Methods for treatment of thyroid eye disease with an Anti-IGF-1r antibody

Abstract

The present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dosing regimen for a treatment period sufficient to reduce one or more symptoms associated with TED with low adverse events, such as hearing impairment.

Description

Attorney Docket No. VRD-022WO1 METHODS FOR TREATMENT OF THYROID EYE DISEASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 692,650, filed September 9, 2024, U.S. Provisional Application No.63 / 763,087, filed February 25, 2025, and U.S. Provisional Application No.63 / 809,083, filed May 20, 2025, each of which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Thyroid Eye Disease (TED) is an autoimmune condition most commonly associated with Graves’ disease and hyperthyroidism but can also be found in patients who are euthyroid or hypothyroid. Pathological remodeling of the orbit and periorbital tissues results in varied presentations which include dry eyes, increased lacrimation, local irritation and eyelid retraction. As the pathophysiology progresses, signs and symptoms increase to include proptosis, diplopia, restriction of ductions and versions and optic nerve compression, with ensuing vision loss. Previous therapies have been broad-based acting as a blunt instrument on this mechanism with varying efficacy but often accompanied with a significant side effect profile. SUMMARY OF INVENTION

[0003] The present invention provides, among other things, a safer and more potent method for treating thyroid eye disease (TED) based on VRDN-001 and other anti-IGF-1R antibodies using dosing regimens described herein. The present invention is, in part, based on the superior clinical results in TED patients receiving VRDN-001 treatment resulting in particularly high diplopia resolution (e.g., ≥ 50% rate; ≥ 35% placebo-adjusted rate), high proptosis responder rate (e.g., ≥ 60% rate; ≥ 50% placebo-adjusted rate), and high CAS responder rate (e.g., ≥60% rate; ≥ 30% placebo-adjusted rate), while keeping the hearing impairment incidence low (e.g., ≤ 20% rate; ≤ 10% placebo adjusted rate).

[0004] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody 1 155110240v10Attorney Docket No. VRD-022WO1 to a patient at a total dose of no more than 80 mg / kg according to a dosing regimen, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0005] In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and one or more subsequent doses of the anti- IGF-1R antibody at 10 mg / kg every three weeks.

[0006] In some embodiments, the total dose is no more than 70 mg / kg. In some embodiments, the total dose is no more than 60 mg / kg. In some embodiments, the total dose is no more than 50 mg / kg. In some embodiments, the total dose is no more than 40 mg / kg. In some embodiments, the total dose is no more than 30 mg / kg. In some embodiments, the total dose is no more than 20 mg / kg. In some embodiments, the total dose is no more than 15 mg / kg. In some embodiments, the total dose is no more than 10 mg / kg.

[0007] In some embodiments, the total dose is 80 mg / kg. In some embodiments, the total dose is 70 mg / kg. In some embodiments, the total dose is 60 mg / kg. In some embodiments, the total dose is 50 mg / kg. In some embodiments, the total dose is 40 mg / kg. In some embodiments, the total dose is 30 mg / kg. In some embodiments, the total dose is 20 mg / kg. In some embodiments, the total dose is 15 mg / kg. In some embodiments, the total dose is 10 mg / kg.

[0008] In some embodiments, the method comprises administering three subsequent doses. In some embodiments, the method comprises administering four subsequent doses. In some embodiments, the method comprises administering five subsequent doses. In some embodiments, the method comprises administering six subsequent doses. In some embodiments, the method comprises administering seven subsequent doses.

[0009] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a total dose of 50 mg / kg, wherein the total dose of 50 mg is administered by the first dose of 10 mg / kg followed by four subsequent doses of 10 mg / kg every three weeks, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain 2 155110240v10Attorney Docket No. VRD-022WO1 comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6.

[0010] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 35% diplopia resolution, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0011] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 35% diplopia resolution, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0012] In some embodiments, diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline.

[0013] In some embodiments, the treatment results in at least 25% diplopia resolution. In some embodiments, the treatment results in at least 30% diplopia resolution. In some embodiments, the treatment results in at least 35% diplopia resolution. In some embodiments, the treatment results in at least 38% diplopia resolution. In some embodiments, the treatment results in at least 40% diplopia resolution. In some 3 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the treatment results in at least 42% diplopia resolution. In some embodiments, the treatment results in at least 45% diplopia resolution. In some embodiments, the treatment results in at least 50% diplopia resolution. In some embodiments, the treatment results in at least 55% diplopia resolution. In some embodiments, the treatment results in at least 60% diplopia resolution. In some embodiments, the treatment results in at least 70% diplopia resolution. In some embodiments, the treatment results in at least 75% diplopia resolution.

[0014] In some embodiments, the diplopia resolution is achieved within 3 weeks from the first administration. In some embodiments, the diplopia resolution is achieved within 6 weeks from the first administration. In some embodiments, the diplopia resolution is achieved within 9 weeks from the first administration. In some embodiments, the diplopia resolution is achieved within 12 weeks from the first administration. In some embodiments, the diplopia resolution is achieved within 15 weeks from the first administration.

[0015] In some embodiments, the at least 30% diplopia resolution is achieved within 3 weeks from the first administration. In some embodiments, the at least 30% diplopia resolution is achieved within 6 weeks from the first administration. In some embodiments, the at least 30% diplopia resolution is achieved within 9 weeks from the first administration. In some embodiments, the at least 30% diplopia resolution is achieved within 12 weeks from the first administration. In some embodiments, the at least 30% diplopia resolution is achieved within 15 weeks from the first administration.

[0016] In some embodiments, the at least 35% diplopia resolution is achieved within 3 weeks from the first administration. In some embodiments, the at least 35% diplopia resolution is achieved within 6 weeks from the first administration. In some embodiments, the at least 35% diplopia resolution is achieved within 9 weeks from the first administration. In some embodiments, the at least 35% diplopia resolution is achieved within 12 weeks from the first administration. In some embodiments, the at least 35% diplopia resolution is achieved within 15 weeks from the first administration.

[0017] In some embodiments, the at least 40% diplopia resolution is achieved within 3 weeks from the first administration. In some embodiments, the at least 40% diplopia resolution is achieved within 6 weeks from the first administration. In some embodiments, the at least 40% diplopia resolution is achieved within 9 weeks from the first administration. In some embodiments, the at least 40% diplopia resolution is achieved within 12 weeks from 4 155110240v10Attorney Docket No. VRD-022WO1 the first administration. In some embodiments, the at least 40% diplopia resolution is achieved within 15 weeks from the first administration.

[0018] In some embodiments, the at least 42% diplopia resolution is achieved within 3 weeks from the first administration. In some embodiments, the at least 42% diplopia resolution is achieved within 6 weeks from the first administration. In some embodiments, the at least 42% diplopia resolution is achieved within 9 weeks from the first administration. In some embodiments, the at least 42% diplopia resolution is achieved within 12 weeks from the first administration. In some embodiments, the at least 42% diplopia resolution is achieved within 15 weeks from the first administration.

