Composition and method for the diagnosis and treatment of iron-related disorders

• US 9,636,398 B2
• Filed: 12/13/2012
• Issued: 05/02/2017
• Est. Priority Date: 12/14/2011
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated), Abbvie Incorporated
• Inventors: Beligere, Gangamani S., Manoj, Shamila, Brate, Elaine M., Grenier, Frank C., Hawksworth, David J., Ziemann, Robert N., Birkenmeyer, Larry G., Mueller, Bernhard, Popp, Andreas, Brophy, Susan
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): Deberry, Regina M
• Application Number:
  US13/714,222
• Publication Number:
  US 20130330359A1
• Time in Patent Office: 1,601 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/26 Infectious diseases, e.g. generalised sepsis
• CPC Class Codes: G01N 2800/347 Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 33/564 for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

Provided herein are antibodies and methods of using the antibodies to treat, prevent, modulate, attenuate and diagnose iron-related disorders.

Claims

1. An isolated antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a domain or region selected from the group consisting of:

(a) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

43, (b) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

47, (c) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

51, (d) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

55, (e) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

59, (f) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

63, (g) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

67, (h) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

71, (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

75, (j) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

79;

(k) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

94;

(l) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

98;

(m) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

43 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

47, (n) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

51 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

55, (o) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

59 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

63, (p) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

67 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

71, (q) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

75 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

79, (r) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

94 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

98, (s) a variable heavy chain a comprising complementarity determining region (CDR)1comprising the amino acid sequence of SEQ ID NO;

44, a CDR2 comprising the amino acid sequence of SEQ ID NO;

45, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

46 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

48, a CDR2 comprising the amino acid sequence of SEQ ID NO;

49, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

50, (t) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

52, a CDR2 comprising the amino acid sequence of SEQ ID NO;

53, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

54 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

56, a CDR2 comprising the amino acid sequence of SEQ ID NO;

57, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

58, (u) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

60, a CDR2 comprising the amino acid sequence of SEQ ID NO;

61, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

62 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

64, a CDR2 comprising the amino acid sequence of SEQ ID NO;

65, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

66, (v) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

68, a CDR2 comprising the amino acid sequence of SEQ ID NO;

69, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

70 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

72, a CDR2 comprising the amino acid sequence of SEQ ID NO;

73, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

74, (w) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

76, a CDR2 comprising the amino acid sequence of SEQ ID NO;

77, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

78 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

80, a CDR2 comprising the amino acid sequence of SEQ ID NO;

81, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

82, and (x) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

95, a CDR2 comprising the amino acid sequence of SEQ ID NO;

96, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

97, and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

99, a CDR2 comprising the amino acid sequence of SEQ ID NO;

100, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

101, wherein the antibody or antigen-binding fragment thereof specifically binds to Repulsive Guidance Molecule c (“

RGMc”

).

2. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof is selected from the group consisting of an immunoglobulin molecule, a disulfide linked Fv, an affinity matured antibody, a scFv, a chimeric antibody, a single domain antibody, a CDR-grafted antibody, a diabody, a monoclonal antibody, a humanized antibody, a human antibody, a multispecific antibody, a Fab, a dual specific antibody, a DVD, a Fab'"'"', a bispecific antibody, a F(ab'"'"')₂, and a Fv.

3. The isolated antibody or antigen-binding fragment thereof of claim 2, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody, a humanized antibody or a human antibody.

4. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain immunoglobulin constant domain selected from the group consisting of a human IgM constant domain, a human IgG4 constant domain, a human IgG1 constant domain, a human IgE constant domain, a human IgG2 constant domain, a human IgG3 constant domain, and a human IgA constant domain.

5. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:

(1) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

43, a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

51, a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

59, a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

67, a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

75, or a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

94, or (2) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

47, a variable light domain region comprising the amino acid sequence of SEQ ID NO;

55, a variable light domain region comprising the amino acid sequence of SEQ ID NO;

63, a variable light domain region comprising the amino acid sequence of SEQ ID NO;

71, a variable light domain region comprising the amino acid sequence of SEQ ID NO;

79, or a variable light domain region comprising the amino acid sequence of SEQ ID NO;

98.

6. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:

a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

43 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

47;

a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

51 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

55;

a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

59 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

63;

a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

67 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

71;

a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

75 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

79;

or

a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

94 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

98.

7. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:

(1) a variable heavy chain comprising a complementarity determining region (CDR)1 comprising the amino acid sequence of SEQ ID NO;

44, a CDR2 comprising the amino acid sequence of SEQ ID NO;

45, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

46 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

48, a CDR2 comprising the amino acid sequence of SEQ ID NO;

49, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

50, (2) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

52, a CDR2 comprising the amino acid sequence of SEQ ID NO;

53, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

54 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

56, a CDR2 comprising the amino acid sequence of SEQ ID NO;

57, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

58, (3) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

60, a CDR2 comprising the amino acid sequence of SEQ ID NO;

61, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

62 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

64, a CDR2 comprising the amino acid sequence of SEQ ID NO;

65, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

66, (4) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

68, a CDR2 comprising the amino acid sequence of SEQ ID NO;

69, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

70 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

72, a CDR2 comprising the amino acid sequence of SEQ ID NO;

73, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

74, (5) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

76, a CDR2 comprising the amino acid sequence of SEQ ID NO;

77, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

78 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

80, a CDR2 comprising the amino acid sequence of SEQ ID NO;

81, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

82, or (6) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

95, a CDR2 comprising the amino acid sequence of SEQ ID NO;

96, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

97 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

99, a CDR2 comprising the amino acid sequence of SEQ ID NO;

100, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

101.

8. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof further comprises an agent selected from the group consisting of:

an immunoadhesion molecule, an imaging agent, and a therapeutic agent.

9. The isolated antibody or antigen-binding fragment thereof of claim 8, wherein the imaging agent is selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin.

10. A pharmaceutical composition comprising the antibody, antigen-binding fragment thereof or mixture thereof of claim 1.

11. A method of treating a disease of iron metabolism, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 1, wherein the disease of iron metabolism is selected from the group consisting of anemia, anemia of chronic disease (ACD), iron-refractory iron-deficiency anemia and anemia of chronic kidney disease.

12. A kit for assaying a test sample for RGMc (or a fragment thereof), which kit comprises at least one component for assaying the test sample for RGMc (or a fragment thereof) and instructions for assaying the test sample for RGMc (or a fragment thereof), wherein the at least one component includes at least one composition comprising an isolated antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a domain or region selected from the group consisting of:

(a) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

43, (b)) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

47, (c) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

51, (d) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

55, (e) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

59, (f) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

63, (g) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

67, (h) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

71, (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

75, (j) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

79;

(k) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

94;

(l) a variable light domain region comprising the amino acid sequence of SEQ ID NO;

98;

(m) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

43 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

47, (n) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

51 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

55, (o) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

59 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

63, (p) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

67 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

71, (q) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

75 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

79, (r) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO;

94 and a variable light domain region comprising the amino acid sequence of SEQ ID NO;

98, (s) a variable heavy chain comprising a complementarily determining region (CDR)1 comprising the amino acid sequence of SEQ ID NO;

44, a CDR2 comprising the amino acid sequence of SEQ ID NO;

45, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

46 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

48, a CDR2 comprising the amino acid sequence of SEQ ID NO;

49, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

50, (t) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

52, a CDR2 comprising the amino acid sequence of SEQ ID NO;

53, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

54 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

56, a CDR2 comprising the amino acid sequence of SEQ ID NO;

57, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

58, (u) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

60, a CDR2 comprising the amino acid sequence of SEQ ID NO;

61, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

62 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

64, a CDR2 comprising the amino acid sequence of SEQ ID NO;

65, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

66, (v) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

68, a CDR2 comprising the amino acid sequence of SEQ ID NO;

69, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

70 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

72, a CDR2 comprising the amino acid sequence of SEQ ID NO;

73, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

74, (w) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

76, a CDR2 comprising the amino acid sequence of SEQ ID NO;

77, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

78 and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

80, a CDR2 comprising the amino acid sequence of SEQ ID NO;

81, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

82, and (x) a variable heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

95, a CDR2 comprising the amino acid sequence of SEQ ID NO;

96, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

97, and a variable light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO;

99, a CDR2 comprising the amino acid sequence of SEQ ID NO;

100, and a CDR3 comprising the amino acid sequence of SEQ ID NO;

101, Wherein the isolated antibody or antigen-binding fragment thereof is optionally detectably labeled, and wherein the isolated antibody or antigen-binding fragment thereof specifically binds to RGMc (or a fragment thereof).

13. The kit of claim 12, wherein the RGMc or a fragment thereof assayed in the test sample is used to determine or assess whether a subject has or is at risk of developing an iron-related disorder.

14. The kit of claim 13, wherein the RGMc is membrane-associated RGMc or soluble RGMc.

15. The kit of claim 12, wherein the kit further comprises at least one component for assaying a test sample for hepcidin and instructions for assaying the test sample for hepcidin.

16. The kit of claim 12, wherein the RGMc is a membrane-associated RGMc, a soluble RGMc, a fragment of a membrane-associated RGMc, a fragment of a soluble RGMc, a variant of a membrane-associated RGMc, a variant of a soluble RGMc, or a combination of any of the foregoing.