Optimization of a protein’s pharmaceutical properties is usually carried out by rational design and/or directed evolution. Here we test an alternative approach based on ancestral sequence reconstruction. Using available genomic sequence data on coagulation factor VIII and predictive models of molecular evolution, we engineer protein variants with improved activity, stability. biosynthesis potential, and reduced inhibition by clinical anti-drug antibodies. In principle, this approach can be applied to any protein drug based on a conserved gene sequence.
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