title: A low-toxicity IL-2-based immunocytokine retains antitumor activity despite its high degree of IL-2 receptor selectivity.
abstract: OBJECTIVE
  The goal of the study was to engineer a form of interleukin 2 (IL-2) that, when delivered as a tumor-specific antibody fusion protein, retains the ability to stimulate an antitumor immune response via interaction with the high-affinity IL-2 receptor but has lower toxicity because of the reduced activation of the intermediate-affinity IL-2 receptor.
  
  
  METHODS
  We investigated changes in the proposed toxin motif of IL-2 by introducing a D20T mutation that has little effect on the activity of free IL-2. We expressed this IL-2 variant as a fusion protein with an antibody (NHS76) that targets the necrotic core of tumors and characterized this molecule (NHS-IL2LT) in vitro and in vivo.
  
  
  RESULTS
  NHS-IL2LT was shown to have near normal biological activity in vitro by using T-cell lines expressing the high-affinity IL-2 receptor, but little or no activity by using cell lines expressing only the intermediate IL-2 receptor. Relative to the control antibody fusion protein containing wild-type IL-2, NHS-IL2LT retained antitumor activity against established neuroblastoma and non-small cell lung cancer metastases in syngeneic mouse tumor models but was much better tolerated in immune-competent mice and in cynomolgus monkeys.
  
  
  CONCLUSIONS
  The qualities of low toxicity and single-agent efficacy shown suggest that NHS-IL2LT is a good candidate for therapeutic approaches combining standard cytotoxic and immune therapies. In fact, this molecule (also known as Selectikine or EMD 521873) is currently in phase I clinical trial.
authors.affiliation: EMD Serono Research Institute, Middlesex, MA 01821-3936, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Yan
authors.initials: Y
authors.lastname: Lan
authors.forename: Thore
authors.initials: T
authors.lastname: Hettmann
authors.forename: Beatrice
authors.initials: B
authors.lastname: Brunkhorst
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Mueller
authors.forename: Kin-Ming
authors.initials: KM
authors.lastname: Lo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D007135:Immunoglobulin Variable Region / Q000378:metabolism; D007376:Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008252:Macaca fascicularis; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology; D009154:Mutation; D009447:Neuroblastoma / Q000276:immunology; D015202:Protein Engineering; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C578499:EMD 521873; D007135:Immunoglobulin Variable Region; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins