Poster Presentation Lorne Infection and Immunity 2013

An Engineered Type-I interferon variant with enhanced biological activities (#128)

Daniel Harari 1 , Renne Abramovich 1 , Nadine Kallweit 2 , Arne Skerra 2 , Alla Zozulya-Weidenfeller 3 , Paul Smith 3 , Sandrine Pouly 4 , Gideon Schreiber 1
  1. Weizmann Institute of Science, Rehovot, Israel
  2. Lehrstuhl für Biologische Chemie, Universitaet Muenchen, Freising-Weihenstephan, Germany
  3. MS Pharmacology & Early PK/PD, Merck Serono S.A., Geneva, Switzerland
  4. MS Platform – Research , Merck Serono S.A, Geneva, Switzerland

A Type-I Interferon (IFN-I) Long-Life Superagonist:  Our laboratory studies the relationship between structure, activities and function of Human IFNs, and we have applied this understanding to generate a potent IFN high affinity human superagonist with biological activities far superior to any known natural or engineered IFN-I counterpart.  The half-life of all IFN-Is are notoriously short.  To extend the half-life of our superagnonist, it was fused as a chimeric protein to an unstructured tail of 600 amino acids comprising  of Proline, Alanine and Serine residues (PAS). The PASylated superagonist retains full receptor-binding activity, but due to its PAS tail, has a 10-fold extended half-life.

A Transgenic Mouse responsive to Human IFN-I:  A species barrier prevents the study of human IFNs in non-primate models: Although rodents have their own IFN signaling system, interspecies sequence divergence of the IFN receptors render human IFNs inactive in mice. Thus, despite the uniqueness of our superagonist, its study in rodent models cannot take place. In order to overcome this problem, we have successfully created transgenic mice that are humanized for type I IFN signaling. This mouse harbors humanized IFN receptors (Hu-extracellular domain fused to mouse intracellular domain) rendering them fully responsive to Hu-IFNs.  Human IFN-I faithfully and sensitively induced STAT activation and induction of IFN-response genes using our transgenic model.  Pharmotokinetic  and pharmacodynamic studies of our HyBNAR mice demonstrate both much stronger and long-lasting signaling response achieved using our long-life IFN-superagonist.

Potential Multiple Sclerosis Drug:  Injection of our superagonist in a Multiple Sclerosis (EAE) model was then performed, providing the HyBNAR mice with strong protection from disease symptoms, and far outperforming disease suppression exerted by human IFN-Beta (Rebif; a Multiple Sclerosis drug commonly used today).  

Herein I will present an overview of our studies, including preliminary EAE immunophenotype analyses of the IFN-treated HyBNAR mice.

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  2. evin D, Harari D, Schreiber G. Stochastic receptor expression determines cell fate upon interferon treatment. Mol Cell Biol. 2011 Aug;31(16):3252-66
  3. Kalie E, Jaitin DA, Abramovich R, Schreiber G. An interferon alpha2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities. J Biol Chem. 2007 Apr 13;282:11602-11