APC Mutants with Reduced Bleeding Risk

The patent applies local quality by creating specific amino acid mutations at defined locations in the protein sequence (residues 191-193 and 229-230) to selectively alter anticoagulant activity while preserving anti-apoptotic activity. This localized modification allows different regions of the protein to have different functional properties.

The patent changes the amino acid sequence parameters at specific positions (Lys191-193 and Arg229-230) to modify the protein's biological activity. By altering these specific residues, the anticoagulant activity is reduced while maintaining cytoprotective functions, thereby changing the activity parameters to achieve desired therapeutic profile.

The patent extracts the harmful anticoagulant activity from the protein by introducing mutations that specifically reduce this function while leaving the cytoprotective activity intact. The mutations at residues 191-193 and 229-230 selectively impair anticoagulant function, effectively separating this harmful property from the beneficial cytoprotective properties.

The patent converts the potentially harmful high anticoagulant activity into a benefit by selectively reducing it through mutation, thereby creating a protein variant where the remaining activity is sufficient for thrombus inhibition but not excessive enough to cause harmful bleeding effects.

The patent maintains local quality by introducing mutations only at specific, well-defined locations (residues 191-193 and 229-230) that are known to be involved in anticoagulant activity, while leaving the rest of the protein structure intact and unchanged, thereby preserving overall structural stability.

The patent creates protein variants that copy the overall structure and cytoprotective function of wild-type activated protein C while introducing specific local differences (mutations) that reduce anticoagulant activity. The variants maintain the fundamental protein fold and functional domains while having modified regions.