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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Feb 01 [Epub]
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
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