title: NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Nektar Therapeutics, San Francisco, California. dcharych@nektar.com.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Charych
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: John L
authors.initials: JL
authors.lastname: Langowski
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Lee
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Addepalli
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kirk
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Dawei
authors.initials: D
authors.lastname: Sheng
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sims
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: VanderVeen
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Cherie F
authors.initials: CF
authors.lastname: Ali
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Chang
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Marina
authors.initials: M
authors.lastname: Konakova
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Rhoneil L
authors.initials: RL
authors.lastname: Pena
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Rupesh S
authors.initials: RS
authors.lastname: Kanhere
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Yolanda M
authors.initials: YM
authors.lastname: Kirksey
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Ji
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Jicai
authors.initials: J
authors.lastname: Huang
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Theresa D
authors.initials: TD
authors.lastname: Sweeney
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Seema S
authors.initials: SS
authors.lastname: Kantak
authors.affiliation: Nektar Therapeutics, San Francisco, California.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Doberstein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D007376:Interleukin-2; D011355:Prodrugs; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C000611752:bempegaldesleukin; C082598:aldesleukin