A2M polypeptide compositions containing a non-natural bait region are disclosed. Methods of producing wild-type and variant A2M polypeptides and polynucleotides containing a non-natural bait region are also disclosed. The bait regions of the variant A2M polypeptides demonstrate enhanced
protease inhibitory characteristics compared to wild-type A2M. Variant A2M polypeptides that demonstrate longer half-lives upon administration to an
organism compared to wild-type A2M are disclosed. The A2M compositions are useful in treating a number of diseases and conditions including
inflammation, chronic wounds, and diseases with a
pathology associated with
proteases.