METHODS FOR THE TREATMENT OF THYROID EYE DISEASE
The invention provides a method of treating or reducing the severity of thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED) or Graves' ophthalmopathy or orbitopathy (GO), as well as antibodies, or antigen binding fragments thereof, and pharmaceutical compositions comprising them, useful in the methods.
1 .- 37 . (canceled)
38 . A method of a) reducing proptosis by at least 2 mm and/or b) reducing the clinical activity score (CAS) in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an antibody, or an antigen binding fragment thereof, wherein the antibody specifically binds to and inhibits insulin like growth factor-I receptor (IGF-1R).
39 . A method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an antibody, or an antigen binding fragment thereof, wherein the antibody specifically binds to and inhibits IGF-1R.
40 . A method of complete resolution of diplopia in a in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an antibody, or an antigen binding fragment thereof, wherein the antibody specifically binds to and inhibits IGF-1R.
41 . A method of improving the visual appearance of a subject with thyroid eye disease (TED) by at least 8 points, comprising administering to the subject an effective amount of an antibody, or an antigen binding fragment thereof, wherein the antibody specifically binds to and inhibits IGF-1R.
42 . The method of claim 41 , wherein the treatment improves the visual appearance of the subject by at least 16 points.
43 . The method of claim 40 , wherein the treatment efficacy persists in at least 50% of the subjects at least 48 weeks after cessation of treatment.
44 . The method of claim 40 , wherein the antibody is administered at a dosage of about 5 mg/kg to about 10 mg/kg antibody as a first dose.
45 . The method of claim 40 , wherein the antibody is administered at a dosage of about 5 mg/kg to about 20 mg/kg antibody in subsequent doses.
46 . The method of claim 45 , wherein the subsequent doses are administered every three weeks for at least 21 weeks.
47 . The method of claim 46 , wherein the antibody, or an antigen binding fragment thereof, has a binding affinity (K D ) of 10 −8 M or less for the IGF-1R.
48 . The method of claim 46 , wherein the antibody, or an antigen binding fragment thereof, has an IC 50 values for the binding of IGF-I and IGF-II to IGF-1R of no more than about 2 nM.
49 . The method of claim 46 , wherein the antibody, or an antigen binding fragment thereof, comprises a heavy chain comprising CDR1, CDR2 and CDR3 and a light chain comprising CDR1, CDR2 and CDR3,
wherein the heavy chain CDR1, CDR2, and CDR3 amino acid sequences and light chain CDR1, CDR2, and CDR3 amino acid sequences are at least 90% identical to
(i) the amino acid sequences of SEQ ID NOs: 1-6, respectively; or
(ii) the amino acid sequences of SEQ ID NOs: 1, 9, 3, 4, 10, 6, respectively.
50 . The method of claim 46 , wherein the antibody, or an antigen binding fragment thereof, comprises:
(i) a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 8; or
(ii) a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 11 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 12.
51 . The method of claim 46 , wherein the antibody is antibody 1 or antibody 2, or an antigen binding fragment thereof.
52 . The method of claim 46 , wherein the antibody is teprotumumab.
53 . The method of claim 46 , wherein the antibody, or an antigen binding fragment thereof, is a human antibody, a monoclonal antibody, a human monoclonal antibody, a purified antibody, a diabody, a single-chain antibody, a multi-specific antibody, Fab, Fab′, F(ab′)2, Fv or scFv.
54 . The method of claim 52 , wherein the antibody, or an antigen binding fragment thereof, is administered in a pharmaceutical composition that additionally comprises a pharmaceutically acceptable diluent or excipient or carrier.
55 . The method of claim 54 , wherein the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TED.
56 . The method of claim 55 , wherein the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFα antibodies or a thyroid-stimulating hormone receptor (TSHR) inhibitor.
57 . The method of claim 52 , wherein the treatment is efficacious for at least 4 weeks beyond the last administered dose.