IP Library › Patent Application 18548484

Patent Application

App. No. 18/548,484

METHODS FOR THE TREATMENT OF THYROID EYE DISEASE

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Patent No.: US None
App. No.: 18/548,484

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Abstract

Provided herein are methods of treating or reducing the severity of thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO), or Graves' ophthalmopathy or orbitopathy (GO), as well as antibodies, or antigen binding fragments thereof, and pharmaceutical compositions comprising them, useful in the methods.

Claims (181)

1 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), comprising either:

a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat; or

a variant Fc region comprising mutations that substitute a first mutation that is a tyrosine at position 252 (Met252Tyr), a second mutation that is a threonine at position 254 (Ser254Thr), and a third mutation that is a glutamic acid at position 256 (Thr256Glu), wherein the amino acid substitution numbering is EU as in Kabat.

2 . The antibody of claim 1 , wherein the antibody binds to and inhibits IGF-1R.

3 . The antibody of either of claims 1 - 2 , wherein the antibody or antigen-binding portion thereof cross-competes for binding to IGF-1R with a reference antibody or reference antigen-binding portion thereof.

4 . The antibody of claim 3 , wherein the reference antibody is chosen from αIR3, dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumab, cituxumumab, BIIB022, robatumumab, teprotumumab, and Antibody 2.

5 . The antibody of any of claims 1 - 4 , wherein the antibody is chosen from an IgA, IgD, IgE, and IgG.

6 . The antibody of claim 5 , wherein the antibody is an IgG.

7 . The antibody of claim 6 , wherein the antibody is chosen from an IgG1, IgG2, IgG3, and IgG4.

8 . The antibody of claim 7 , wherein the antibody is an IgG1.

9 . The antibody of any of claims 1 - 8 , wherein the antibody:

is capable of reducing insulin like growth factor-I receptor (IGF-1R) signaling;

is capable of inhibiting thyroid stimulating hormone receptor (TSHR)/IGF-1R crosstalk (i.e., formation of a TSHR/IGF-1R signalosome);

is capable of reducing hyaluronan (HA) secretion in orbital fibroblasts;

is capable of persisting for an extended period of time in vivo (i.e., has a longer half-life) compared to an antibody that does not comprise the M428L/N434S or M252Y/S254T/T256E substitutions; and/or

is capable of being dosed less frequently, or in a lower amount per dose, compared to an antibody that does not comprise the M428L/N434S or M252Y/S254T/T256E substitutions.

10 . The antibody of any of claims 1 - 9 , wherein the antibody comprises complementarity determining regions (CDRs) derived from an antibody chosen from dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumab, cituxumumab, BIIB022, robatumumab, teprotumumab, and Antibody 2.

11 . The antibody of any of claims 1 - 10 wherein the antibody comprises a heavy chain variable region that comprises HCDR1, HCDR2, and HCDR3 domains; and a light chain variable region that comprises LCDR1, LCDR2, and LCDR3 domains, comprising:

a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:9, a HCDR2 comprising the amino acid sequence of SEQ ID NO:10, a HCDR3 comprising the amino acid sequence of SEQ ID NO:11, a LCDR1 comprising the amino acid sequence of SEQ ID NO:12, a LCDR2 comprising the amino acid sequence of SEQ ID NO:13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:14;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:17, a HCDR2 comprising the amino acid sequence of SEQ ID NO:18, a HCDR3 comprising the amino acid sequence of SEQ ID NO:19, a LCDR1 comprising the amino acid sequence of SEQ ID NO:20, a LCDR2 comprising the amino acid sequence of SEQ ID NO:21, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:22;

