TY - JOUR
T1 - Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy
AU - Ghasemi, Reza
AU - Lazear, Eric
AU - Wang, Xiaoli
AU - Arefanian, Saeed
AU - Zheleznyak, Alexander
AU - Carreno, Beatriz M.
AU - Higashikubo, Ryuji
AU - Gelman, Andrew E.
AU - Kreisel, Daniel
AU - Fremont, Daved H.
AU - Krupnick, Alexander Sasha
N1 - Publisher Copyright:
© The Author(s) 2016.
PY - 2016/9/21
Y1 - 2016/9/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84988892445&partnerID=8YFLogxK
U2 - 10.1038/ncomms12878
DO - 10.1038/ncomms12878
M3 - Article
C2 - 27650575
AN - SCOPUS:84988892445
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 12878
ER -