Abstract: This disclosure is directed to a fusion protein composition comprising an alpha-1-antitrypsin or ?1-antitrypsin (also known as A1AT, A1A, or AAT) polypeptide (AAT), a modified AAT (mAAT) or a functional variant thereof and a bioactive polypeptide. This disclosure is particularly directed to a pharmaceutical composition comprising the fusion protein for treating a disease, such as a cancer or an autoimmune disease. The bioactive polypeptide can be a peptide hormone, interferon, or cytokine, such as interleukin-2 (IL-2), a modified IL-2 (mIL-2), IL-15, G-CSF, GM-CSF, IFN-?2, IFN-?1, GLP-1, FGF21, sdAb, a fragment thereof, a modified polypeptide thereof, or a combination thereof. One advantage of the fusion protein is to enhance the activity, stability, bioavailability or a combination thereof, of the bioactive polypeptide.