[0019] In some embodiments, the diplopia resolution is maintained for at least 6 weeks. In some embodiments, the diplopia resolution is maintained for at least 9 weeks. In some embodiments, the diplopia resolution is maintained for at least 12 weeks. In some embodiments, the diplopia resolution is maintained for at least 15 weeks. In some embodiments, the diplopia resolution is maintained for at least 18 weeks. In some embodiments, the diplopia resolution is maintained for at least 21 weeks. In some embodiments, the diplopia resolution is maintained for at least 24 weeks. In some embodiments, the diplopia resolution is maintained for at least 27 weeks. In some embodiments, the diplopia resolution is maintained for at least 30 weeks. In some embodiments, the diplopia resolution is maintained for at least 36 weeks. In some embodiments, the diplopia resolution is maintained for at least 52 weeks. In some embodiments, the diplopia resolution is maintained for at least 4 months. In some embodiments, the diplopia resolution is maintained for at least 5 months. In some embodiments, the diplopia resolution is maintained for at least 6 months. In some embodiments, the diplopia resolution is maintained for at least 7 months. In some embodiments, the diplopia resolution is maintained for at least 8 months. In some embodiments, the diplopia resolution is maintained for at least 9 months. In some embodiments, the diplopia resolution is maintained for at least 10 months. In some embodiments, the diplopia resolution is maintained for at least 12 months.

[0020] In some embodiments, the at least 30% diplopia resolution is maintained for at least 6 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 9 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 12 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for 5 155110240v10Attorney Docket No. VRD-022WO1 at least 15 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 18 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 21 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 24 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 27 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 30 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 36 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 52 weeks. In some embodiments, the at least 30% diplopia resolution is maintained for at least 4 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 5 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 6 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 7 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 8 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 9 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 10 months. In some embodiments, the at least 30% diplopia resolution is maintained for at least 12 months.

[0021] In some embodiments, the at least 35% diplopia resolution is maintained for at least 6 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 9 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 12 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 15 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 18 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 21 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 24 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 27 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 30 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 36 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 52 weeks. In some embodiments, the at least 35% diplopia resolution is maintained for at least 4 months. In some embodiments, the at least 35% diplopia resolution is maintained for at least 5 months. In some embodiments, the at least 35% diplopia resolution is maintained for at least 6 months. In 6 155110240v10Attorney Docket No. VRD-022WO1 some embodiments, the at least 35% diplopia resolution is maintained for at least 7 months. In some embodiments, the at least 35% diplopia resolution is maintained for at least 8 months. In some embodiments, the at least 35% diplopia resolution is maintained for at least 9 months. In some embodiments, the at least 35% diplopia resolution is maintained for at least 10 months. In some embodiments, the at least 35% diplopia resolution is maintained for at least 12 months.

[0022] In some embodiments, the at least 40% diplopia resolution is maintained for at least 6 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 9 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 12 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 15 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 18 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 21 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 24 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 27 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 30 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 36 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 52 weeks. In some embodiments, the at least 40% diplopia resolution is maintained for at least 4 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 5 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 6 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 7 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 8 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 9 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 10 months. In some embodiments, the at least 40% diplopia resolution is maintained for at least 12 months.

[0023] In some embodiments, the at least 50% diplopia resolution is maintained for at least 6 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 9 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 12 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 15 weeks. In some embodiments, the at least 50% diplopia resolution is maintained 7 155110240v10Attorney Docket No. VRD-022WO1 for at least 18 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 21 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 24 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 27 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 30 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 36 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 52 weeks. In some embodiments, the at least 50% diplopia resolution is maintained for at least 4 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 5 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 6 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 7 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 8 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 9 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 10 months. In some embodiments, the at least 50% diplopia resolution is maintained for at least 12 months.

[0024] In some embodiments, at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24. In some embodiments, at least 40% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24. In some embodiments, at least 50% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24. In some embodiments, at least 60% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24. In some embodiments, at least 70% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24. In some embodiments, at least 80% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24.

[0025] In some embodiments, at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36. In some embodiments, at least 40% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36. In some embodiments, at least 50% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36. In some embodiments, at least 60% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36. In some embodiments, at least 70% of patients achieving diplopia resolution at week 15 maintain 8 155110240v10Attorney Docket No. VRD-022WO1 diplopia resolution at week 36. In some embodiments, at least 80% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36.

[0026] In some embodiments, at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52. In some embodiments, at least 40% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52. In some embodiments, at least 50% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52. In some embodiments, at least 60% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52. In some embodiments, at least 70% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52. In some embodiments, at least 80% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52.

[0027] In some embodiments, the % diplopia resolution is a placebo-adjusted value. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of >0. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 1. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 2. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 3.

[0028] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0029] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm 9 155110240v10Attorney Docket No. VRD-022WO1 from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0030] In some embodiments, the treatment results in at least 40% proptosis responder rate. In some embodiments, the treatment results in at least 50% proptosis responder rate. In some embodiments, the treatment results in at least 55% proptosis responder rate. In some embodiments, the treatment results in at least 60% proptosis responder rate. In some embodiments, the treatment results in at least 65% proptosis responder rate. In some embodiments, the treatment results in at least 70% proptosis responder rate. In some embodiments, the treatment results in at least 75% proptosis responder rate.

[0031] In some embodiments, the proptosis responder rate is achieved within 3 weeks from the first administration. In some embodiments, the proptosis responder rate is achieved within 6 weeks from the first administration. In some embodiments, the proptosis responder rate is achieved within 9 weeks from the first administration. In some embodiments, the proptosis responder rate is achieved within 12 weeks from the first administration. In some embodiments, the proptosis responder rate is achieved within 15 weeks from the first administration.

[0032] In some embodiments, the at least 40% proptosis responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 40% proptosis responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 40% proptosis responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 40% proptosis responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 40% proptosis responder rate is achieved within 15 weeks from the first administration.

[0033] In some embodiments, the at least 45% proptosis responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 45% proptosis responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 45% proptosis responder rate is achieved within 9 weeks from the 10 155110240v10Attorney Docket No. VRD-022WO1 first administration. In some embodiments, the at least 45% proptosis responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 45% proptosis responder rate is achieved within 15 weeks from the first administration.

[0034] In some embodiments, the at least 50% proptosis responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 50% proptosis responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 50% proptosis responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 50% proptosis responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 50% proptosis responder rate is achieved within 15 weeks from the first administration.

[0035] In some embodiments, the at least 55% proptosis responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 55% proptosis responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 55% proptosis responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 55% proptosis responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 55% proptosis responder rate is achieved within 15 weeks from the first administration.

[0036] In some embodiments, the at least 60% proptosis responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 60% proptosis responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 60% proptosis responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 60% proptosis responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 60% proptosis responder rate is achieved within 15 weeks from the first administration.

[0037] In some embodiments, the proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the proptosis responder rate is maintained for at least 27 weeks. In some 11 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the proptosis responder rate is maintained for at least 4 months. In some embodiments, the proptosis responder rate is maintained for at least 5 months. In some embodiments, the proptosis responder rate is maintained for at least 6 months. In some embodiments, the proptosis responder rate is maintained for at least 7 months. In some embodiments, the proptosis responder rate is maintained for at least 8 months. In some embodiments, the proptosis responder rate is maintained for at least 9 months. In some embodiments, the proptosis responder rate is maintained for at least 10 months. In some embodiments, the proptosis responder rate is maintained for at least 12 months.

[0038] In some embodiments, the at least 30% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 6 months. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 8 months. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 30% proptosis responder rate is 12 155110240v10Attorney Docket No. VRD-022WO1 maintained for at least 10 months. In some embodiments, the at least 30% proptosis responder rate is maintained for at least 12 months.

