MONOCLONAL ANTIBODIES AGAINST THE RGM A PROTEIN FOR USE IN THE TREATMENT OF RETINAL NERVE FIBER LAYER DEGENERATION

• US 20110135664A1
• Filed: 12/08/2010
• Published: 06/09/2011
• Est. Priority Date: 12/08/2009
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Inventors: Mueller, Bernhard K.
• Granted Patent: US 9,175,075 B2
• Time in Patent Office: Days
• US Class Current: 424/172.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• 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

The present application describes RGM A binding proteins, particularly monoclonal antibodies, and in particular CDR grafted, humanized versions thereof, which have the ability to bind to RGM A and prevent binding of RGM proteins to RGM A receptor and other RGM A binding proteins, and therefore neutralize the function of RGM A, for use in the treatment of retinal nerve fiber layer (RNFL) degeneration as well as methods of therapeutically or prophylactically treating a mammal against RNFL degeneration.

Claims

1. A binding protein for human RGM A for use in the treatment of retinal nerve fiber layer (RNFL) degeneration.

2. The binding protein for use as defined in claim 1, wherein

said treatment is an therapeutic or prophylactic, neuroregenerative or neuroprotective, local or systemic treatment.

3. The binding protein for use as defined in claim 1, wherein as a result of said treatment

a) retinal neuron sprouting is observed;

and/or

b) RGC (Retinal Ganglion Cell) axons in the retina are preserved from degeneration.

4. The binding protein for use as defined in claim 1, wherein said

RNFL degeneration is associated with a disease selected from:

diabetic retinopathy, ischemic optic neuropathy, X-chromosome linked retinoschisis, drug-induced optic neuropathy, retinal dystrophy, age-related macula degeneration, eye diseases characterized by optic nerve head drusen, eye disease characterized by genetic determinants of photoreceptor degeneration, autosomal recessive cone-rod dystrophy, and mitochondrial disorders with optic neuropathy.

5. The binding protein for use as defined in claim 1 that dissociates

from human RGM A with a K_D of 1×

10−

⁷M or less and a k_off rate constant of 1×

10−

² s<sup>−

1</sup> or less, both determined by surface plasmon resonance.

6. The binding protein for use as defined in claim 1 that binds to

human RGM A and neutralizes the neurite outgrowth inhibitory activity of human RGM A as determined in a standard in vitro assay.

7. The binding protein for use as defined in claim 1, which is a

humanized antibody.

8. The binding protein for use as defined in claim 1, comprising an

antigen binding domain, said binding protein capable of binding an epitope of an RGM molecule, said antigen binding domain comprising at least one CDR selected from the group consisting of:

a) the CDR-H3 group amino acid sequences consisting of SEQ ID NO;

59 and 65,

and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences;

and/or

b) the CDR-L3 group amino acid sequences consisting of SEQ ID NO;

62 and 68, and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.

9. The binding protein for use as defined in claim 8, further

comprising at least one CDR selected from:

a) the CDR-H1 group of amino acid sequences consisting of SEQ ID NO;

57 and 63; and

/or

b) the CDR-L1 group of amino acid sequences consisting of SEQ ID NO;

60 an 66; and

/or

c) the CDR-H2 group of amino acid sequences consisting of SEQ ID NO;

58 and 64; and

/or

d) the CDR-L2 group of amino acid sequences consisting of SEQ ID NO;

61 and 67; and

modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.

10. The binding protein for use as defined in claim 9, comprising at least 3 CDRs which are selected from a variable domain CDR set consisting of:

11. The binding protein for use as defined in claim 10, comprising at least two variable domain CDR sets.

12. The binding protein for use as defined in claim 11, wherein said at least two variable domain CDR sets are selected from a group consisting of:

VH 5F9 set&

VL 5F9 set; and

VH 8D1 set &

VL 8D1 set.

13. The binding protein for use as defined in claim 12, further

comprising a human acceptor framework.

14. The binding protein for use as defined in claim 1, comprising at

least one heavy chain variable domain selected from SEQ ID NO:

35, 36, 37, 38, 39, 40, 41, 42, and 43; and

/or at least one light chain variable domain selected from SEQ ID NO;

44, 45, and 46.

15. The binding protein for use as defined in claim 13, wherein said

human acceptor framework comprises at least one framework region amino acid substitution at a key residue, said key residue selected from the group consisting of:

(heavy chain sequence position);

1, 5, 37, 48, 49, 88, 98;

(light chain sequence position);

2, 4, 41, 51.

16. The binding protein of claim 1, wherein said binding protein

comprises at least one (framework mutated) variable domain having an amino acid sequence selected from the groups consisting of:

(heavy chain sequences) SEQ ID NO;

47, 48, 49, 50; and

(light chain sequences) SEQ ID NO;

51, 52, 53, and 54.

17. The binding protein for use as defined in claim 1, which is an

antibody selected from 5F9 and 8D1.

18. A method of treating RNFL degeneration, comprising the step of administering to a mammal in need thereof an effective amount of a composition comprising an isolated binding protein as defined in claim 1.

19. The method of claim 18, wherein said treatment is an therapeutic or prophylactic, neuroregenerative or neuroprotective, local or systemic treatment.