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

Clin Cancer Res. 2016 Feb 1;22(3):680-90. doi: 10.1158/1078-0432.CCR-15-1631.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Humans
  • Immunologic Memory
  • Interleukin-2 / analogs & derivatives*
  • Interleukin-2 / chemistry
  • Interleukin-2 / pharmacology
  • Lymphocytes, Tumor-Infiltrating
  • Male
  • Melanoma, Experimental
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacology*
  • Prodrugs*
  • Protein Binding
  • Receptors, Interleukin-2 / chemistry
  • Receptors, Interleukin-2 / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / pharmacology*
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Burden / drug effects


  • Antineoplastic Agents
  • CTLA-4 Antigen
  • Interleukin-2
  • Prodrugs
  • Receptors, Interleukin-2
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Polyethylene Glycols
  • bempegaldesleukin
  • aldesleukin