[0039] In some embodiments, the at least 35% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 6 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 8 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 10 months. In some embodiments, the at least 35% proptosis responder rate is maintained for at least 12 months.

[0040] In some embodiments, the at least 45% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 24 weeks. 13 155110240v10Attorney Docket No. VRD-022WO1 In some embodiments, the at least 45% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 6 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 8 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 10 months. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 12 months.

[0041] In some embodiments, the at least 50% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 6 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 8 14 155110240v10Attorney Docket No. VRD-022WO1 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 10 months. In some embodiments, the at least 50% proptosis responder rate is maintained for at least 12 months.

[0042] In some embodiments, the at least 55% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 6 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 8 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 10 months. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 12 months.

[0043] In some embodiments, the at least 60% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at 15 155110240v10Attorney Docket No. VRD-022WO1 least 60% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 6 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 8 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 10 months. In some embodiments, the at least 60% proptosis responder rate is maintained for at least 12 months.

[0044] In some embodiments, the at least 70% proptosis responder rate is maintained for at least 6 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 9 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 12 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 15 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 18 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 21 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 24 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 27 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 30 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 36 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 4 months. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 5 months. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 6 months. In some 16 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the at least 70% proptosis responder rate is maintained for at least 7 months. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 8 months. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 9 months. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 10 months. In some embodiments, the at least 70% proptosis responder rate is maintained for at least 12 months.

[0045] In some embodiments, at least 30% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 35% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 40% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 45% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 50% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 55% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 60% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 65% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 75% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 85% of week 15 proptosis responders maintained a proptosis response at week 52.

[0046] In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 55% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 60% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 35% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 40% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 45% of week 15 proptosis responders maintained a proptosis response at week 24. In some 17 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the proptosis responder rate at week 15 is at least 50% and at least 55% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 60% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 65% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 24.

[0047] In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 55% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 60% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 35% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 40% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 45% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 55% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 60% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 65% of week 15 proptosis responders maintained a proptosis response at week 36. In some 18 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 36.

[0048] In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 55% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 60% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 35% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 40% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 45% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 55% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 60% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 65% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 52. In some 19 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the proptosis responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 52.

[0049] In some embodiments, the % proptosis responder rate is a placebo-adjusted value.

[0050] In some embodiments, the baseline proptosis is the proptosis measurement prior to the first administration.

[0051] In some embodiments, the patient had a baseline proptosis of ≥ 16 mm. In some embodiments, the patient had a baseline proptosis of ≥ 17 mm. In some embodiments, the patient had a baseline proptosis of between 17 mm and 33 mm. I n some embodiments, the patient had a baseline proptosis of between 16 mm and 30 mm. In some embodiments, the patient had a baseline proptosis of between 15 mm and 28 mm.

[0052] In some embodiments, the patient had a baseline proptosis of 20 mm. In some embodiments, the patient had a baseline proptosis of 21 mm. In some embodiments, the patient had a baseline proptosis of 22 mm. In some embodiments, the patient had baseline proptosis of 23 mm. In some embodiments, the patient had a baseline proptosis of 24 mm. In some embodiments, the patient had a baseline proptosis of 25 mm.

[0053] In some embodiments, the patient had a baseline proptosis of at least 20 mm. In some embodiments, the patient had a baseline proptosis of less than 20 mm.

[0054] In some embodiments, the treatment results in the reduction of proptosis of ≥1.0 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥1.5 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥2.0 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥2.5 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥3.0 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥3.5 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥4.0 mm from the baseline. In some embodiments, the treatment results in the reduction of proptosis of ≥4.5 mm from the baseline.

[0055] In some embodiments, proptosis is measured by exophthalmometer. In some embodiments, proptosis is measured by hertel exophthalmometer. In some embodiments, proptosis is measured by imaging. In some embodiments, the imaging is magnetic resonance imaging (MRI). In some embodiments, the imaging is computed tomography (CT). In some 20 155110240v10Attorney Docket No. VRD-022WO1 embodiments, proptosis is measured by magnetic resonance imaging (MRI). In some embodiments, proptosis is measured by computed tomography (CT).

[0056] In some embodiments, the treatment results in hearing impairment incidence of less than 20%. In some embodiments, the treatment results in hearing impairment incidence of less than 18%. In some embodiments, the treatment results in hearing impairment incidence of less than 16%. In some embodiments, the treatment results in hearing impairment incidence of less than 15%. In some embodiments, the treatment results in hearing impairment incidence of less than 12%. In some embodiments, the treatment results in hearing impairment incidence of less than 10%. In some embodiments, the treatment results in hearing impairment incidence of less than 8%. In some embodiments, the treatment results in hearing impairment incidence of less than 6%. In some embodiments, the treatment results in hearing impairment incidence of less than 5.5%. In some embodiments, the treatment results in hearing impairment incidence of less than 5%. In some embodiments, the treatment results in hearing impairment incidence of less than 4%. In some embodiments, the treatment does not result in hearing impairment incidence.

[0057] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to reduce one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6.

[0058] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to reduce one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain 21 155110240v10Attorney Docket No. VRD-022WO1 and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0059] In some embodiments, the hearing impairment is less than 15%. In some embodiments, the hearing impairment is less than 12%. In some embodiments, the hearing impairment is less than 10%. In some embodiments, the hearing impairment is less than 8%. In some embodiments, the hearing impairment is less than 7%. In some embodiments, the hearing impairment is less than 6%. In some embodiments, the hearing impairment is less than 5%. In some embodiments, the hearing impairment is less than 4%. In some embodiments, the hearing impairment is less than 3%. In some embodiments, the hearing impairment is less than 2%. In some embodiments, the hearing impairment is less than 1%.

[0060] In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 12 weeks.

[0061] In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 6 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 9 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 12 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 15 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 18 weeks. In some embodiments, hearing impairment incidence of less than 15% is maintained for at least 21 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 24 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 27 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 30 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 36 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 52 weeks. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 4 months. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 5 months. In some embodiments, the hearing impairment incidence of 22 155110240v10Attorney Docket No. VRD-022WO1 less than 15% is maintained for at least 6 months. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 7 months. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 8 months. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 9 months. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 10 months. In some embodiments, the hearing impairment incidence of less than 15% is maintained for at least 12 months.

[0062] In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 6 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 9 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 12 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 15 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 18 weeks. In some embodiments, hearing impairment incidence of less than 10% is maintained for at least 21 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 24 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 27 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 30 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 36 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 52 weeks. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 4 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 5 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 6 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 7 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 8 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 9 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 10 months. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 12 months. 23 155110240v10Attorney Docket No. VRD-022WO1

[0063] In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 6 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 9 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 12 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 15 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 18 weeks. In some embodiments, hearing impairment incidence of less than 6% is maintained for at least 21 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 24 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 27 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 30 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 36 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 52 weeks. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 4 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 5 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 6 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 7 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 8 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 9 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 10 months. In some embodiments, the hearing impairment incidence of less than 6% is maintained for at least 12 months.

[0064] In some embodiments, the % of hearing impairment incidence is a placebo- adjusted value.

