Monoclonal antibodies against ANGPTL3

• US 8,742,075 B2
• Filed: 03/28/2011
• Issued: 06/03/2014
• Est. Priority Date: 12/08/2006
• Status: Active Grant

• Current Assignee: Lexicon Pharmaceuticals, Inc. (The Invus Group LLC)
• Original Assignee: Lexicon Pharmaceuticals, Inc. (The Invus Group LLC)
• Inventors: Lee, E-Chiang, Landes, Gregory, Hong, Seokjoo, Desai, Urvi, Powell, David, Feng, Xiao
• Primary Examiner(s): WEN, SHARON X
• Application Number:
  US13/073,617
• Publication Number:
  US 20110243948A1
• Time in Patent Office: 1,163 Days
• US Class Current: 530/388.24
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Monoclonal antibodies that specifically bind to ANGPTL3 are provided. Monoclonal antibodies that neutralize at least one activity of ANGPTL3 are provided. Methods of treating a disorder of lipid metabolism using neutralizing monoclonal antibodies are provided.

Claims

1. A monoclonal antibody that binds to angiopoietin-like protein 3 (ANGPTL3) and neutralizes at least one activity of ANGPTL3, wherein the antibody binds to a peptide consisting of the amino acid sequence of SEQ ID NO:

9 with at least 3-fold greater affinity than the antibody binds to a peptide consisting of the amino acid sequence of SEQ ID NO;

86, 87, or 88.

2. The antibody of claim 1, wherein the antibody decreases the level of at least one serum lipid in vivo.

3. The antibody of claim 2, wherein the at least one serum lipid is selected from serum triglycerides, total cholesterol, and free fatty acids.

4. The antibody of claim 3, wherein the antibody decreases the level of at least two serum lipids in vivo.

5. The antibody of claim 1, wherein the antibody binds to mouse ANGPTL3 and human ANGPTL3.

6. The antibody of claim 1, wherein the antibody is selected from a mouse monoclonal antibody, a humanized monoclonal antibody, and a human monoclonal antibody.

7. The antibody of claim 1, wherein the antibody is an antibody fragment.

8. The antibody of claim 7, wherein the antibody fragment is selected from a scFv, a Fab, a Fab′

, and a F(ab′

)₂.

9. The monoclonal antibody of claim 1, wherein the heavy chain comprises a CDR1 as set forth in SEQ ID NO:

35, a CDR2 as set forth in SEQ ID NO;

36, and a CDR3 as set forth in SEQ ID NO;

37; and

the light chain comprises a CDR1 as set forth in SEQ ID NO;

44, a CDR2 as set forth in SEQ ID NO;

45, and a CDR3 as set forth in SEQ ID NO;

46.

10. The monoclonal antibody of claim 1, wherein the heavy chain comprises a CDR1 as set forth in SEQ ID NO:

38, a CDR2 as set forth in SEQ ID NO;

39, and a CDR3 as set forth in SEQ ID NO;

40; and

the light chain comprises a CDR1 as set forth in SEQ ID NO;

47, a CDR2 as set forth in SEQ ID NO;

48, and a CDR3 as set forth in SEQ ID NO;

49.

11. The monoclonal antibody of claim 1, wherein the heavy chain comprises a CDR1 as set forth in SEQ ID NO:

41, a CDR2 as set forth in SEQ ID NO;

42, and a CDR3 as set forth in SEQ ID NO;

43; and

the light chain comprises a CDR1 as set forth in SEQ ID NO;

50, a CDR2 as set forth in SEQ ID NO;

51, and a CDR3 as set forth in SEQ ID NO;

52.

12. The monoclonal antibody of claim 1, wherein the heavy chain comprises a CDR1 as set forth in SEQ ID NO:

53, a CDR2 as set forth in SEQ ID NO;

54, and a CDR3 as set forth in SEQ ID NO;

55; and

the light chain comprises a CDR1 as set forth in SEQ ID NO;

56, a CDR2 as set forth in SEQ ID NO;

57, and a CDR3 as set forth in SEQ ID NO;

58.

13. The monoclonal antibody of claim 1, wherein the heavy chain comprises a CDR1 as set forth in SEQ ID NO:

71, a CDR2 as set forth in SEQ ID NO;

72, and a CDR3 as set forth in SEQ ID NO;

73; and

the light chain comprises a CDR1 as set forth in SEQ ID NO;

77, a CDR2 as set forth in SEQ ID NO;

78, and a CDR3 as set forth in SEQ ID NO;

79.

14. The monoclonal antibody of claim 1, wherein the heavy chain comprises a CDR1 as set forth in SEQ ID NO:

74, a CDR2 as set forth in SEQ ID NO;

75, and a CDR3 as set forth in SEQ ID NO;

76; and

the light chain comprises a CDR1 as set forth in SEQ ID NO;

80, a CDR2 as set forth in SEQ ID NO;

81, and a CDR3 as set forth in SEQ ID NO;

82.

15. A pharmaceutical composition comprising the antibody of claim 1.

16. A method of treating a disorder of lipid metabolism comprising administering to a patient an effective amount of the pharmaceutical composition of claim 15, wherein the disorder of lipid metabolism is selected from hypertriglyceridemia and hypercholesterolemia.

17. A method of decreasing the level of one or more serum lipids comprising administering to a patient an effective amount of the pharmaceutical composition of claim 15.