Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12878
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Funding
- Biostatistics Shared Resource and Siteman Flow Cytometry Core [P30 CA091842]
- Rheumatic Diseases Core Center [P30 AR48335]
- NIH [R01HL094601, PO1 AI116501]
- Barnes Jewish Hospital Research Foundation
- Doug and Ann Brown Foundation
- NIH/NIAID [R01 AI019687, U19 AI109948]
- NIAID [HHSN272200700058C, HHSN272201200026C]
- Jordan and Paula Bergstein
- Courier Therapeutics
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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-2R alpha 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-2R alpha. 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-2R alpha-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.
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