Compositions and methods of use for alpha-1 antitrypsin having no significant serine protease inhibitor activity
View Patent ↗Embodiments herein illustrate methods and compositions for treating medical disorders. In certain embodiments, compositions and methods relate to reducing, inhibiting or treating graft rejection, transplant rejection or diabetes in a subject. Other embodiments herein relate to compounds including naturally occurring and synthetic mutant compositions of alpha-1 antitrypsin, wherein the alpha-1 antitrypsin has no significant serine protease inhibitor activity.
1. A pharmaceutical composition comprising:
mutated human alpha-1 antitrypsin (AAT) wherein the mutated AAT comprises AAT with one or more mutations at one or more of residues 356-361 of SEQ ID NO: 61 wherein the mutations comprise a proline to cysteine substitution at position 357 or an alanine, glycine, arginine, leucine and asparagine substitution at corresponding positions 356-358, 360 and 361 respectively of SEQ ID NO: 61; and the one or more mutations significantly reduces or eliminates serine protease inhibition activity of the mutated AAT compared to a control human AAT; and a pharmaceutically acceptable excipient.
2. The pharmaceutical composition of claim 1 , wherein the one or more mutations are introduced by site-directed mutagenesis.
3. The pharmaceutical composition of claim 1 , further comprising an agent selected from the group consisting of an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, an anti-microbial agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, an anti-parasitic agent or any combination thereof.
4. The pharmaceutical composition of claim 1 , further comprising an immunosuppressive agent.
5. A kit comprising: a composition of claim 1 ; and at least one container.
6. The kit of claim 5 , further comprising an agent selected from the group consisting of an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, an anti-microbial agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, an anti-parasitic agent or any combination thereof.
7. The pharmaceutical composition of claim 1 , wherein a protease-binding site within the mutated AAT's reactive center loop (RCL) remains intact.
8. The pharmaceutical composition of claim 1 , wherein the mutated AAT is hAAT cys having a mutation at amino acid residue 357 of SEQ ID NO: 61 where proline is mutated to cysteine.
9. The pharmaceutical composition of claim 1 , wherein the mutated AAT is part of a fusion polypeptide and wherein the fusion polypeptide comprises mutated AAT fused to an immunoglobulin constant region.
10. The pharmaceutical composition of claim 9 , wherein the immunoglobulin constant region is a human IgG1 constant region.