# US 10,118,958 B2 · Composition and method for the diagnosis and treatment of iron-related disorders

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- Number: US 10,118,958 B2
- Document ID: US10118958B2
- Status: Granted
- Kind: B2
- Application number: 13/714,238
- Filed: 2012-12-13
- Published: 2013-12-12
- Granted: 2018-11-06
- Earliest claimed: 2011-12-14
- Assignees: AbbVie Deutschland GmbH & Co. KG; AbbVie Inc.
- Applicants: AbbVie Deutschland GmbH & Co. KG; AbbVie Inc.
- Inventors: Bernhard Mueller; Andreas Popp; Jennifer M. Perez
- Web page: https://patentgrep.com/patent/US10118958B2

## CPC

- C07K 16/18: against material from animals or humans
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- 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}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Provided herein are methods of using the antibodies that bind to RGMc to treat and diagnose iron-related disorders.

## Claims

### Claim 1

An isolated anti-human Repulsive Guidance Molecule c (“RGMc”) antibody comprising (a) a variable heavy chain region comprising a complementarity determining region (CDR)1 comprising the amino acid sequence of SEQ ID NO:11, a CDR2 comprising the amino acid sequence of SEQ ID NO:12, and a CDR3 comprising the amino acid sequence of SEQ ID NO:13 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:14, a CDR2 comprising the amino acid sequence of SEQ ID NO:15, and a CDR3 comprising the amino acid sequence of SEQ ID NO:16, (b) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:17, a CDR2 comprising the amino acid sequence of SEQ ID NO:18, and a CDR3 comprising the amino acid sequence of SEQ ID NO:19 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:20, a CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a CDR3 comprising the amino acid sequence of SEQ ID NO:22, (c) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:23, a CDR2 comprising the amino acid sequence of SEQ ID NO:24, and a CDR3 comprising the amino acid sequence of SEQ ID NO:25 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:26, a CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a CDR3 comprising the amino acid sequence of SEQ ID NO:28, or (d) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:29, a CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a CDR3 comprising the amino acid sequence of SEQ ID NO:31 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:32, a CDR2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR3 comprising the amino acid sequence of SEQ ID NO:34.

### Claim 2 (depends on 1)

The isolated anti-human RGMc antibody of claim 1, wherein the anti-human RGMc antibody is selected from the group consisting of an affinity matured antibody, a monoclonal antibody, and a humanized antibody.

### Claim 3 (depends on 1)

The isolated anti-human RGMc antibody of claim 1, wherein the antibody further comprises an agent selected from the group consisting of an immunoadhesion molecule, an imaging agent, and a therapeutic agent, 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, and wherein the radiolabel is selected from the group consisting of 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, and 153Sm.

### Claim 4 (depends on 1)

An isolated nucleic acid encoding the anti-human RGMc antibody of claim 1.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 1 and a pharmaceutically acceptable carrier.

### Claim 6 (depends on 1)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 1.

### Claim 7 (depends on 6)

The method of claim 6, wherein the anti-human RGMc antibody is selected from the group consisting of a monoclonal antibody, an affinity matured antibody, and a humanized antibody.

### Claim 8

A kit for assaying a test sample for human Repulsive Guidance Molecule c (“RGMc”), which kit comprises at least one component for assaying the test sample for RGMc and instructions for assaying the test sample for RGMc, wherein the at least one component includes at least one composition comprising an isolated anti-human RGMc antibody comprising (a) a variable heavy chain region comprising a complementarity determining region (CDR)1 comprising the amino acid sequence of SEQ ID NO:11, a CDR2 comprising the amino acid sequence of SEQ ID NO:12, and a CDR3 comprising the amino acid sequence of SEQ ID NO:13 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:14, a CDR2 comprising the amino acid sequence of SEQ ID NO:15, and a CDR3 comprising the amino acid sequence of SEQ ID NO:16, (b) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:17, a CDR2 comprising the amino acid sequence of SEQ ID NO:18, and a CDR3 comprising the amino acid sequence of SEQ ID NO:19 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:20, a CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a CDR3 comprising the amino acid sequence of SEQ ID NO:22, (c) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:23, a CDR2 comprising the amino acid sequence of SEQ ID NO:24, and a CDR3 comprising the amino acid sequence of SEQ NO:25 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:26, a CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a CDR3 comprising the amino acid sequence of SEQ ID NO:28, or (d) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:29, a CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a CDR3 comprising the amino acid sequence of SEQ ID NO:31 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:32, a CDR2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR3 comprising the amino acid sequence of SEQ ID NO:34, wherein the anti-human RGMc antibody is optionally detectably labeled.

### Claim 9 (depends on 8)

The kit of claim 8, wherein the human RGMc is membrane-associated RGMc or soluble RGMc.

### Claim 10 (depends on 8)

The kit of claim 8, 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.

### Claim 11

A kit for assaying a test sample for human Repulsive Guidance Molecule c (“RGMc”), which kit comprises at least one component for assaying the test sample for RGMc and instructions for assaying the test sample for RGMc, wherein the at least one component includes at least one composition comprising an isolated anti-human RGMc antibody comprising (a) a variable heavy chain region comprising a complementarity determining region (CDR)1 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 region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:98, a CDR2 comprising the amino acid sequence of SEQ ID NO:99, and a CDR3 comprising the amino acid sequence of SEQ ID NO:100, (b) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:119, a CDR2 comprising the amino acid sequence of SEQ ID NO:120, and a CDR3 comprising the amino acid sequence of SEQ ID NO:121 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:122, a CDR2 comprising the amino acid sequence of SEQ ID NO:123, and a CDR3 comprising the amino acid sequence of SEQ ID NO:124, (c) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:125, a CDR2 comprising the amino acid sequence of SEQ ID NO:126, and a CDR3 comprising the amino acid sequence of SEQ ID NO:127 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:128, a CDR2 comprising the amino acid sequence of SEQ ID NO:129, and a CDR3 comprising the amino acid sequence of SEQ ID NO:130, (d) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:137, a CDR2 comprising the amino acid sequence of SEQ ID NO:138, and a CDR3 comprising the amino acid sequence of SEQ ID NO:139 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:140, a CDR2 comprising the amino acid sequence of SEQ ID NO:141, and a CDR3 comprising the amino acid sequence of SEQ ID NO:142, or (e) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:173, a CDR2 comprising the amino acid sequence of SEQ ID NO:174, and a CDR3 comprising the amino acid sequence of SEQ ID NO:175 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:176, a CDR2 comprising the amino acid sequence of SEQ ID NO:177, and a CDR3 comprising the amino acid sequence of SEQ ID NO:178, wherein the anti-human RGMc antibody is optionally detectably labeled.

### Claim 12 (depends on 11)

The kit of claim 11, wherein the human RGMc is membrane-associated RGMc or soluble RGMc.

### Claim 13 (depends on 11)

The kit of claim 11, 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.

### Claim 14

An isolated anti-human Repulsive Guidance Molecule c (“RGMc”) antibody comprising (a) a variable heavy chain region comprising a complementarity determining region (CDR)1 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:98, a CDR2 comprising the amino acid sequence of SEQ ID NO:99, and a CDR3 comprising the amino acid sequence of SEQ ID NO:100, (b) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:119, a CDR2 comprising the amino acid sequence of SEQ ID NO:120, and a CDR3 comprising the amino acid sequence of SEQ ID NO:121 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:122, a CDR2 comprising the amino acid sequence of SEQ ID NO:123, and a CDR3 comprising the amino acid sequence of SEQ ID NO:124, (c) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:125, a CDR2 comprising the amino acid sequence of SEQ ID NO:126, and a CDR3 comprising the amino acid sequence of SEQ ID NO:127 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:128, a CDR2 comprising the amino acid sequence of SEQ ID NO:129, and a CDR3 comprising the amino acid sequence of SEQ ID NO:130, (d) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:137, a CDR2 comprising the amino acid sequence of SEQ ID NO:138, and a CDR3 comprising the amino acid sequence of SEQ ID NO:139 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:140, a CDR2 comprising the amino acid sequence of SEQ ID NO:141, and a CDR3 comprising the amino acid sequence of SEQ ID NO:142, or (e) a variable heavy chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:173, a CDR2 comprising the amino acid sequence of SEQ ID NO:174, and a CDR3 comprising the amino acid sequence of SEQ ID NO:175 and a variable light chain region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:176, a CDR2 comprising the amino acid sequence of SEQ ID NO:177, and a CDR3 comprising the amino acid sequence of SEQ ID NO:178.