[0065] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED), comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light 24 155110240v10Attorney Docket No. VRD-022WO1 chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0066] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED), comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0067] In some embodiments, the treatment results in at least 25% CAS responder rate. In some embodiments, the treatment results in at least 30% CAS responder rate. In some embodiments, the treatment results in at least 35% CAS responder rate. In some embodiments, the treatment results in at least 40% CAS responder rate. In some embodiments, the treatment results in at least 45% CAS responder rate. In some embodiments, the treatment results in at least 50% CAS responder rate. In some embodiments, the treatment results in at least 55% CAS responder rate. In some embodiments, the treatment results in at least 60% CAS responder rate. In some embodiments, the treatment results in at least 65% CAS responder rate.

[0068] In some embodiments, the at least 25% CAS responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 25% CAS responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 25% CAS responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 25% CAS responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 25% CAS responder rate is achieved within 15 weeks from the first administration. 25 155110240v10Attorney Docket No. VRD-022WO1

[0069] In some embodiments, the at least 30% CAS responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 30% CAS responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 30% CAS responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 30% CAS responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 30% CAS responder rate is achieved within 15 weeks from the first administration.

[0070] In some embodiments, the at least 35% CAS responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 35% CAS responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 35% CAS responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 35% CAS responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 35% CAS responder rate is achieved within 15 weeks from the first administration.

[0071] In some embodiments, the at least 50% CAS responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 50% CAS responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 50% CAS responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 50% CAS responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 50% CAS responder rate is achieved within 15 weeks from the first administration.

[0072] In some embodiments, the at least 60% CAS responder rate is achieved within 3 weeks from the first administration. In some embodiments, the at least 60% CAS responder rate is achieved within 6 weeks from the first administration. In some embodiments, the at least 60% CAS responder rate is achieved within 9 weeks from the first administration. In some embodiments, the at least 60% CAS responder rate is achieved within 12 weeks from the first administration. In some embodiments, the at least 60% CAS responder rate is achieved within 15 weeks from the first administration.

[0073] In some embodiments, the at least 30% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 30% CAS responder rate 26 155110240v10Attorney Docket No. VRD-022WO1 is maintained for at least 15 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 18 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 21 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 30% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 6 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 7 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 30% CAS responder rate is maintained for at least 12 months.

[0074] In some embodiments, the at least 35% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 15 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 18 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 21 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 35% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 6 27 155110240v10Attorney Docket No. VRD-022WO1 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 7 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 35% CAS responder rate is maintained for at least 12 months.

[0075] In some embodiments, the at least 50% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 15 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 18 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 21 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 50% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 6 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 7 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 50% CAS responder rate is maintained for at least 12 months.

[0076] In some embodiments, the at least 60% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 15 weeks. In some embodiments, the at least 60% CAS responder 28 155110240v10Attorney Docket No. VRD-022WO1 rate is maintained for at least 18 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 21 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 60% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 6 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 7 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 60% CAS responder rate is maintained for at least 12 months.

[0077] In some embodiments, the at least 70% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 15 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 18 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 21 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 70% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 6 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 29 155110240v10Attorney Docket No. VRD-022WO1 7 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 70% CAS responder rate is maintained for at least 12 months.

[0078] In some embodiments, the at least 80% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 15 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 18 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 21 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 80% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 6 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 7 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 80% CAS responder rate is maintained for at least 12 months.

[0079] In some embodiments, the at least 90% CAS responder rate is maintained for at least 6 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 9 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 12 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 15 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 18 weeks. In some embodiments, the at least 90% CAS 30 155110240v10Attorney Docket No. VRD-022WO1 responder rate is maintained for at least 21 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 24 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 27 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 30 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 36 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 52 weeks. In some embodiments, the at least 90% CAS responder rate is maintained for at least 4 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 5 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 6 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 7 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 8 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 9 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 10 months. In some embodiments, the at least 90% CAS responder rate is maintained for at least 12 months.

[0080] In some embodiments, at least 50% of CAS responders at week 15 maintained a CAS response at week 24. In some embodiments, at least 60% of CAS responders at week 15 maintained a CAS response at week 24. In some embodiments, at least 70% of CAS responders maintained a CAS response at week 24. In some embodiments, at least 75% of CAS responders maintained a CAS response at week 24. In some embodiments, at least 80% of CAS responders maintained a CAS response at week 24. In some embodiments, at least 85% of CAS responders maintained a CAS response at week 24. In some embodiments, at least 90% of CAS responders maintained a CAS response at week 24.

[0081] In some embodiments, at least 50% of CAS responders at week 15 maintained a CAS response at week 36. In some embodiments, at least 60% of CAS responders at week 15 maintained a CAS response at week 36. In some embodiments, at least 70% of CAS responders maintained a CAS response at week 36. In some embodiments, at least 75% of CAS responders maintained a CAS response at week 36. In some embodiments, at least 80% of CAS responders maintained a CAS response at week 36. In some embodiments, at least 85% of CAS responders maintained a CAS response at week 36. In some embodiments, at least 90% of CAS responders maintained a CAS response at week 36. 31 155110240v10Attorney Docket No. VRD-022WO1

[0082] In some embodiments, at least 50% of CAS responders at week 15 maintained a CAS response at week 52. In some embodiments, at least 60% of CAS responders at week 15 maintained a CAS response at week 52. In some embodiments, at least 70% of CAS responders maintained a CAS response at week 52. In some embodiments, at least 75% of CAS responders maintained a CAS response at week 52. In some embodiments, at least 80% of CAS responders maintained a CAS response at week 52. In some embodiments, at least 85% of CAS responders maintained a CAS response at week 52. In some embodiments, at least 90% of CAS responders maintained a CAS response at week 52.

[0083] In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 80% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 95% of week 15 proptosis responders maintained a proptosis response at week 52.

[0084] In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 80% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 24. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 95% of week 15 proptosis responders maintained a proptosis response at week 24. 32 155110240v10Attorney Docket No. VRD-022WO1

[0085] In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 80% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 36. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 95% of week 15 proptosis responders maintained a proptosis response at week 36.

[0086] In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 80% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the CAS responder rate at week 15 is at least 50% and at least 95% of week 15 proptosis responders maintained a proptosis response at week 52.

[0087] In some embodiments, the treatment results in a reduction of CAS of ≥1.5 from a baseline in the study eye. In some embodiments, the treatment results in a reduction of CAS of ≥2.0 from a baseline in the study eye. In some embodiments, the treatment results in a reduction of CAS of ≥2.5 from a baseline in the study eye. In some embodiments, the treatment results in a reduction of CAS of ≥3.0 from a baseline in the study eye. In some embodiments, the treatment results in a reduction of CAS of ≥3.5 from a baseline in the study eye. In some embodiments, the treatment results in a reduction of CAS of ≥4.5 from a baseline in the study eye. 33 155110240v10Attorney Docket No. VRD-022WO1

[0088] In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 6 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 9 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 12 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 15 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 18 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 21 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 24 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 27 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 30 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 36 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 52 weeks. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 4 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 5 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 6 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 7 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 8 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 9 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 10 months. In some embodiments, the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 12 months.

[0089] In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 6 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 9 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 12 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 15 weeks. In some embodiments, the reduction of CAS of ≥3 from a 34 155110240v10Attorney Docket No. VRD-022WO1 baseline in the study eye is maintained for at least 18 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 21 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 24 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 27 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 30 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 36 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 52 weeks. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 4 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 5 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 6 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 7 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 8 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 9 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 10 months. In some embodiments, the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 12 months.

