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Interferons (IFNs) are proteins which are naturally produced by the immune system and possess a wide range of immune properties including antiviral activity, promotion of antigen presentation as well as inhibition of cell growth and proliferation. Interferons are therefore used in the treatment of hepatitis C, multiple sclerosis, some types of cancer, and autoimmune disorders.
Human interferons are classified into three different groups according to the type of receptor to which they bind in order to signal. Type I IFNs (IFN-alpha, IFN-beta and IFN-omega) bind to a cell surface receptor complex known as the IFN-alpha receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. A research group, lead by Professor Gideon Schreiber from the Biological Chemistry Department of the Weizmann Institute of Science previously revealed that the different types of interferons’ activity originate from the different ways interferons bind to their receptor. The group also identified the precise amino acids (building blocks of proteins) and structural features that affect the binding.
All natural alpha-interferons bind the IFNAR1 receptor subunit with low affinity. The Weizmann Institute’s scientists have already shown that the increased antiproliferative activity of IFN-beta when compared with that of IFN-alpha is due to IFN-beta’s tighter binding to the IFNAR1 receptor subunit. In a recent study, they tried to mimic this increased binding affinity and antiproliferative potency by randomizing three positions (amino acids) on IFN-alpha2 previously shown to weaken binding to IFNAR1. This manipulation of the interferon-receptor bond by replacing amino acids in the interferon’s binding site has yielded several engineered interferon variants.
One of them, called YNS, binds IFNAR1 60-fold tighter than the natural IFN-alpha2, and 70-150 times higher antiproliferative potency in a laboratory dish. The high antiproliferative activity is related to an induction of apoptosis (programmed cell death). YNS’s potency in laboratory mice was determined by its twice weekly injection to mice carrying transplanted human breast cancer cells. After five weeks, the tumors were completely eradicated in mice treated with YNS, while most mice treated with natural IFN- alpha2 still showed visible tumors.
The researchers believe that the YNS interferon variant has the potential to be highly active against cancer and other diseases related to increased proliferative activity. Due to its high potency in comparison with currently used IFN-alpha2, or even IFN-beta2, low therapeutic dosages of YNS may be required. Moreover, the YNS variant antiviral potency is relatively low (3 fold higher than that of the natural IFN-alpha2) and it is therefore expected to have reduced side effects.
TFOT previously covered other research studies of natural immune system cells which have the ability to counteract cancer development. Not only have our innate immune system cells been shown to fight and resist cancerous cells, but these immune cells and a cancer-detecting protein expressed by them have also been identified in these studies. Another study has demonstrated for the first time the link between a natural factor called a TRAIL receptor, and tumor death-induction.
More information about the IFN-a2 manipulation can be found on Yeda’s webpage – the Weizmann Institute’s technology transfer arm that patented the YNS molecule.
