Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy

Reza Ghasemi, Eric Lazear, Xiaoli Wang, Saeed Arefanian, Alexander Zheleznyak, Beatriz M. Carreno, Ryuji Higashikubo, Andrew E. Gelman, Daniel Kreisel, Daved H. Fremont () and Alexander Sasha Krupnick ()
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Reza Ghasemi: Washington University in St Louis
Eric Lazear: Washington University in St Louis
Xiaoli Wang: Washington University in St Louis
Saeed Arefanian: Washington University in St Louis
Alexander Zheleznyak: Washington University in St Louis
Beatriz M. Carreno: Washington University in St Louis
Ryuji Higashikubo: Washington University in St Louis
Andrew E. Gelman: Washington University in St Louis
Daniel Kreisel: Washington University in St Louis
Daved H. Fremont: Washington University in St Louis
Alexander Sasha Krupnick: Washington University in St Louis

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12878

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