title: Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy.
abstract: Despite over 20 years of clinical use, IL-2 has not fulfilled expectations as a safe and effective form of tumour immunotherapy. Expression of the high affinity IL-2Rα chain on regulatory T cells mitigates the anti-tumour immune response and its expression on vascular endothelium is responsible for life threatening complications such as diffuse capillary leak and pulmonary oedema. Here we describe the development of a recombinant fusion protein comprised of a cowpox virus encoded NKG2D binding protein (OMCP) and a mutated form of IL-2 with poor affinity for IL-2Rα. This fusion protein (OMCP-mutIL-2) potently and selectively activates IL-2 signalling only on NKG2D-bearing cells, such as natural killer (NK) cells, without broadly activating IL-2Rα-bearing cells. OMCP-mutIL-2 provides superior tumour control in several mouse models of malignancy and is not limited by mouse strain-specific variability of NK function. In addition, OMCP-mutIL-2 lacks the toxicity and vascular complications associated with parental wild-type IL-2.
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Ghasemi
authors.affiliation: Department of Pathology &Immunology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazear
authors.affiliation: Department of Pathology &Immunology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Saeed
authors.initials: S
authors.lastname: Arefanian
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zheleznyak
authors.affiliation: Department of Medicine, Washington University in St Louis, St Louis, Missouri 63110, USA.
authors.forename: Beatriz M
authors.initials: BM
authors.lastname: Carreno
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Higashikubo
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.|Department of Pathology &Immunology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.|Department of Pathology &Immunology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.affiliation: Department of Pathology &Immunology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.|Department of Molecular Microbiology, and Biochemistry &Molecular Biophysics, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.|The Alvin Siteman Cancer Center of Washington University School of Medicine, 4921 Parkview Place, St Louis, Missouri 63110, USA.
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.affiliation: Department of Surgery, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.|Department of Pathology &Immunology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.|The Alvin Siteman Cancer Center of Washington University School of Medicine, 4921 Parkview Place, St Louis, Missouri 63110, USA.
authors.forename: Alexander Sasha
authors.initials: AS
authors.lastname: Krupnick
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005805:Genes, MHC Class I; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D018155:Orthopoxvirus; D011485:Protein Binding; D011994:Recombinant Proteins
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins