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Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy
- Source :
- Nature Communications, Nature Communications, Vol 7, Iss 1, Pp 1-15 (2016)
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
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.<br />High-affinity IL-2Rα expressed by Tregs mitigates the potential of IL-2 use in cancer therapy. Here, the authors fuse IL-2 with an NKDG2 binding domain, and show that it induces IL-2 signalling selectively in NKG2D+ cells, delaying tumour growth in mice without the side effects of conventional IL-2 therapy.
- Subjects :
- Male
0301 basic medicine
Science
medicine.medical_treatment
Genes, MHC Class I
General Physics and Astronomy
Orthopoxvirus
CD8-Positive T-Lymphocytes
medicine.disease_cause
Article
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
Immune system
MHC class I
medicine
Animals
Humans
Mutation
Multidisciplinary
biology
Binding protein
Interleukin-2 Receptor alpha Subunit
Neoplasms, Experimental
General Chemistry
Immunotherapy
NKG2D
biology.organism_classification
Fusion protein
Recombinant Proteins
3. Good health
Killer Cells, Natural
030104 developmental biology
Gene Expression Regulation
NK Cell Lectin-Like Receptor Subfamily K
Immunology
biology.protein
Interleukin-2
Protein Binding
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....9c2f7d0cbbcdbc14dc509be8799ef20b