NKTR-214: An immunotherapy with altered selectivity at the IL2 receptor; pharmacokinetics (PK) and pharmacodynamics (PD) in animal models.

Background: Aldesleukin (IL2) has been successfully used to treat cancer, with the potential for durable responses. However, its efficacy is limited by concomitant enhancement of immunosuppression. An immunostimulatory therapeutic approach that lacks certain immunosuppressive side effects can be achieved by targeting the appropriate subunits of the heterotrimeric interleukin 2 receptor, IL2R. NKTR-214 is a releasable multi-PEGylated conjugate of IL2. Upon in vivo administration, active forms of less conjugated-IL2 are released, which exhibit altered IL2R subunit selectivity. These forms favor proliferation of tumor-killing immune cells (CD8T) over immunosuppressive T cells (Treg) in the tumor (Charych, JCO 2013, 31:15, Suppl. 1). Here we show that polymer conjugation also prolongs exposure and activates known immune pharmacodynamic markers in mice, rats, and monkeys. These combined attributes improve efficacy and tolerability of NKTR-214 compared to the clinically approved cytokine aldesleukin. Methods: NKTR-214 PK and PD were assessed after single IV bolus doses in mice bearing B16F10 melanoma (2 mg/kg), rats (1 mg/kg), and monkeys (0.1 mg/kg). Aldesleukin was assessed in mice bearing B16F10 melanoma after 3 mg/kg IP qdx5. For assessment of PK, serial plasma samples were assayed for IL2 by ELISA. For NKTR-214, conjugated-IL2 was chemically released prior to ELISA. Immune system activation was monitored in plasma by sequential measurement of sCD25, C-reactive protein (CRP), lymphocyte counts, IFNγ, and TNFα. Results: The half-life of NKTR-214 was 20 hr in mice, which is considerably longer than the 5 hr half-life for aldesleukin, contributing to a 600-fold greater dose-normalized exposure. Consistent with the sustained exposure, altered receptor selectivity and favorable immune cell response, a single 2 mg/kg dose of NKTR-214 maintained greater suppression of tumor growth compared to daily 3 mg/kg doses of aldesleukin. NKTR-214 half-life was similar in rats and monkeys. In addition, NKTR-214 triggered a robust activation of known systemic immune system markers. For example, after a single efficacious dose of NKTR-214 in mice (2 mg/kg), sCD25 increased 25-fold compared to 5-fold for 5 daily doses of aldesleukin. In monkeys, an equally robust activation of sCD25 was observed at a single dose of 0.1 mg/kg (MTD) of NKTR-214. The kinetic profiles of CRP and lymphocyte counts following NKTR-214 were similar to that of sCD25 in monkeys, while the inflammatory cytokines IFNγ and TNFα remained undetectable. Conclusions: A single dose of NKTR-214 results in sustained exposure, robust immune system activation, and favorable immune cell changes in the tumor microenvironment. Based on NKTR-214 PK and PD in animals, infrequent dosing is feasible in humans, allowing convenient combination with other immunotherapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B296. Citation Format: Ute Hoch, Paul Sims, Murali Addepalli, Yuan Song, Chunmei Ji, Peter Kirk, Theresa Sweeney, Deborah Charych, Seema Kantak. NKTR-214: An immunotherapy with altered selectivity at the IL2 receptor; pharmacokinetics (PK) and pharmacodynamics (PD) in animal models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B296.