[0090] In some embodiments, the patient has a baseline CAS of 0-7. In some embodiments, the patient has a baseline CAS of 0. In some embodiments, the patient has a baseline CAS of 1. In some embodiments, the patient has a baseline CAS of 2. In some embodiments, the patient has a baseline CAS of 3. In some embodiments, the patient has a baseline CAS of 4. In some embodiments, the patient has a baseline CAS of 5. In some embodiments, the patient has a baseline CAS of 6. In some embodiments, the patient has a baseline CAS of 7.

[0091] In some embodiments, the patient has a baseline CAS of ≥ 1. In some embodiments, the patient has a baseline CAS of ≥ 2. In some embodiments, the patient has a baseline CAS of ≥ 3. In some embodiments, the patient has a baseline CAS of ≥ 4. In some embodiments, the patient has a baseline CAS of ≥ 5. In some embodiments, the patient has a baseline CAS of ≥ 6. 35 155110240v10Attorney Docket No. VRD-022WO1

[0092] In some embodiments, the treatment results in at least 15% clinical activity responder rate. In some embodiments, the treatment results in at least 20% clinical activity responder rate. In some embodiments, the treatment results in at least 25% clinical activity responder rate. In some embodiments, the treatment results in at least 30% clinical activity responder rate. In some embodiments, the treatment results in at least 35% clinical activity responder rate. In some embodiments, the treatment results in at least 40% clinical activity responder rate. In some embodiments, the treatment results in at least 45% clinical activity responder rate. In some embodiments, the treatment results in at least 50% clinical activity responder rate. In some embodiments, the treatment results in at least 55% clinical activity responder rate. In some embodiments, the treatment results in at least 60% clinical activity responder rate. In some embodiments, the treatment results in at least 65% clinical activity responder rate. In some embodiments, the treatment results in at least 70% clinical activity responder rate. In some embodiments, the treatment results in at least 75% clinical activity responder rate.

[0093] In some embodiments, the treatment results in at least 20% diplopia responder rate within 3 weeks of the first administration. In some embodiments, the treatment results in at least 20% diplopia responder rate within 6 weeks of the first administration. In some embodiments, the treatment results in at least 20% diplopia responder rate within 9 weeks of the first administration. In some embodiments, the treatment results in at least 20% diplopia responder rate within 12 weeks of the first administration. In some embodiments, the treatment results in at least 20% diplopia responder rate within 15 weeks of the first administration.

[0094] In some embodiments, the treatment results in at least 25% diplopia responder rate within 3 weeks of the first administration. In some embodiments, the treatment results in at least 25% diplopia responder rate within 6 weeks of the first administration. In some embodiments, the treatment results in at least 25% diplopia responder rate within 9 weeks of the first administration. In some embodiments, the treatment results in at least 25% diplopia responder rate within 12 weeks of the first administration. In some embodiments, the treatment results in at least 25% diplopia responder rate within 15 weeks of the first administration.

[0095] In some embodiments, the treatment results in at least 30% diplopia responder rate within 3 weeks of the first administration. In some embodiments, the treatment results in 36 155110240v10Attorney Docket No. VRD-022WO1 at least 30% diplopia responder rate within 6 weeks of the first administration. In some embodiments, the treatment results in at least 30% diplopia responder rate within 9 weeks of the first administration. In some embodiments, the treatment results in at least 30% diplopia responder rate within 12 weeks of the first administration. In some embodiments, the treatment results in at least 30% diplopia responder rate within 15 weeks of the first administration.

[0096] In some embodiments, the treatment results in at least 35% diplopia responder rate within 3 weeks of the first administration. In some embodiments, the treatment results in at least 35% diplopia responder rate within 6 weeks of the first administration. In some embodiments, the treatment results in at least 35% diplopia responder rate within 9 weeks of the first administration. In some embodiments, the treatment results in at least 35% diplopia responder rate within 12 weeks of the first administration. In some embodiments, the treatment results in at least 35% diplopia responder rate within 15 weeks of the first administration.

[0097] In some embodiments, the treatment results in at least 40% diplopia responder rate within 3 weeks of the first administration. In some embodiments, the treatment results in at least 40% diplopia responder rate within 6 weeks of the first administration. In some embodiments, the treatment results in at least 40% diplopia responder rate within 9 weeks of the first administration. In some embodiments, the treatment results in at least 40% diplopia responder rate within 12 weeks of the first administration. In some embodiments, the treatment results in at least 20% diplopia responder rate within 15 weeks of the first administration.

[0098] In some embodiments, the treatment results in at least 20% diplopia responder rate. In some embodiments, the treatment results in at least 25% diplopia responder rate. In some embodiments, the treatment results in at least 30% diplopia responder rate. In some embodiments, the treatment results in at least 35% diplopia responder rate. In some embodiments, the treatment results in at least 40% diplopia responder rate. In some embodiments, the treatment results in at least 45% diplopia responder rate. In some embodiments, the treatment results in at least 50% diplopia responder rate. In some embodiments, the treatment results in at least 55% diplopia responder rate. In some embodiments, the treatment results in at least 60% diplopia responder rate. In some embodiments, the treatment results in at least 65% diplopia responder rate. In some 37 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the treatment results in at least 70% diplopia responder rate. In some embodiments, the treatment results in at least 75% diplopia responder rate. In some embodiments, the treatment results in at least 80% diplopia responder rate.

[0099] In some embodiments, at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 40% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 50% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 60% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 70% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 75% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 80% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 85% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 90% of patients achieving diplopia response at week 15 maintain diplopia response at week 24.

[0100] In some embodiments, at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 40% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 50% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 60% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 70% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 75% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 80% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 85% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 90% of patients achieving diplopia response at week 15 maintain diplopia response at week 36.

[0101] In some embodiments, at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 40% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In 38 155110240v10Attorney Docket No. VRD-022WO1 some embodiments, at least 50% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 60% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 70% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 75% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 80% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 85% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 90% of patients achieving diplopia response at week 15 maintain diplopia response at week 52.

[0102] In some embodiments, the treatment results in at least 1.5 mm reduction from baseline in proptosis within 3 weeks of the first administration. In some embodiments, the treatment results in at least 1.5 mm reduction from baseline in proptosis within 6 weeks of the first administration. In some embodiments, the treatment results in at least 1.5 mm reduction from baseline in proptosis within 9 weeks of the first administration. In some embodiments, the treatment results in at least 1.5 mm reduction from baseline in proptosis within 12 weeks of the first administration. In some embodiments, the treatment results in at least 1.5 mm reduction from baseline in proptosis within 15 weeks of the first administration.

[0103] In some embodiments, the treatment results in at least 2.0 mm reduction from baseline in proptosis within 3 weeks of the first administration. In some embodiments, the treatment results in at least 2.0 mm reduction from baseline in proptosis within 6 weeks of the first administration. In some embodiments, the treatment results in at least 2.0 mm reduction from baseline in proptosis within 9 weeks of the first administration. In some embodiments, the treatment results in at least 2.0 mm reduction from baseline in proptosis within 12 weeks of the first administration. In some embodiments, the treatment results in at least 2.0 mm reduction from baseline in proptosis within 15 weeks of the first administration.

