IP Library Granted Patent US 12,297,277
Granted Patent B2
US 12,297,277 · App. 17/836,707 · Granted May 13, 2025

Anti-sortilin antibodies and methods of use thereof

Inventors: Tina Schwabe (San Francisco, CA); Michael Kurnellas (San Francisco, CA); Arnon Rosenthal (Woodside, CA); Robert Pejchal (Lebanon, NH); Anthony B. Cooper (White River Junction, VT)
Assignee: Alector LLC
C07K16/286C07K2317/31C07K2317/52C07K2317/76C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 12,297,277
App. No.
17/836,707
Granted
May 13, 2025
Kind
B2
Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, affinity-matured, humanized antibodies, antibody fragments, etc., that specifically bind a Sortilin protein, e.g., human Sortilin or mammalian Sortilin, and have improved and/or enhanced functional characteristics, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

Claims (94)

1. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds to a Sortilin protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein:

(a) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32);

(b) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRVS (SEQ ID NO: 30), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33);

(c) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32);

(d) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32);

(e) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32);

(f) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33);

(g) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO: 26), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33);

(h) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO: 27), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32);

(i) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSSGYNYLD (SEQ ID NO: 10), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); or

(j) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSIGYNYLD (SEQ ID NO: 21), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

2. A vector comprising the nucleic acid of claim 1 .

3. An isolated host cell comprising the vector of claim 2 .

4. A method of producing an antibody that binds to a Sortilin protein, comprising culturing the host cell of claim 3 so that the antibody is produced.

5. The method of claim 4 , further comprising recovering the antibody produced by the host cell.

6. The nucleic acid of claim 1 , wherein the antibody:

(a) decreases cell surface levels of Sortilin more than the level of decrease caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79;

(b) increases extracellular levels of Progranulin more than the level of increase caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79;

(c) inhibits the interaction between Sortilin expressed on a cell and Progranulin more than the level of inhibition caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79; or

(d) any combination of (a)-(c).

7. The nucleic acid of claim 1 , wherein the antibody:

(a) has a dissociation constant (K D ) for human Sortilin that is at least 1.1-fold lower than an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79, wherein the K D is determined by FACS; and/or

(b) has a dissociation constant (K D ) for human Sortilin that ranges from about 5.0E-10 M to about 1.0E-9 M wherein the K D is determined by FACS, or about 250-500 pM wherein the K D is determined by Bio-layer interferometry.

8. The nucleic acid of claim 1 , wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

9. A vector comprising the nucleic acid of claim 8 .

10. An isolated host cell comprising the vector of claim 9 .

11. A method of producing an antibody that binds to a Sortilin protein, comprising culturing the host cell of claim 10 so that the antibody is produced.

12. The method of claim 11 , further comprising recovering the antibody produced by the host cell.

13. The nucleic acid of claim 8 , wherein the antibody has an IgG1 isotype and comprises an Fc region comprising amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.

14. The nucleic acid of claim 1 , wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

15. The nucleic acid of claim 1 , wherein the antibody comprises:

(a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57;

(b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 58;

(c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59;

(d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57;

(e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 58;

(f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57;

(g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77;

(h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 78;

(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 79;

(j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80;

(k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60;

(l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 61; or

(m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 72.

16. The nucleic acid of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60.

17. The nucleic acid of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57.

18. The nucleic acid of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.

19. The nucleic acid of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.

20. The nucleic acid of claim 1 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.

21. The nucleic acid of claim 20 , wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

22. The nucleic acid of claim 21 , wherein:

(a) the antibody has an IgG1 or IgG2 isotype and comprises an Fc region comprising an amino acid substitution at position P331S, wherein the numbering of the residue position is according to EU numbering;

(b) the antibody has an IgG1 isotype and comprises an Fc region comprising amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering;

(c) the antibody has an IgG1, IgG2, or IgG4 isotype and comprises an Fc region comprising an amino acid substitution at position N297A, wherein the numbering of the residue position is according to EU numbering; or

(d) comprises an Fc region comprising an amino acid substitution at positions S267E and L328F, wherein the numbering of the residue position is according to EU numbering.

23. The nucleic acid of claim 21 , wherein the antibody has an IgG1 isotype and comprises an Fc region comprising amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.

24. The nucleic acid of claim 1 , wherein the Sortilin protein is a human Sortilin protein.

25. The nucleic acid of claim 24 , wherein the human Sortilin protein comprises the amino acid sequence of SEQ ID NO: 81.

26. The nucleic acid of claim 1 , wherein the Sortilin protein is a wild-type protein, a naturally occurring variant, or a disease variant.

27. The nucleic acid of claim 1 , wherein the antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, or a conjugated antibody.

28. The nucleic acid of claim 27 , wherein the antibody is a bispecific antibody recognizing a first antigen and a second antigen.

29. The nucleic acid of claim 28 , wherein the first antigen is the Sortilin protein and the second antigen is an antigen facilitating transport across the blood-brain-barrier.

30. The nucleic acid of claim 29 , wherein the second antigen is selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30 (A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopep peptide, basigin, Glut1, CD98hc, and ANG1005.

31. The nucleic acid of claim 1 , wherein the antibody is an antibody fragment that binds to a human Sortilin protein.

32. The nucleic acid of claim 31 , wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F (ab′) 2, Fv, or scFv fragment.

33. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds to a Sortilin protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 56 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 60.

34. The nucleic acid of claim 33 , wherein the antibody has an IgG1 isotype and comprises an Fc region comprising amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.

35. A vector comprising the nucleic acid of claim 33 .

36. An isolated host cell comprising the vector of claim 35 .

37. A method of producing an antibody that binds to a Sortilin protein, comprising culturing the host cell of claim 36 so that the antibody is produced.

38. The method of claim 37 , further comprising recovering the antibody produced by the host cell.

39. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds to a Sortilin protein, wherein the antibody comprises a light chain variable region comprising:

(a) an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); or

(b) the amino acid sequence of SEQ ID NO: 60.

40. A vector comprising the nucleic acid of claim 39 .

41. An isolated host cell comprising the vector of claim 40 .

42. A method of producing an antibody that binds to a Sortilin protein, comprising culturing the host cell of claim 41 so that the antibody is produced.

43. The method of claim 42 , further comprising recovering the antibody produced by the host cell.

44. An isolated host cell comprising nucleic acid encoding an antibody that binds to a Sortilin protein, wherein the host cell comprises:

(a) a first nucleic acid encoding a polypeptide comprising a heavy chain variable region, wherein the heavy chain variable region comprises:

i. an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); or

ii. the amino acid sequence of SEQ ID NO: 56; and

(b) a second nucleic acid encoding a polypeptide comprising a light chain variable region, wherein the light chain variable region comprises:

i. an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); or

ii. the amino acid sequence of SEQ ID NO: 60.

45. A method of producing an antibody that binds to a Sortilin protein, comprising culturing the host cell of claim 44 so that the antibody is produced.

46. The method of claim 45 , further comprising recovering the antibody produced by the host cell.

47. The isolated host cell of claim 44 , wherein the antibody has an IgG1 isotype and comprises an Fc region comprising amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.

48. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds to a Sortilin protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

49. The nucleic acid of claim 48 , wherein the antibody has an IgG1 isotype and comprises an Fc region comprising amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.

50. A vector comprising the nucleic acid of claim 49 .

51. An isolated host cell comprising the vector of claim 50 .

52. A method of producing an antibody that binds to a Sortilin protein, comprising culturing the host cell of claim 51 so that the antibody is produced.

53. The method of claim 52 , further comprising recovering the antibody produced by the host cell.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2022
From: SCHWABE, TINA; KURNELLAS, MICHAEL; ROSENTHAL, ARNON
To: ALECTOR LLC
Reel/Frame 060339/0142 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2022
From: PEJCHAL, ROBERT; COOPER, ANTHONY B.
To: ADIMAB LLC
Reel/Frame 060339/0149 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2022
From: ADIMAB LLC
To: ALECTOR LLC
Reel/Frame 060339/0152 →
Continuity (5)
Division 16510773 · Jul 12, 2019
Provisional Application 62868849 · Jun 28, 2019
Provisional Application 62860184 · Jun 11, 2019
Provisional Application 62698007 · Jul 13, 2018
Related Publication 20220348656A1 · Nov 3, 2022
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