a HCDR1 comprising HCDR1 comprising the amino acid sequence of SEQ ID NO:25 or SEQ ID NO:75, a HCDR2 comprising the amino acid sequence of SEQ ID NO:26 or SEQ ID NO:76 or SEQ ID NO:77, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:33, a HCDR2 comprising the amino acid sequence of SEQ ID NO:34, a HCDR3 comprising the amino acid sequence of SEQ ID NO:35, a LCDR1 comprising the amino acid sequence of SEQ ID NO:36, a LCDR2 comprising the amino acid sequence of SEQ ID NO:37, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:38;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:41, a HCDR2 comprising the amino acid sequence of SEQ ID NO:42, a HCDR3 comprising the amino acid sequence of SEQ ID NO:43, a LCDR1 comprising the amino acid sequence of SEQ ID NO:44, a LCDR2 comprising the amino acid sequence of SEQ ID NO:45, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:46;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:49, a HCDR2 comprising the amino acid sequence of SEQ ID NO:50, a HCDR3 comprising the amino acid sequence of SEQ ID NO:51, a LCDR1 comprising the amino acid sequence of SEQ ID NO:52, a LCDR2 comprising the amino acid sequence of SEQ ID NO:53, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:54;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:57, a HCDR2 comprising the amino acid sequence of SEQ ID NO:58, a HCDR3 comprising the amino acid sequence of SEQ ID NO:59, a LCDR1 comprising the amino acid sequence of SEQ ID NO:60, a LCDR2 comprising the amino acid sequence of SEQ ID NO:61, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:62;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:84, a HCDR2 comprising the amino acid sequence of SEQ ID NO:85, a HCDR3 comprising the amino acid sequence of SEQ ID NO:86, a LCDR1 comprising the amino acid sequence of SEQ ID NO:87, a LCDR2 comprising the amino acid sequence of SEQ ID NO:88, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:89; or

a HCDR1 comprising the amino acid sequence of SEQ ID NO:84, a HCDR2 comprising the amino acid sequence of SEQ ID NO:92, a HCDR3 comprising the amino acid sequence of SEQ ID NO:86, a LCDR1 comprising the amino acid sequence of SEQ ID NO:87, a LCDR2 comprising the amino acid sequence of SEQ ID NO:93, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:89.

12 . The antibody of any of claims 1 - 9 , wherein the antibody comprises heavy chain variable domain (V H ) and a light chain variable domain (V L ) derived from an antibody chosen from dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumab, cituxumumab, BIIB022, robatumumab, teprotumumab, and Antibody 2.

13 . The antibody of any of claims 1 - 9 , comprising:

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:8;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:15, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:16;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:23, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:24;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:31 or 78 or 79, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:32 or 80 or 81 or 82 or 83;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:39, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:40;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:47, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:48;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:55, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:56;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:63, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:64; or

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:65, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:66;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:90, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:91;

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:94, or and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:95.

14 . The antibody of any of claims 1 - 10 , comprising a HCDR1 comprising HCDR1 comprising the amino acid sequence of SEQ ID NO:25 or SEQ ID NO:75, a HCDR2 comprising the amino acid sequence of SEQ ID NO:26 or SEQ ID NO:76 or SEQ ID NO:77, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30.

15 . The antibody of any of claims 1 - 9 , comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:25, a HCDR2 comprising the amino acid sequence of SEQ ID NO:76, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30.

16 . The antibody of any of claims 1 - 9 , comprising

a HCDR1 comprising the amino acid sequence of SEQ ID NO:25, a HCDR2 comprising the amino acid sequence of SEQ ID NO:76, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:25, a HCDR2 comprising the amino acid sequence of SEQ ID NO:77, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:25, a HCDR2 comprising the amino acid sequence of SEQ ID NO:26, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:75, a HCDR2 comprising the amino acid sequence of SEQ ID NO:76, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30;

a HCDR1 comprising the amino acid sequence of SEQ ID NO:75, a HCDR2 comprising the amino acid sequence of SEQ ID NO:77, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30; or

a HCDR1 comprising the amino acid sequence of SEQ ID NO:75, a HCDR2 comprising the amino acid sequence of SEQ ID NO:26, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30.

17 . The antibody of any of claims 1 - 9 , wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:31 or 78 or 79, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:32 or 80 or 81 or 82 or 83.

18 . The antibody of claim 17 , wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:78 and a light chain variable domain comprising the amino acid sequence of SEQ ID NOs:80 or 81 or 82 or 83.

19 . The antibody of claim 18 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:80.

20 . The antibody of claim 19 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:81.

21 . The antibody of claim 19 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:82.

22 . The antibody of claim 19 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:83.

23 . The antibody of claim 18 , wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:31 and a light chain variable domain comprising the amino acid sequence of SEQ ID NOs:80 or 81 or 82 or 83.

24 . The antibody of claim 23 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:80.