### Claim 15 (depends on 1)

The isolated anti-human RGMc antibody of claim 1, wherein the variable heavy chain region comprises a complementarity determining region (CDR)1 comprising the amino acid sequence of SEQ ID NO:11, a CDR2 comprising the amino acid sequence of SEQ ID NO:12, and a CDR3 comprising the amino acid sequence of SEQ ID NO:13 and the variable light chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:14, a CDR2 comprising the amino acid sequence of SEQ ID NO:15, and a CDR3 comprising the amino acid sequence of SEQ ID NO:16.

### Claim 16 (depends on 15)

The isolated anti-human RGMc antibody of claim 15, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO:3 and the variable light chain region comprises the amino acid of sequence of SEQ ID NO:4.

### Claim 17 (depends on 1)

The isolated anti-human RGMc antibody of claim 1, wherein the variable heavy chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:23, a CDR2 comprising the amino acid sequence of SEQ ID NO:24, and a CDR3 comprising the amino acid sequence of SEQ ID NO:25 and the variable light chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:26, a CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a CDR3 comprising the amino acid sequence of SEQ ID NO:28.

### Claim 18 (depends on 17)

The isolated anti-human RGMc antibody of claim 17, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO:7 and the variable light chain region comprises the amino acid sequence of SEQ ID NO:8.

### Claim 19 (depends on 1)

The isolated anti-human RGMc antibody of claim 1, wherein the variable heavy chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:29, a CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a CDR3 comprising the amino acid sequence of SEQ ID NO:31 and the variable light chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:32, a CDR2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR3 comprising the amino acid sequence of SEQ ID NO:34.

### Claim 20 (depends on 19)

The isolated anti-human RGMc antibody of claim 19, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO:9 and the variable light chain region comprises the amino acid sequence of SEQ ID NO:10.

### Claim 21 (depends on 1)

The isolated anti-human RGMc antibody of claim 1, wherein the variable heavy chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:17, a CDR2 comprising the amino acid sequence of SEQ ID NO:18, and a CDR3 comprising the amino acid sequence of SEQ ID NO:19 and the variable light chain region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:20, a CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a CDR3 comprising the amino acid sequence of SEQ ID NO:22.

### Claim 22 (depends on 21)

The isolated anti-human RGMc antibody of claim 21, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO:5 and the variable light chain region comprises the amino acid sequence of SEQ ID NO:6.

### Claim 23 (depends on 22)

The isolated anti-human RGMc antibody of claim 22, wherein the anti-human RGMc antibody comprises a heavy chain immunoglobulin constant domain which is a human IgG1 constant domain.

### Claim 24 (depends on 23)

The isolated anti-human RGMc antibody of claim 23, wherein the anti-human RGMc antibody is a monoclonal antibody.

### Claim 25 (depends on 24)

The isolated anti-human RGMc antibody of claim 24, wherein the anti-human RGMc antibody is a humanized antibody.

### Claim 26 (depends on 25)

The isolated anti-human RGMc antibody of claim 25, wherein the anti-human RGMc antibody is an affinity matured antibody.

### Claim 27 (depends on 21)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 21 and a pharmaceutically acceptable carrier.

### Claim 28 (depends on 22)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 22 and a pharmaceutically acceptable carrier.

### Claim 29 (depends on 23)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 23 and a pharmaceutically acceptable carrier.

### Claim 30 (depends on 24)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 24 and a pharmaceutically acceptable carrier.

### Claim 31 (depends on 25)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 25 and a pharmaceutically acceptable carrier.

### Claim 32 (depends on 26)

A pharmaceutical composition comprising the anti-human RGMc antibody of claim 26 and a pharmaceutically acceptable carrier.

### Claim 33 (depends on 21)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 21.

### Claim 34 (depends on 22)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 22.

### Claim 35 (depends on 23)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 23.

### Claim 36 (depends on 24)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 24.

### Claim 37 (depends on 25)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 25.

### Claim 38 (depends on 26)

A method of treating Anemia of Chronic Disease (ACD), iron-refractory iron-deficiency anemia or anemia of chronic kidney disease, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-human RGMc antibody of claim 26.