Lingo-1 antagonists and uses for treatment of demyelinating disorders

Abstract

Methods, compositions and kits are described herein useful for detecting and/or treating a CNS demyelinating disease.

1 . (canceled) 
     
     
         2 . A method of treating or preventing a CNS demyelinating disorder chosen from one or both of multiple sclerosis (MS) or an inflammatory condition of the optic nerve, said method comprising administering to a human subject in need thereof, an anti-LINGO-1 antibody molecule, wherein the anti-LINGO-1 antibody molecule is administered in an amount to treat or prevent the CNS demyelinating disease at a selected time interval chosen from one, two, or all of:
 (i) prior to the onset or relapse of one or more symptoms of the CNS demyelinating disease;   (ii) within 7 days after the onset or relapse of one or more symptoms of the CNS demyelinating disease; or   (iii) within 30 days after the onset or relapse of one or more symptoms of the CNS demyelinating disease.   
     
     
         3 .- 7 . (canceled) 
     
     
         8 . The method of  claim 2 , wherein administration of the anti-LINGO antibody molecule is initiated before the onset or relapse of one or more symptoms of the inflammatory condition of the optic nerve in one or both eyes of the subject. 
     
     
         9 . The method of  claim 2 , wherein the anti-LINGO antibody molecule is administered prophylactically or chronically. 
     
     
         10 .- 14 . (canceled) 
     
     
         15 . The method of  claim 2 , wherein administration of the anti-LINGO antibody molecule is initiated less than 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 day, or hours after an acute lesion in MS, an MS relapse, or AON. 
     
     
         16 . The method of  claim 15 , wherein the anti-LINGO antibody molecule is administered, as a monotherapy or as a combination therapy, at about 1, 3, 10, 30, 60, 100 or 150 mg/kg once every one, two, three, four or five weeks by intravenous, subcutaneous, or intramuscular injection. 
     
     
         17 .- 22 . (canceled) 
     
     
         23 . The method of  claim 2 , wherein the subject is asymptomatic at the time of treatment. 
     
     
         24 .- 25 . (canceled) 
     
     
         26 . The method of  claim 2 , wherein the subject is diagnosed with the optic nerve disorder in one or both eyes, but does not show an MS symptom. 
     
     
         27 .- 44 . (canceled) 
     
     
         45 . The method of  claim 2 , wherein the anti-LINGO antibody molecule is administered as a monotherapy in an amount ranging from about 10 to 300 mg/kg, 20 to 250 mg/kg, 50 to 200 mg/kg, 75 to 150 mg/kg, 90 to 120 mg/kg, or about 100 mg/kg. 
     
     
         46 . The method of  claim 2 , wherein the anti-LINGO antibody molecule is administered as a combination therapy in an amount ranging from about 1 to 150 mg/kg, or 3 to 100 mg/kg. 
     
     
         47 . (canceled) 
     
     
         48 . The method of  claim 2 , wherein the anti-LINGO-1 antibody is administered in combination with an immunosuppressive agent chosen from one or more of:
 an IFN-β 1 molecule;   a corticosteroid;   a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer;   an antibody or fragment thereof against alpha-4 integrin or natalizumab;   an anthracenedione molecule or mitoxantrone;   a fingolimod or FTY720 or other SIP1 functional modulator;   a dimethyl fumarate;   an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab;   an antibody against CD52 or alemtuzumab;   an antibody against CD20; or   an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.   
     
     
         49 . (canceled) 
     
     
         50 . The method of  claim 2 , wherein the anti-LINGO-1 antibody molecule is a monoclonal antibody against human LINGO-1. 
     
     
         51 .- 53 . (canceled) 
     
     
         54 . The method of  claim 2 , wherein the anti-LINGO-1 antibody molecule is modified to reduce effector cell and complement function compared to wild-type IgG1. 
     
     
         55 . The method of  claim 2 , wherein the anti-LINGO-1 antibody molecule comprises:
 (i) three CDRs of a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6, 7 or 8, or SEQ ID NO: 2, 3 or 30;   (ii) three CDRs of a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14, 15 or 16, or SEQ ID NO: 10, 11 or 12;   (iii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 66;   (iv) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 9; or   (v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 275, or a sequence substantially identical thereto; and a light chain comprising the amino acid sequence of SEQ ID NO: 276.   
     
     
         56 .- 62 . (canceled) 
     
     
         63 . The method of  claim 48 , wherein the anti-LINGO-1 antibody molecule comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 66, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 9; and the immunosuppressive agent is Avonex®. 
     
     
         64 .- 84 . (canceled) 
     
     
         85 . The method of  claim 48 , wherein:
 the anti-LINGO-1 antibody molecule is administered once every four weeks by IV infusion dosed at about 3 mg/kg, about 10 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 100 mg/kg; and   the immunosuppressive agent is IFN-β 1 and is administered at one or more of:   (i) at 20-45 microgram once a week via intramuscular injection;   (ii) at 20-30 microgram once or three times a week, or at 40-50 micrograms once or three times a week, via subcutaneous injection; or   (iii) in an amount of between 10 and 50 μg intramuscularly, e.g., three times a week, or every five to ten days.   
     
     
         86 . The method of  claim 2 , wherein the subject has been, or is being evaluated by one or more of:
 performing a neurological examination;   acquiring the subject's status on the Expanded Disability Status Scale (EDSS); acquiring the subject's status on the Multiple Sclerosis Functional Composite (MSFC);   detecting the subject's lesion status;   acquiring a measure of upper and/or lower extremity function;   acquiring a measure of short distance ambulatory function;   acquiring a measure of long distance ambulatory function;   acquiring a measure of cognitive function; or   acquiring a measure of visual function.   
     
     
         87 . The method of  claim 2 , further comprising one or more of:
 acquiring the subject's status on the MSFC;   performing a neurological examination;   acquiring the subject's status on the Expanded Disability Status Scale (EDSS);   detecting the subject's lesion status;   acquiring a measure of upper and/or lower extremity function;   acquiring a measure of short distance ambulatory function;   acquiring a measure of long distance ambulatory function;   acquiring a measure of cognitive function; or   acquiring a measure of visual function.   
     
     
         88 .- 95 . (canceled) 
     
     
         96 . The method of  claim 86 , wherein an improvement in the subject is defined by one or more of:
 a. ≥1.0 point decrease in EDSS from a baseline score of ≤6.0;   b. ≥15% improvement from baseline in T25FW;   c. ≥15% improvement from baseline in 9HPT; or   d. ≥15% improvement from baseline in PASAT or SDMT.   
     
     
         97 .- 98 . (canceled) 
     
     
         99 . A method of diagnosing a human subject at risk of developing, a CNS demyelinating disorder, comprising acquiring measuring one or both of optic nerve damage or optic nerve conductance for one or both eyes of the subject, wherein the presence of optic nerve damage and/or a delay in optic nerve conductance in one or both eyes indicates that the subject is at risk for developing the CNS demyelinating disorder. 
     
     
         100 .- 106 . (canceled) 
     
     
         107 . A kit comprising an antibody molecule against human LINGO-1 with instructions for use in treating multiple sclerosis or an inflammatory condition of the optic nerve, wherein the antibody is instructed to be administered at a selected time interval chosen from one, two, or all of:
 (i) prior to the onset or relapse of one or more symptoms of the CNS demyelinating disease;   (ii) within 7 days after the onset or relapse of one or more symptoms of the CNS demyelinating disease; or   (iii) within 30 days after the onset or relapse of one or more symptoms of the CNS demyelinating disease.   
     
     
         108 .- 112 . (canceled)