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Linker Length Matters,Fynomer-Fc Fusion with an Optimized Linker Displaying Picomolar IL-17A Inhibition Potency
Authors:Michela Silacci  Nadja Baenziger-Tobler  Wibke Lembke  Wenjuan Zha  Sarah Batey  Julian Bertschinger  Dragan Grabulovski
Institution:From Covagen AG, Wagistrasse 25, CH-8952 Schlieren, Switzerland
Abstract:Fynomers are small binding proteins derived from the human Fyn SH3 domain. Using phage display technology, Fynomers were generated inhibiting the activity of the proinflammatory cytokine interleukin-17A (IL-17A). One specific Fynomer called 2C1 inhibited human IL-17A in vitro with an IC50 value of 2.2 nm. Interestingly, when 2C1 was genetically fused to the Fc part of a human antibody via four different amino acid linkers to yield bivalent IL-17A binding proteins (each linker differed in length), the 2C1-Fc fusion protein with the longest linker displayed the most potent inhibitory activity. It blocked homodimeric IL-17A with an IC50 value of 21 pm, which corresponds to a hundredfold improved IC50 value as compared to the value obtained with monovalent Fynomer 2C1. In contrast, the 2C1-Fc fusion with the shortest linker showed only an ∼8-fold improved IC50 value of 260 pm. Furthermore, in a mouse model of acute inflammation, we have shown that the most potent 2C1-Fc fusion protein is able to efficiently inhibit IL-17A in vivo. With their suitable biophysical properties, Fynomer-Fc fusion proteins represent new drug candidates for the treatment of IL-17A mediated inflammatory conditions such as psoriasis, psoriatic arthritis, or rheumatoid arthritis.
Keywords:Drug Discovery  Inflammation  Interleukin  Protein Engineering  SH3 Domains  Fynomer
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