[0104] In some embodiments, the treatment results in at least 2.5 mm reduction from baseline in proptosis within 3 weeks of the first administration. In some embodiments, the treatment results in at least 2.5 mm reduction from baseline in proptosis within 6 weeks of the first administration. In some embodiments, the treatment results in at least 2.5 mm reduction from baseline in proptosis within 9 weeks of the first administration. In some embodiments, the treatment results in at least 2.5 mm reduction from baseline in proptosis within 12 weeks 39 155110240v10Attorney Docket No. VRD-022WO1 of the first administration. In some embodiments, the treatment results in at least 2.5 mm reduction from baseline in proptosis within 15 weeks of the first administration.

[0105] In some embodiments, the treatment results in at least 3.0 mm reduction from baseline in proptosis within 3 weeks of the first administration. In some embodiments, the treatment results in at least 3.0 mm reduction from baseline in proptosis within 6 weeks of the first administration. In some embodiments, the treatment results in at least 3.0 mm reduction from baseline in proptosis within 9 weeks of the first administration. In some embodiments, the treatment results in at least 3.0 mm reduction from baseline in proptosis within 12 weeks of the first administration. In some embodiments, the treatment results in at least 3.0 mm reduction from baseline in proptosis within 15 weeks of the first administration.

[0106] In some embodiments, the treatment results in CAS of 0 or 1 in the study eye. In some embodiments, the treatment results in CAS of 0 in the study eye. In some embodiments, the treatment results in CAS of 1 in the study eye.

[0107] In some embodiments, the treatment period is at least 6 weeks. In some embodiments, the treatment period is at least 9 weeks. In some embodiments, the treatment period is at least 12 weeks. In some embodiments, the treatment period is at least 15 weeks. In some embodiments, the treatment period is at least 18 weeks. In some embodiments, the treatment period is at least 21 weeks. In some embodiments, the treatment period is at least 24 weeks.

[0108] In some embodiments, the treatment period is 6 weeks. In some embodiments, the treatment period is 9 weeks. In some embodiments, the treatment period is 12 weeks. In some embodiments, the treatment period is 15 weeks. In some embodiments, the treatment period is 18 weeks. In some embodiments, the treatment period is 21 weeks. In some embodiments, the treatment period is 24 weeks.

[0109] In some embodiments, the treatment period is no more than 24 weeks. In some embodiments, the treatment period is no more than 21 weeks. In some embodiments, the treatment period is no more than 18 weeks. In some embodiments, the treatment period is no more than 15 weeks.

[0110] In some embodiments, the patient does not have hearing impairment prior to the treatment. In some embodiments, the patient has hearing impairment prior to treatment.

[0111] In some embodiments, the e patient, prior to treatment, had proptosis of ≥1 mm above normal values for race and gender. In some embodiments, the e patient, prior to 40 155110240v10Attorney Docket No. VRD-022WO1 treatment, had proptosis of ≥2 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of ≥3 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of ≥4 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of ≥5 mm above normal values for race and gender.

[0112] In some embodiments, the patient had a CAS of ≥1 prior to treatment. In some embodiments, the patient had a CAS of ≥2 prior to treatment. In some embodiments, the patient had a CAS of ≥3 prior to treatment. In some embodiments, the patient had a CAS of ≥4 prior to treatment. In some embodiments, the patient had a CAS of ≥5 prior to treatment. In some embodiments, the patient had a CAS of ≥6 prior to treatment. In some embodiments, the patient had a CAS of ≥7 prior to treatment.

[0113] In some embodiments, the patient, prior to treatment, had lid retraction of ≥1 mm. In some embodiments, the patient, prior to treatment, had lid retraction of ≥2 mm. In some embodiments, the patient, prior to treatment, had lid retraction of ≥3 mm. In some embodiments, the patient, prior to treatment, had lid retraction of ≥4 mm. In some embodiments, the patient, prior to treatment, had lid retraction of ≥5 mm. In some embodiments, the patient, prior to treatment, had lid retraction of ≥6 mm.

[0114] In some embodiments, the patient, prior to treatment, had moderate or severe soft tissue involvement. In some embodiments, the patient, prior to treatment, had soft tissue involvement. In some embodiments, the patient, prior to treatment, had severe soft tissue involvement.

[0115] In some embodiments, patient, prior to treatment, had periodic or constant diplopia.

[0116] In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 9 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 10 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 11 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 12 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 13 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 14 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 15 months. In some 41 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the patient has had documented signs and symptoms of TED for no longer than 16 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 17 months. In some embodiments, the patient has had documented signs and symptoms of TED for no longer than 18 months.

[0117] In some embodiments, the patient has had documented signs and symptoms of TED for less than 15 months. In some embodiments, the patient has had documented signs and symptoms of TED for less than 12 months. In some embodiments, the patient has had documented signs and symptoms of TED for less than 10 months. In some embodiments, the patient has had documented signs and symptoms of TED for less than 9 months.

[0118] In some embodiments, the treatment results in low incidence of anti-drug antibody (ADA).

[0119] In some embodiments, the treatment results in substantially no incidence of anti-drug antibody (ADA) as compared to placebo.

[0120] In some embodiments, the anti-IGF-1R antibody comprises a heavy chain variable region (VH) of SEQ ID NO: 3, and a light chain variable region (VL) of SEQ ID NO: 2.

[0121] In some embodiments, the anti-IGF-1R antibody comprises a heavy chain of SEQ ID NO: 10, and a light chain of SEQ ID NO: 11.

[0122] In some embodiments, the anti-IGF-1R antibody comprises a heavy chain of SEQ ID NO: 14, and a light chain of SEQ ID NO: 15.

[0123] In some embodiments, the patient is at least 18 years of age or older.

[0124] In some embodiments, the patient had not received prior treatment with another anti-IGF-1R therapy. In some embodiments, the patient received prior treatment with another anti-IGF-1R therapy.

[0125] In some embodiments, the patient, prior to the treatment, did not have a compressive optic neuropathy of TED that is expected to require surgical decompression in the immediate future.

[0126] In some embodiments, the patient, prior to the treatment, did not have corneal decompensation in the study eye unresponsive to medical management.

[0127] In some embodiments, the patient did not have a decrease in CAS of ≥2 points in the study eye between screening assessment and Day -1 42 155110240v10Attorney Docket No. VRD-022WO1

[0128] In some embodiments, the patient did not a decrease in proptosis of ≥2 mm in the study eye between screening assessment and Day -1.

[0129] In some embodiments, the patent, prior to the treatment, have not had previous orbital irradiation or decompression surgery involving excision of fat for TED to the study eye’s orbit.

[0130] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0131] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment results in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0132] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment results in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid 43 155110240v10Attorney Docket No. VRD-022WO1 sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0133] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment results in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0134] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0135] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 44 155110240v10Attorney Docket No. VRD-022WO1 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0136] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0137] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0138] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to reduce one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) 45 155110240v10Attorney Docket No. VRD-022WO1 having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0139] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment reduces one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0140] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment reduces one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0141] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment reduces one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and 46 155110240v10Attorney Docket No. VRD-022WO1 a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0142] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED), comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0143] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED), comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0144] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED), comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 47 155110240v10Attorney Docket No. VRD-022WO1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0145] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED), comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0146] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0147] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment results in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a 48 155110240v10Attorney Docket No. VRD-022WO1 LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0148] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment results in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0149] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment results in at least 35% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6.

