Therapeutic variant alpha-2-macroglobulin compositions
AssigneeCytonics Corporation
InventorsLewis Hanna, John David Laughlin, Shawn Robert Browning
Life of this patent
Estimating the term…
Abstract
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.
Claims17
A pharmaceutical composition comprising:
- (a) a therapeutically effective amount of a recombinant alpha-2-macroglobulin (A2M) polypeptide comprising a non-natural bait region, wherein the non-natural bait region comprises a sequence comprising SEQ ID NO:
- 82:
- X1X2X3X4X5X6X7X8
- wherein:
- X1 is an amino acid selected from the group consisting of glycine (G), proline (P) and glutamic acid (E),
- X2 is any natural amino acid,
- X3 is any natural amino acid,
- X4 is glycine (G) or glutamic acid (E),
- X5 is an amino acid selected from the group consisting of glycine (G), valine (V), leucine (L), serine (S), alanine (A), phenylalanine (F) and threonine (T),
- X6 is any natural amino acid,
- X7 is any natural amino acid, and
- X8 is glycine (G);
- and
- (b) a pharmaceutically acceptable carrier, wherein the non-natural bait region further comprises a sequence comprising EXEΘ4XG (SEQ ID NO:
- 83), wherein each X is any natural amino acid and Θ4 is an amino acid selected from the group consisting of glycine (G), valine (V), glutamic acid (E), alanine (A), threonine (T), serine (S), glutamine (Q), proline (P), asparagine (N) and aspartic acid (D);
- wherein the non-natural bait region comprises a sequence with at least 70% sequence identity to SEQ ID NO:
- 20;
- and
- wherein the non-natural bait region does not comprise SEQ ID NO:
- 104, SEQ ID NO:
- 105, SEQ ID NO:
- 106, SEQ ID NO:
- 109, SEQ ID NO:
- 111, SEQ ID NO:
- 112, SEQ ID NO:
- 114, SEQ ID NO:
- 120, SEQ ID NO:
- 121, SEQ ID NO:
- 122 or SEQ ID NO:
- 123.
A method of formulating a pharmaceutical composition comprising:
- combining
- (a) a therapeutically effective amount of a recombinant alpha-2-macroglobulin (A2M) polypeptide comprising a non-natural bait region, wherein the non-natural bait region comprises a sequence comprising SEQ ID NO:
- 82:
- X1X2X3X4X5X6X7X8
- wherein:
- X1 is an amino acid selected from the group consisting of glycine (G), proline (P) and glutamic acid (E),
- X2 is any natural amino acid,
- X3 is any natural amino acid,
- X4 is glycine (G) or glutamic acid (E),
- X5 is an amino acid selected from the group consisting of glycine (G), valine (V), leucine (L), serine (S), alanine (A), phenylalanine (F) and threonine (T),
- X6 is any natural amino acid,
- X7 is any natural amino acid, and
- X8 is glycine (G);
- and
- (b) a pharmaceutically acceptable carrier,
- wherein the non-natural bait region further comprises a sequence comprising EXEΘ4XG (SEQ ID NO:
- 83), wherein each X is any natural amino acid and Θ4 is an amino acid selected from the group consisting of glycine (G), valine (V), glutamic acid (E), alanine (A), threonine (T), serine (S), glutamine (Q), proline (P), asparagine (N) and aspartic acid (D);
- wherein the non-natural bait region comprises a sequence with at least 70% sequence identity to SEQ ID NO:
- 20;
- and
- wherein the non-natural bait region does not comprise SEQ ID NO:
- 104, SEQ ID NO:
- 105, SEQ ID NO:
- 106, SEQ ID NO:
- 109, SEQ ID NO:
- 111, SEQ ID NO:
- 112, SEQ ID NO:
- 114, SEQ ID NO:
- 120, SEQ ID NO:
- 121, SEQ ID NO:
- 122 or SEQ ID NO:
- 123.
Dependencies are inferred from the claim text.