25 . The antibody of claim 23 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:81.

26 . The antibody of claim 23 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:82.

27 . The antibody of claim 23 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:83.

28 . The antibody of any of claims 1 - 9 , comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:84, a HCDR2 comprising the amino acid sequence of SEQ ID NO:85, a HCDR3 comprising the amino acid sequence of SEQ ID NO:86, a LCDR1 comprising the amino acid sequence of SEQ ID NO:87, a LCDR2 comprising the amino acid sequence of SEQ ID NO:88, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:89.

29 . The antibody of any of claims 1 - 9 , wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO:90 and a light chain variable domain comprising SEQ ID NO:91.

30 . The antibody of any of claims 1 - 29 , wherein the antibody comprises a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat.

31 . The antibody of any of claims 1 - 29 , wherein the antibody comprises a variant Fc region comprising mutations that substitute a first mutation that is a tyrosine at position 252 (Met252Tyr), a second mutation that is a threonine at position 254 (Ser254Thr), and a third mutation that is a glutamic acid at position 256 (Thr256Glu), wherein the amino acid substitution numbering is EU as in Kabat.

32 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), wherein the antibody comprises a heavy chain variable region that comprises HCDR1, HCDR2, and HCDR3 domains; and a light chain variable region that comprises LCDR1, LCDR2, and LCDR3 domains, comprising:

33 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), wherein the antibody comprises a heavy chain variable region that comprises HCDR1, HCDR2, and HCDR3 domains; and a light chain variable region that comprises LCDR1, LCDR2, and LCDR3 domains, comprising:

34 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), wherein the antibody comprises a heavy chain variable region that comprises HCDR1, HCDR2, and HCDR3 domains; and a light chain variable region that comprises LCDR1, LCDR2, and LCDR3 domains, comprising:

35 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), wherein the antibody comprises:

36 . The antibody of claim 35 , wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:78 and a light chain variable domain comprising the amino acid sequence of SEQ ID NOs:80 or 81 or 82 or 83.

37 . The antibody of claim 36 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:80.

38 . The antibody of claim 36 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:81.

39 . The antibody of claim 36 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:82.

40 . The antibody of claim 36 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:83.

41 . The antibody of claim 35 , wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:31 and a light chain variable domain comprising the amino acid sequence of SEQ ID NOs:80 or 81 or 82 or 83.

42 . The antibody of claim 41 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:80.

43 . The antibody of claim 41 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:81.

44 . The antibody of claim 41 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:82.

45 . The antibody of claim 41 , wherein the antibody comprises the light chain variable domain comprising the amino acid sequence of SEQ ID NO:83.

46 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), wherein the antibody comprises a heavy chain variable region that comprises HCDR1, HCDR2, and HCDR3 domains; and a light chain variable region that comprises LCDR1, LCDR2, and LCDR3 domains, comprising:

47 . An antibody which binds to the insulin like growth factor-I receptor (IGF-1R), wherein the antibody comprises:

a heavy chain variable domain comprising SEQ ID NO:7 and a light chain variable domain comprising SEQ ID NO:8; and either

48 . The antibody of any of claims 32 - 47 , wherein the antibody comprises a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat.

49 . The antibody of any of claims 32 - 47 , wherein the antibody comprises a variant Fc region comprising mutations that substitute a first mutation that is a tyrosine at position 252 (Met252Tyr), a second mutation that is a threonine at position 254 (Ser254Thr), and a third mutation that is a glutamic acid at position 256 (Thr256Glu), wherein the amino acid substitution numbering is EU as in Kabat.

50 . A nucleotide sequence encoding the polypeptide sequence of the antibody of any of claims 1 - 49 .

51 . An expression vector comprising the nucleotide sequence of claim 50 .

52 . A Chinese hamster ovary (CHO) cell line expressing the vector of claim 51 .

53 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody as recited in any of claims 1 - 49 , and a pharmaceutically acceptable carrier.

54 . The pharmaceutical composition of claim 53 , wherein the therapeutically effective amount comprises a dosage of 1-10 mg/kg.

55 . The pharmaceutical composition of claim 54 , wherein the therapeutically effective amount comprises a dosage of 1-5 mg/kg.

