Abstract A95: NKTR-214, a novel CD122-biased immunostimulatory cytokine, does not cause hypotension in non-human primates despite greater cytokine exposure than achieved with high dose Interleukin-2 (HD-IL-2)
Authors: Ji Chunmei , Hoch Ute , Charych Deborah H. , Sweeney Theresa D. 
Published: May 2016

Abstract
Background: IL-2 was the first cancer immunotherapy approved, producing durable responses in ∼10% of patients treated for metastatic melanoma and renal cancer. However, IL-2 has poor pharmacokinetics, is both an activator and suppressor of the immune system, and is associated with severe cardiovascular side effects of hypotension and vascular leak syndrome, limiting widespread use. NKTR-214 is a novel immunotherapeutic consisting of IL-2 conjugated at a defined region within the protein to 4-6 polyethylene glycol (PEG) chains. Once administered, PEG chains slowly release to generate active IL-2 conjugates biased towards activation of CD122, the IL-2 receptor beta subunit (IL-2Rβ), highly expressed on memory effector CD8+ T cells (CD8T). In the tumor microenvironment, NKTR-214 preferentially expands CD8T over regulatory T cells (Treg), thus tipping the balance in favor of immune activation with a CD8T/Treg &gt;400. In syngeneic mouse tumor models, NKTR-214 demonstrated robust single agent efficacy, synergized with checkpoint inhibitor antibodies, and protected against tumor rechallenge. Here we describe the cardiovascular safety of NKTR-214 in monkeys.
Methods: Cardiovascular function was assessed in telemeterized male monkeys after single IV bolus injections of 0.01, 0.03, and 0.1 mg/kg using a Latin square design with a 14-day washout period between doses. Telemetry recordings were collected from three critical 24 hr time periods post-dose. Arterial blood pressure was collected continuously, averaged every 5 min, and reported every 0.25 hour. Inflammatory cytokines (TNFα and IFNγ), immune system activation markers (sCD25, lymphocytes), and IL-2 conjugate exposure were analyzed by ELISA in blood collected by venipuncture at multiple timepoints post dose.
Results: There were no ECG changes that were attributed to NKTR-214 treatment at doses up to 0.1 mg/kg/dose. sCD25 and total lymphocyte counts increased from baseline in a dose-responsive manner, producing a 24-fold and 4-fold increase in sCD25 and lymphocytes respectively at 0.1 mg/kg. Continuous monitoring of blood pressure for up to 104 hrs post-dose indicated the absence of hypotension at all dose levels. The inflammatory cytokines TNFα and IFNγ remained undetectable, suggesting no-associated cytokine release, despite the robust immune activation. Exposure to active IL-2 conjugate was high and sustained, exceeding that achieved with the HD-IL-2 regimen in patients.
Conclusion: The results support the safety and tolerability of NKTR-214 at doses expected to activate the immune system and support the development of this agent for patients with intractable cancers.
Citation Format: Chunmei Ji, Ute Hoch, Deborah H. Charych, Theresa D. Sweeney. NKTR-214, a novel CD122-biased immunostimulatory cytokine, does not cause hypotension in non-human primates despite greater cytokine exposure than achieved with high dose Interleukin-2 (HD-IL-2). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A95.