	238
abstract_inverted_index.supporting	157
abstract_inverted_index.<i>In	70
abstract_inverted_index.<i>in	97
abstract_inverted_index.bioactivity	86
abstract_inverted_index.combination	114, 209
abstract_inverted_index.immunology,	101
abstract_inverted_index.potentially	242
abstract_inverted_index.rechallenge	207
abstract_inverted_index.recombinant	2
abstract_inverted_index.Aldesleukin,	1
abstract_inverted_index.Tolerability	122
abstract_inverted_index.aldesleukin,	156
abstract_inverted_index.aldesleukin.	57, 190
abstract_inverted_index.polyethylene	66
abstract_inverted_index.preferential	158
abstract_inverted_index.<i>Clin	246
abstract_inverted_index.anti–CTLA-4	116, 211
abstract_inverted_index.approximately	19
abstract_inverted_index.immunotherapy	8
abstract_inverted_index.tumor-killing	137
abstract_inverted_index.vivo</i>,	71
abstract_inverted_index.immunotherapies.	245
abstract_inverted_index.vitro;</i>	98
abstract_inverted_index.Design:</b>	82
abstract_inverted_index.pharmacokinetics,	103
abstract_inverted_index.CD8<sup>+</sup>	138
abstract_inverted_index.Foxp3<sup>+</sup>	142
abstract_inverted_index.AACR</i>.</p></div>	252
abstract_inverted_index.conjugates.</p><p><b>Experimental	81
abstract_inverted_index.<div>Abstract<p><b>Purpose:</b>	0
abstract_inverted_index.primates.</p><p><b>Results:</b>	127
abstract_inverted_index.primates.</p><p><b>Conclusions:</b>	219
cited_by_percentile_year
countries_distinct_count	0
institutions_distinct_count	22
sustainable_development_goals[0].id	https://metadata.un.org/sdg/3
sustainable_development_goals[0].score	0.550000011920929
sustainable_development_goals[0].display_name	Good health and well-being
citation_normalized_percentile.value	0.05810937
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False