[0150] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an 49 155110240v10Attorney Docket No. VRD-022WO1 amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0151] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0152] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0153] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 50 155110240v10Attorney Docket No. VRD-022WO1 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0154] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to reduce one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0155] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment reduces one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0156] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment reduces one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a 51 155110240v10Attorney Docket No. VRD-022WO1 LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0157] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment reduces one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0158] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED), comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0159] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED), comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 12 weeks, wherein the treatment results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of 52 155110240v10Attorney Docket No. VRD-022WO1 SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0160] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED), comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 15 weeks, wherein the treatment results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0161] In one aspect, the present invention provides, among other things, a method of treating active thyroid eye disease (TED), comprising administering to a patient an anti-IGF- 1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for at least 24 weeks, wherein the treatment results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0162] In some embodiments, administering an anti-IGF-1R antibody to a patient results in an improvement in orbital fat volume. In some embodiments, administering an anti-IGF-1R antibody to a patient results in an improvement in orbital fat volume as compared to a baseline. In some embodiments, orbital fat volume is determined using MRI or CT.

[0163] In some embodiments, administering an anti-IGF-1R antibody to a patient results in an improvement in extraocular muscle volume. In some embodiments, administering an anti-IGF-1R antibody to a patient results in an improvement in extraocular 53 155110240v10Attorney Docket No. VRD-022WO1 muscle volume as compared to a baseline. In some embodiments, extraocular muscle volume is determined using MRI or CT.

[0164] In one aspects, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in a reduction in orbital fat volume as compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0165] In one aspects, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in a reduction in extraocular muscle volume as compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0166] In one aspects, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in a reduction in orbital fat volume as compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6. 54 155110240v10Attorney Docket No. VRD-022WO1

[0167] In one aspects, the present invention provides, among other things, a method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in a reduction in extraocular muscle volume as compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0168] In some embodiments, the orbital fat volume is reduced by at least 100 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 200 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 300 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 400 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 600 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 700 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 800 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 900 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 1,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 1,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least ,3500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5,500 µL as compared to a baseline. In some embodiments, the orbital 55 155110240v10Attorney Docket No. VRD-022WO1 fat volume is reduced by at least 6,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 6,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 10,000 µL as compared to a baseline.

[0169] In some embodiments, the extraocular muscle volume is reduced by at least 500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 2000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 2500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 6000 µL as compared to a baseline.

[0170] In some embodiments, the baseline is a value prior to the administration of the anti-IGF-1R antibody. In some embodiments, the baseline is a patient without the administration of the anti-IGF-1R antibody. In some embodiments, the baseline is a historical data of the same disease condition. 56 155110240v10Attorney Docket No. VRD-022WO1

[0171] In some embodiments, the method comprises administering the anti-IGF-1R antibody at a first dose of 10 mg / kg and at least four subsequent doses of 10 mg / kg every three weeks.

[0172] In some embodiments, the method comprises administering the anti-IGF-1R antibody at a first dose of 3 mg / kg and at least four subsequent doses of 3 mg / kg every three weeks.

[0173] In some embodiments, the method comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and four subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks.

[0174] In some embodiments, the method comprises administering a first dose of the anti-IGF-1R antibody at 3 mg / kg and four subsequent doses of the anti-IGF-1R antibody at 3 mg / kg every three weeks.

[0175] In some embodiments, the method comprises administering the anti-IGF-1R antibody to the patient at a total dose of 15 mg / kg.

[0176] In some embodiments, the method comprises administering the anti-IGF-1R antibody to the patient at a total dose of 50 mg / kg.

[0177] In some embodiments, the method comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and seven subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks.

[0178] In some embodiments, the method comprises administering the anti-IGF-1R antibody to the patient at a total dose of 80 mg / kg.

[0179] In some embodiments, a method further comprises administering magnesium to the subject. In some embodiments, the magnesium is administered prior to the administration of the anti-IGF-1R antibody. In some embodiments, the magnesium is administered during the administration of the anti-IGF-1R antibody. In some embodiments, the magnesium is administered after the administration of the anti-IGF-1R antibody. In some embodiments, the magnesium is administered 1-2 days prior to subsequent administration of the anti-IGF-1R antibody.

[0180] In some embodiments, the magnesium is administered at a dose of 100-1000 mg. In some embodiments, the magnesium is administered at a dose of 200-800 mg. In some embodiments, the magnesium is administered at a dose of 200-600 mg. In some embodiments, the magnesium is administered at a dose of 300-500 mg. In some 57 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the magnesium is administered at a dose of 300 mg. In some embodiments, the magnesium is administered at a dose of 400 mg. In some embodiments, the magnesium is administered at a dose of 500 mg. In some embodiments, the magnesium is administered orally.

[0181] In some embodiments, the method comprises treating active TED.

[0182] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to at least ≥8 point improvement in GO-QOL score as compared to baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0183] In some embodiments, the improvement in GO-QOL score is in GO-QOL combined score. In some embodiments, the improvement in GO-QOL score is in GO-QOL activity subscale score. In some embodiments, the improvement in GO-QOL score is in GO- QOL appearance subscale score. In some embodiments, the improvement in GO-QOL score is in GO-QOL combined score, activity subscale score, and appearance subscale score. In some embodiments, a patient has a GO-QOL combined score of ≤92 at baseline. In some embodiments, a method results in a ≥8 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥10 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥12 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥14 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥16 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥18 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥20 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥30 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results 58 155110240v10Attorney Docket No. VRD-022WO1 in a ≥40 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥50 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥60 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥70 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥80 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a ≥90 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL combined score as compared to baseline.

[0184] In some embodiments, a patient has a GO-QOL activity subscale score of ≤92 at baseline. In some embodiments, a method results in a ≥8 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥10 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥12 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥14 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥16 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥18 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥20 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥30 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥40 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥50 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥60 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥70 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥80 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a ≥90 point improvement in GO-QOL activity subscale score as compared to baseline. In some 59 155110240v10Attorney Docket No. VRD-022WO1 embodiments, a method results in a 100 point improvement in GO-QOL activity subscale score as compared to baseline.

[0185] In some embodiments, a patient has a GO-QOL appearance subscale score of ≤92 at baseline. In some embodiments, a method results in a ≥8 point improvement in GO- QOL appearance subscale score. In some embodiments, a method results in a ≥10 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥12 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥14 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥16 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥18 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥20 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥30 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥40 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥50 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥60 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥70 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥80 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥90 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL appearance subscale score as compared to baseline.

[0186] In some embodiments, a method results in a ≥8 point improvement in GO- QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥10 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥12 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to 60 155110240v10Attorney Docket No. VRD-022WO1 baseline. In some embodiments, a method results in a ≥14 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥16 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥18 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥20 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥30 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥40 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥50 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥60 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥70 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥80 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a ≥90 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline.

[0187] In some embodiments, an improvement in GO-QOL is achieved within 3 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, an improvement in GO-QOL is achieved within 6 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, an improvement in GO-QOL is achieved within 9 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, an improvement in GO-QOL is achieved within 12 weeks from the first 61 155110240v10Attorney Docket No. VRD-022WO1 administration of the anti-IGF-1R antibody. In some embodiments, an improvement in GO- QOL is achieved within 15 weeks from the first administration of the anti-IGF-1R antibody.

[0188] In some embodiments, an improvement in GO-QOL is maintained for at least 6 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 9 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 12 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 15 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 18 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 21 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 24 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 27 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 30 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 36 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 52 weeks. BRIEF DESCRIPTION OF THE DRAWINGS

[0189] FIG.1A is an exemplary graph showing the proptosis responder rate of VRDN-001 as compared to placebo. FIG.1B is an exemplary graph showing a comparison of the proptosis responder rate of VRDN-001 to historical data of a reference anti-IGF-1R antibody therapy.

