A Biological Drug (PAS- YNS8) for Cancer Therapy (No. T4-1360)
Lead Researcher: Gideon Schreiber
The human type I interferons number 12 distinct non-allelic alpha proteins, one beta, and one omega, all sharing the same structure and binding the same two cell surface receptors, IFNAR1 and IFNAR2. Interferons promote a wide range of activities, including antiviral activity, inhibition of cell growth and proliferation, modulation of the immune system, promoting antigen presentation, inducing the production of another cytokine, and promoting T cell maturation and clonal propagation. Early on, interferons were recognized for their medical potential, and today they are in use to treat hepatitis C, multiple sclerosis, some sorts of cancer and autoimmune disorders. It was realized that the different type I IFN subtypes optimally promote different cellular activities. Particularly, IFNβ has a much higher antiproliferative activity then IFN α's. In a recent study, we have demonstrated that this increased activity is due to the tighter binding of IFN to the IFNAR1 receptor subunit and that this higher activity can be mimicked by engineering a tighter binding IFNAR1 variant of IFN α2.
The new invention is based on varying the binding affinity of alpha-interferons to either IFNAR1 or IFNAR2 by using protein engineering. The following IFNα2 variants were produced: YNS - binds IFNAR1 50-fold tighter compared to wt. As a result, its antiproliferative activity is 70-150 fold higher compared to IFNα2 and 3-5 fold higher compared to IFNβ. α8-tail - Is an IFNα2 variant that binds IFNAR2 20 fold tighter compared to the wild-type protein. As a result, it possesses a higher antiviral and antiproliferative activity compared to wt. NLYY - Is an IFNα2 variant that does not bind IFNAR1 at a detectable level but binds IFNAR2 similar to wt.
The extremely high antiproliferative activity of YNS was shown in a mice model to completely eradicate human breast cancer cell xenographs. We believe that the YNS interferon variant has the potential to be highly active against cancer, or another disease that is related to the increased antiproliferative activity, due to its extremely high antiproliferative activity in comparison with currently used IFNα2, or even IFNβ2. Moreover, the YNS variant is expected to have reduced side-effects due to the low dosage required and its relatively low antiviral potency (only 3 fold that of wt IFNα2). NLYY and α8-tail variants: Based on the increased level of IFN- α expression in patients with systemic lupus erythematosus (SLE), IFN-α has been implicated in the pathogenesis of SLE. The NLYY variant alone, or in combination with the α8-tail variant are potent antagonists to interferon function through their tight binding to the IFNAR2 receptor, and the lack of binding to the IFNAR1 receptor, making them biologically non-active. Treatment with these proteins should therefore be beneficial to SLE patients, as it will decrease significantly the ability for IFN to induced signaling