56 . The pharmaceutical composition of claim 55 , wherein the therapeutically effective amount comprises a dosage of about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, or about 5 mg/kg.

57 . The pharmaceutical composition of any of claims 53 - 56 , wherein the therapeutically effective amount is formulated for administration every 1, 2, 3, 4, or 5 weeks (i.e., QW, Q2W, Q3W, Q4W, or Q5W).

58 . The pharmaceutical composition of any of claims 53 - 57 , wherein the pharmaceutically acceptable carrier is suitable for intravenous (IV) or subcutaneous (SC) administration.

59 . The pharmaceutical composition of claim 53 , comprising a therapeutically effective amount of the antibody as recited in any of claims 14 - 27 and 32 - 45 , wherein the therapeutically effective amount comprises a dosage of:

1-60 mg/kg or 75-4500 mg; or

0.6-40 mg/kg or 45-3000 mg; or

0.3-20 mg/kg or 22-1500 mg.

60 . The pharmaceutical composition of claim 59 , formulated for IV administration.

61 . The pharmaceutical composition of claim 60 , formulated for dosing every 4, 3, 2, or 1 weeks.

62 . The pharmaceutical composition of claim 53 , comprising a therapeutically effective amount of the antibody as recited in any of claims 14 - 27 and 32 - 45 , wherein the therapeutically effective amount comprises a dosage of:

1-30 mg/kg or 75-2250 mg;

0.6-20 mg/kg or 1500 mg;

0.3-10 mg/kg or 750 mg.

63 . The pharmaceutical composition of claim 53 , comprising a therapeutically effective amount of the antibody as recited in any of claims 14 - 27 and 32 - 45 , wherein the therapeutically effective amount comprises a dosage of:

1-20 mg/kg or 75-1500 mg;

0.6-13.5 mg/kg or 1000 mg;

0.3-7 mg/kg or 500 mg.

64 . The pharmaceutical composition of any of claims 62 - 63 , formulated for subcutaneous administration.

65 . The pharmaceutical composition of claim 64 , formulated for dosing every 4, 3, 2, or 1 weeks.

66 . An autoinjector comprising the pharmaceutical formulation as recited in claim 64 .

67 . A method of treating thyroid eye disease (TED) in a subject with TED, comprising administering to the subject a therapeutically effective amount of the antibody of any of claims 1 - 49 or the pharmaceutical composition of any of claims 53 - 65 .

68 . A method of reducing proptosis in a subject with thyroid eye disease (TED), comprising administering to the subject a therapeutically effective amount of the antibody of any of claims 1 - 49 or the pharmaceutical composition of any of claims 53 - 65 .

69 . The method of claim 68 , wherein proptosis is reduced by at least 2 mm.

70 . The method of claim 69 , wherein proptosis is reduced by at least 3 mm.

71 . The method of claim 70 , wherein proptosis is reduced by at least 4 mm.

72 . The method of claim 68 , wherein the method additionally comprises reducing the clinical activity score (CAS) in the subject with TED.

73 . The method of claim 72 , wherein proptosis is reduced by at least 2 mm and CAS is reduced by at least 2 points.

74 . The method of claim 73 , wherein CAS is reduced by at least 3 points.

75 . The method of claim 74 , wherein proptosis is reduced by at least 3 mm and CAS is reduced by at least 3 points.

76 . A method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject a therapeutically effective amount of the antibody of any of claims 1 - 49 or the pharmaceutical composition of any of claims 53 - 65 .

77 . The method of claim 76 , wherein the diplopia is constant diplopia.

78 . The method of claim 76 , wherein the diplopia is intermittent diplopia.

79 . The method of claim 76 , wherein the diplopia is inconstant diplopia.

80 . The method of claim 76 , wherein the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of inhibitor administration.

81 . The method of claim 80 , wherein the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of inhibitor administration.

82 . A method of reducing Clinical Activity Score (CAS) of thyroid eye disease (TED) in a subject with TED, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any of claims 1 - 49 or the pharmaceutical composition of any of claims 53 - 65 .

83 . The method of claim 82 , wherein CAS is reduced by at least 2 points.

84 . The method of claim 83 , wherein CAS is reduced by at least 3 points.

