NK cells attacking a cancer cell

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

Ghasemi R, Lazear E, Arefanian R, Gelman AE, Kreisel D, Fremont DH, Krupnick AS
Nature Communications 7, Article number: 12878 (2016) doi:10.1038/ncomms12878

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.

Targeting of IL-2 to cytotoxic lymphocytes as an improved method of cytokine-driven immunotherapy

Lazear E, Ghasemi R, Hein SM, Westwick J, Watkins D, Fremont DH, Krupnick AS
OncoImmunology (2017) doi:10.1080/2162402X.2016.1265721

The use of high-dose interleukin-2 (IL-2) has fallen out of favor due to severe life-threatening side effects. We have recently described a unique way of directly targeting IL-2 to cytotoxic lymphocytes using a virally encoded immune evasion protein and an IL-2 mutant that avoids off-target side effects such as activation of regulatory T cells and vascular endothelium.