IP Library Granted Patent US 12,331,102
Granted Patent B2
US 12,331,102 · App. 15/909,314 · Granted Jun 17, 2025

APOA-1 fusion polypeptides and related compositions

Inventors: Martha S. Hayden-Ledbetter (Shoreline, WA); Jeffrey A. Ledbetter (Shoreline, WA)
Assignee: Theripion, Inc.
C07K14/775C12N9/18C12N9/22C12N15/62C12Y301/01002C12Y301/01047C12Y301/08001C07K2319/30C12Y301/27005
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Quick Facts
Patent No.
US 12,331,102
App. No.
15/909,314
Granted
Jun 17, 2025
Kind
B2
Abstract

Compositions and methods relating to ApoA-1 fusion polypeptides are disclosed. The fusion polypeptides include a first polypeptide segment corresponding to an ApoA-1 polypeptide or ApoA-1 mimetic, and may also include a dimerizing domain such as, e.g., an Fc region, which is typically linked carboxyl-terminal to the first polypeptide segment via a flexible linker. In some embodiments, the fusion polypeptide further includes a second polypeptide segment located carboxyl-terminal to the first polypeptide segment and which confers a second biological activity (e.g., an RNase, paraoxonase, platelet-activating factor acetylhydrolase, cholesterol ester transfer protein, lecithin-cholesterol acyltransferase, polypeptide that specifically binds to proprotein convertase subtilisin/kexin type 9, or polypeptide that specifically binds to amyloid beta). Also disclosed are dimeric proteins comprising first and second ApoA-1 fusion polypeptides as disclosed herein. The fusion polypeptides and dimeric proteins are useful in methods for therapy.

Claims (69)

1. A fusion polypeptide comprising, from an amino-terminal position to a carboxyl-terminal position, ApoA1-L1-D, wherein:

ApoA1 is a first polypeptide segment comprising the amino acid sequence shown in residues 19-267 or 25-267 of SEQ ID NO:2, wherein said first polypeptide segment has cholesterol efflux activity;

L1 is a first polypeptide linker consisting of 16 to 36 amino acid residues; and

D is an immunoglobulin Fc region,

wherein the fusion polypeptide has increased cholesterol efflux activity as compared to the ApoA1-L1-D fusion polypeptide in which L1 is a two amino acid linker or is absent, and

wherein the fusion polypeptide comprises the amino acid sequence shown in

(i) residues 19-525, 19-524, 25-525, or 25-524 of SEQ ID NO:2,

(ii) residues 19-525, 19-524, 25-525, or 25-524 of SEQ ID NO:13,

(iii) residues 19-515, 19-514, 25-515, or 25-514 of SEQ ID NO:22,

(iv) residues 19-520, 19-519, 25-520, or 25-519 of SEQ ID NO:26, or

(v) residues 19-535, 19-534, 25-535, or 25-534 of SEQ ID NO:24.

2. The fusion polypeptide of claim 1 , further comprising a second polypeptide segment located carboxyl-terminal to the immunoglobulin Fc region, wherein the second polypeptide segment is selected from the group consisting of an RNase and a paraoxonase,

wherein the fusion polypeptide comprises, from an amino-terminal position to a carboxyl-terminal position, ApoA1-L1-D-L2-P, wherein ApoA1, L1, and D are as defined in claim 1 , L2 is a second polypeptide linker, wherein L2 is optionally present, and P is the second polypeptide segment.

3. The fusion polypeptide of claim 2 , wherein the second polypeptide segment is the RNase.

4. The fusion polypeptide of claim 3 , wherein the RNase has at least 95% identity with amino acid residues 544-675 or 548-675 of SEQ ID NO:4.

5. The fusion polypeptide of claim 4 , wherein the RNase has the amino acid sequence shown in residues 544-675 or 548-675 of SEQ ID NO:4.

6. The fusion polypeptide of claim 3 , wherein the fusion polypeptide comprises the amino acid sequence shown in

(i) residues 19-675 or 25-675 of SEQ ID NO:4,

(ii) residues 19-675 or 25-675 of SEQ ID NO:14,

(iii) residues 19-671 or 25-671 of SEQ ID NO:58, or

(iv) residues 19-671 or 25-671 of SEQ ID NO:59.

7. The fusion polypeptide of claim 2 , wherein the second polypeptide segment is the paraoxonase.

8. The fusion polypeptide of claim 7 , wherein the paraoxonase has at least 95% identity with amino acid residues 16-355 of SEQ ID NO:12, amino acid residues 16-355 of SEQ ID NO:42, or amino acid residues 16-355 of SEQ ID NO:44.

9. The fusion polypeptide of claim 8 , wherein the paraoxonase has the amino acid sequence shown in residues 16-355 of SEQ ID NO:12, residues 16-355 of SEQ ID NO: 42, or residues 16-355 of SEQ ID NO:44.

10. The fusion polypeptide of claim 7 , wherein the fusion polypeptide comprises the amino acid sequence shown in

(i) residues 19-883 or 25-883 of SEQ ID NO:28,

(ii) residues 19-873 or 25-873 of SEQ ID NO:38,

(iii) residues 19-883 or 25-883 of SEQ ID NO:46, or

(iv) residues 19-883 or 25-883 of SEQ ID NO:48.

11. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 1 .

12. A composition comprising:

the dimeric protein of claim 11 ; and

a pharmaceutically acceptable carrier.

13. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 2 .

14. A composition comprising:

the dimeric protein of claim 13 ; and

a pharmaceutically acceptable carrier.

15. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 3 .

16. A composition comprising:

the dimeric protein of claim 15 ; and

a pharmaceutically acceptable carrier.

17. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 4 .

18. A composition comprising:

the dimeric protein of claim 17 ; and

a pharmaceutically acceptable carrier.

19. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 5 .

20. A composition comprising:

the dimeric protein of claim 19 ; and

a pharmaceutically acceptable carrier.

21. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 6 .

22. A composition comprising:

the dimeric protein of claim 21 ; and

a pharmaceutically acceptable carrier.

23. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 7 .

24. A composition comprising:

the dimeric protein of claim 23 ; and

a pharmaceutically acceptable carrier.

25. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 8 .

26. A composition comprising:

the dimeric protein of claim 25 ; and

a pharmaceutically acceptable carrier.

27. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 9 .

28. A composition comprising:

the dimeric protein of claim 27 ; and

a pharmaceutically acceptable carrier.

29. A dimeric protein comprising a first fusion polypeptide and a second fusion polypeptide, wherein each of said first and second fusion polypeptides is a fusion polypeptide as defined in claim 10 .

30. A composition comprising:

the dimeric protein of claim 29 ; and

a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 6, 2018
From: HAYDEN-LEDBETTER, MARTHA S.; LEDBETTER, JEFFREY A.; MONTES, VINCE
To: THERIPION, INC.
Reel/Frame 045998/0661 →
Continuity (3)
Continuation In Part PCTUS2016050405 · Sep 6, 2016
Provisional Application 62215256 · Sep 8, 2015
Related Publication 20180201664A1 · Jul 19, 2018
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