Use of LINGO-4 Antagonists in the Treatment of Conditions Involving Demyelination

• US 20110123553A1
• Filed: 11/10/2008
• Published: 05/26/2011
• Est. Priority Date: 11/08/2007
• Status: Abandoned Application

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: Pepinsky, R. Blake, McCoy, John, Mi, Sha
• Application Number:
  US12/741,957
• Publication Number:
  US 20110123553A1
• Time in Patent Office: Days
• US Class Current: 424/178.1
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 2501/998 Proteins not provided for elsewhere
• CPC Class Codes: C12N 2502/08 cells of the nervous system
• CPC Class Codes: C12N 5/0622 Glial cells, e.g. astrocytes, oligodendrocytes; Schwann cells
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides methods of treating diseases, disorders or injuries involving demyelination and dysmyelination, including multiple sclerosis, by the administration of a LINGO-4 antagonist.

Claims

1. A method for promoting differentiation or survival of an oligodendrocyte, comprising contacting the oligodendrocyte with an effective amount of a composition comprising a LINGO-4 antagonist selected from the group consisting of:

(i) a soluble LINGO-4 polypeptide;

(ii) a LINGO-4 antibody or fragment thereof;

(iii) a LINGO-4 antagonist polynucleotide;

(iv) a LINGO-4 aptamer; and

(v) a combination of two or more of the LINGO-4 antagonists.

8. The method of claim 1, wherein the LINGO-4 antagonist comprises a soluble LINGO-4 polypeptide.

9. The method of claim 8, wherein the said soluble LINGO-4 polypeptide comprises a LINGO-4 region selected from the group consisting of:

(i) a LINGO-4 Ig domain or a fragment, variant, or derivative thereof,

(ii) a LINGO-4 LRR domain or a fragment, variant, or derivative thereof, and

(iii) a combination of the LINGO-4 domains or fragments, variants, or derivatives thereof.

11. The method of claim 8, wherein the LINGO-4 polypeptide comprises an amino acid sequence at least 90% identical to a reference amino acid sequence selected from the group consisting of:

amino acids 30 to 411 of SEQ ID NO;

2, amino acids 30 to 491 of SEQ ID NO;

2, and amino acids 30 to 534 of SEQ ID NO;

2.

15. The method of claim 8, wherein the soluble LINGO-4 polypeptide is a cyclic peptide.

22. The method of claim 8, wherein the said soluble LINGO-4 polypeptide is fused to a heterologous polypeptide.

23. The method of claim 22, wherein the heterologous polypeptide is selected from the group consisting of an immunoglobulin, serum albumin, a targeting polypeptide, a reporter polypeptide, a purification-facilitating polypeptide, a fragment of any of the polypeptides, and a combination of two or more of the polypeptides or fragments.

24. The method of claim 23, wherein the heterologous polypeptide is an immunoglobulin, or fragment thereof.

26. The method of claim 8, wherein the said soluble LINGO-4 polypeptide is conjugated to a polymer.

28. The method of claim 26, wherein the polymer is a polyalkylene glycol.

32. The method of claim 1, wherein the LINGO-4 antagonist comprises a LINGO-4 antibody, or fragment thereof.

34. The method of claim 1, wherein the said LINGO-4 antagonist polynucleotide is selected from the group consisting of:

(i) an antisense polynucleotide;

(ii) a ribozyme;

(iii) a small interfering RNA (siRNA); and

(iv) a small-hairpin RNA (shRNA).

35. The method of claim 1, wherein the LINGO-4 antagonist comprises an LINGO-4 aptamer.

36. The method of claim 1, wherein the oligodendrocyte is in a mammal that has been diagnosed with a disease, disorder, or injury involving demyelination, dysmyelination, or neurodegeneration.

37. The method of claim 36, wherein the disease, disorder, or injury is selected from the group consisting of multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelolysis (CPM), adrenoleukodystrophy, Alexander'"'"'s disease, Pelizaeus Merzbacher disease (PMZ), Wallerian Degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (ALS), Huntington'"'"'s disease, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, AR, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, and Bell'"'"'s palsy.

38. The method of claim 37, wherein the disease, disorder, or injury is multiple sclerosis (MS).

42. The method of claim 1, comprising (a) transfecting the oligodendrocyte with a polynucleotide that encodes the LINGO-4 antagonist through operable linkage to an expression control sequence, and (b) allowing expression of the LINGO-4 antagonist.

43. The method of claim 36, comprising (a) administering to the mammal a polynucleotide that encodes the LINGO-4 antagonist through operable linkage to an expression control sequence, and (b) allowing expression of the LINGO-4 antagonist.

47. The method of claim 43, wherein the administering comprises (a) providing a cultured host cell comprising the polynucleotide, wherein the cultured host cell expresses the LINGO-4 antagonist;

and (b) introducing the cultured host cell into the mammal such that the LINGO-4 antagonist is expressed in the mammal.

2. A method for promoting oligodendrocyte-mediated myelination of a neuron, or of preventing demyelination of a neuron, comprising contacting a mixture of a neuron and an oligodendrocyte with a composition comprising a LINGO-4 antagonist selected from the group consisting of:

(i) a soluble LINGO-4 polypeptide;

(ii) a LINGO-4 antibody or fragment thereof;

(iii) a LINGO-4 antagonist polynucleotide;

(iv) a LINGO-4 aptamer; and

(v) a combination of two or more of the said LINGO-4 antagonists.

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