Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 3, Pages 680-690Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-1631
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- Nektar Therapeutics
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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-killingCD8(+)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. (C) 2016 AACR.
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