85 . A method of:

reducing insulin like growth factor-I receptor (IGF-1R) signaling;

inhibiting thyroid stimulating hormone receptor (TSHR)/IGF-1R crosstalk (i.e., formation of a TSHR/IGF-1R signalosome); and/or

reducing hyaluronan (HA) secretion in orbital fibroblasts;

in a subject with TED, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any of claims 1 - 49 or the pharmaceutical composition of any of claims 53 - 65 ,

wherein the antibody persists for an extended period of time in vivo (i.e., has a longer half-life) compared to an antibody that does not comprise the M428L/N434S or M252Y/S254T/T256E substitutions; and/or

wherein the antibody or pharmaceutical composition is administered less frequently, or in a lower amount per dose, compared to an antibody that does not comprise the M428L/N434S or M252Y/S254T/T256E substitutions.

86 . The method of any of claims 67 - 85 , wherein the therapeutically effective amount comprises a dosage of 1-10 mg/kg.

87 . The method of claim 86 , wherein the therapeutically effective amount comprises a dosage of 1-5 mg/kg.

88 . The method of claim 87 , wherein the therapeutically effective amount comprises a dosage of about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, or about 5 mg/kg.

89 . The method of any of claims 67 - 88 , wherein the therapeutically effective amount is administered every 1, 2, 3, 4, or 5 weeks (i.e., QW, Q2W, Q3W, Q4W, or Q5W).

90 . The method of any of claims 67 - 89 , wherein the therapeutically effective amount is administered intravenously (IV) or subcutaneously (SC).

91 . The method of any of claims 67 - 85 , comprising a therapeutically effective amount of the antibody as recited in any of claims 14 - 27 and 32 - 45 , wherein the therapeutically effective amount comprises a dosage of

1-5 mg/kg or 75-375 mg IV Q3W; or

0.6-4 mg/kg or 45-300 mg IV Q2W; or

0.3-3 mg/kg or 22-225 mg IV QW.

92 . The method of claim 91 , formulated for IV administration.

93 . The method of claim 92 , formulated for dosing every 4, 3, 2, or 1 weeks.

94 . The method of any of claims 67 - 85 , comprising a therapeutically effective amount of the antibody as recited in any of claims 14 - 27 and 32 - 45 , wherein the therapeutically effective amount comprises a dosage of:

1-30 mg/kg or 75-2250 mg;

0.6-20 mg/kg or 1500 mg;

0.3-10 mg/kg or 750 mg.

95 . The method of any of claims 67 - 85 , comprising a therapeutically effective amount of the antibody as recited in any of claims 14 - 27 and 32 - 45 , wherein the therapeutically effective amount comprises a dosage of:

1-20 mg/kg or 75-1500 mg;

0.6-13.5 mg/kg or 1000 mg;

0.3-7 mg/kg or 500 mg.

96 . The method of any of claims 94 - 95 , formulated for subcutaneous administration.

97 . The method of claim 96 , formulated for dosing every 4, 3, 2, or 1 weeks.

98 . The method of claim 95 , wherein the subcutaneous administration is done using an autoinjector.

99 . The use of the antibody of any of claims 1 - 49 , or the pharmaceutical composition of any of claims 53 - 65 or the autoinjector of claim 66 , for the treatment of thyroid eye disease (TED) in a subject with TED, reduction of proptosis in a subject with TED, reduction of the severity of diplopia in a subject with TED, or reduction of CAS in a subject with TED, as recited in any of claims 67 - 99 .

100 . The use of the antibody of any of claims 1 - 49 , or the pharmaceutical composition of any of claims 53 - 65 or the autoinjector of claim 66 , in the manufacture of a medicament for the treatment of thyroid eye disease (TED) in a subject with TED, reduction of proptosis in a subject with TED, reduction of the severity of diplopia in a subject with TED, or reduction of CAS in a subject with TED, as recited in any of claims 67 - 99 .

Assignments (2)

CHANGE OF ADDRESS Recorded Dec 23, 2025

From: HORIZON THERAPEUTICS IRELAND DAC

To: HORIZON THERAPEUTICS IRELAND DAC

Reel/Frame 074050/0087 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 7, 2023

From: SHERMAN, JEFFREY W.

To: HORIZON THERAPEUTICS IRELAND DAC

Reel/Frame 064835/0842 →