[0190] FIG.2A is an exemplary graph showing the change in proptosis from baseline as measured by Hertel exophthalmometer of VRDN-001 as compared to placebo. FIG.2B is an exemplary graph showing a comparison of the change in proptosis from baseline as measured by Hertel exophthalmometer of VRDN-001 to historical data of a reference anti- IGF-1R antibody therapy.

[0191] FIG.3 is an exemplary graph showing the change from baseline in CAS of VRDN-001 as compared to placebo.

[0192] FIG.4 is an exemplary graph showing the CAS Responder Rate of VRDN- 001 as compared to placebo.

[0193] FIG.5 is an exemplary graph showing the Overall Responder Rate of VRDN- 001 as compared to placebo. 62 155110240v10Attorney Docket No. VRD-022WO1

[0194] FIG.6A is an exemplary graph showing the Diplopia Responder Rate of VRDN-001 as compared to placebo. FIG.6B is an exemplary graph showing a comparison of the Diplopia Responder Rate of VRDN-001 to historical data of an anti-IGF-1R antibody therapy.

[0195] FIG.7 is an exemplary graph showing the Diplopia Resolution Rate of VRDN-001 as compared to placebo.

[0196] FIG.8A is an exemplary graph showing the CAS of 0 or 1 of VRDN-001 as compared to placebo. FIG.8B is an exemplary graph showing a comparison of CAS response rate of VRDN-001 to historical data of an anti-IGF-1R antibody therapy.

[0197] FIG.9 is an exemplary graph showing the proptosis responder rate as measured by Hertel exophthalmometer in patients with proptosis <20 mm at baseline as compared to patient with proptosis ≥ 20 mm at baseline.

[0198] FIGs.10A-10G are exemplary graphs demonstrating that VRDN-001 can effectively treat TED as compared to placebo. FIG.10A is an exemplary graph showing the model-based proptosis responder rate by hertel exophthalmometer through Week 15. FIG. 10B is an exemplary graph showing the least squares mean (LSMEAN) change in proptosis from baseline by hertel exophthalmometer through Week 15. FIG.10C is an exemplary graph showing the LSMEAN change in CAS from baseline through Week 15. FIG.10D is an exemplary graph showing the model-based CAS responder rate through Week 15. FIG. 10E is an exemplary graph showing the model-based overall responder rate through Week 15. FIG.10F is an exemplary graph showing the model-based diplopia responder rate through Week 15. FIG.10G is an exemplary graph showing the model-based diplopia responder rate through Week 15. DETAILED DESCRIPTION

[0199] The present invention provides, among other things, a safer and more potent method for treating thyroid eye disease (TED) based on VRDN-001 and other anti-IGF-1R antibodies using dosing regimens described herein. The present invention is, in part, based on the superior clinical results in TED patients receiving VRDN-001 treatment resulting in particularly high diplopia resolution (e.g., ≥ 35% placebo adjusted rate), high proptosis responder rate (e.g., ≥ 50% placebo adjusted rate), and high CAS responder rate (e.g., ≥ 30% 63 155110240v10Attorney Docket No. VRD-022WO1 placebo adjusted rate), while keeping the hearing impairment incidence low (e.g., ≤ 10% placebo adjusted rate).

[0200] Any numerical values used in this application are meant to cover any variations within the standard deviation or normal fluctuations appreciated by one of ordinary skill in the relevant art. Thyroid Eye Disease

[0201] Provided herein are antibodies that bind and modulate the activity of IGF-1R. The antibodies can be used, for example, to treat thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED), Graves’ ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, dysthyroid ophthalmopathy, autoimmune associated eye disorders associated with IGF-1R signaling, inflammatory orbital disorder associated with IGF-1R signaling, and other thyroid eye disorders associated with IGF-1R signaling.

[0202] Thyroid Eye Disease (TED) is an autoimmune condition most commonly associated with Graves’ disease and hyperthyroidism but can also be found in patients who are euthyroid or hypothyroid. Pathological remodeling of the orbit and periorbital tissues results in varied presentations which include dry eyes, increased lacrimation, local irritation and eyelid retraction. As the pathophysiology progresses, signs and symptoms increase to include proptosis, diplopia, restriction of ductions and versions and optic nerve compression, with ensuing vision loss.

[0203] The pathophysiology of TED is incompletely understood. Stimulation of inflammatory cytokines causes proliferation of the orbital fibroblasts which in turn produce collagen and glycosaminoglycans in the extracellular matrix. The polyanionic charge and the high osmotic pressure of this matrix substance causes swelling of the extraocular muscles. In addition, a subgroup of orbital fibroblasts differentiates into new mature fat cells (adipogenesis), which adds to increased orbital tissue volume. There is also a role for the humoral-mediated immune response in which thyrotropin receptor autoantibodies and immunoglobulins targeting insulin-like growth factor-1 receptors contribute to fibroblast activation and glycosaminoglycan secretion. Levator and Muller muscle inflammation and fibrosis account for upper eyelid retraction, which is seen in up to 90% of affected patients. Proptosis is caused by the expansion of orbital fat (type 1 orbitopathy), extraocular muscles 64 155110240v10Attorney Docket No. VRD-022WO1 (type 2 orbitopathy), or both. Blindness is caused by compression of the optic nerve, presumably within the apex of the orbit. Dramatic proptosis itself can lead to visual loss via exposure keratopathy and corneal ulceration. This constellation of signs and symptoms causes difficulty with working, driving, reading and other activities of daily living, and leads to psychosocial distress and social withdrawal.

[0204] Ultimately, the alterations in the extracellular matrix lead to proptosis, strabismus, diplopia and disfigurement of facial and periorbital anatomy. Many patients with TED endure at least 5 to 7 years of medical and surgical therapy before reaching a point of stability, transformed physically, emotionally and visually, with overwhelming dysfunction in their quality of life.

[0205] The disease course has historically been said to transition from an active and progressive phase (characterized by inflammation of orbital and external periorbital tissues) to a more stabilized and fibrotic, inactive phase, though this nomenclature is inexact and changing. Active TED has been characterized by local inflammation of conjunctivae, orbital fat and extraocular muscles, and is said to last between 1-3 years. Inactive, or chronic, TED occurs when the autoimmune inflammation dampens, leaving sequelae of expanded, fibrotic orbital tissues and dysfunctional, tethered extraocular muscles, though evidence exists that even chronic TED patients may exhibit an underlying inflammatory component that needs to be further understood.

[0206] The present invention provides, among other things, a safer and more effective therapy for TED, particularly active TED. Patient Population

[0207] As used herein, the terms “a patient” or “the patient” encompasses a single patent and a patient population.

[0208] In some embodiments, a patient has documented evidence of ocular symptoms or signs associated with TED that began within 15 months of commencing treatment. In some embodiments, a patient has documented evidence of ocular symptoms or signs associated with TED that began within 12 months of commencing treatment. In some embodiments, a patient has documented evidence of ocular symptoms or signs associated with TED that began within 9 months of commencing treatment. 65 155110240v10Attorney Docket No. VRD-022WO1

[0209] In some embodiments, a patient with TED is at least 18 years old. In some embodiments, a patient with TED is 18 to 34 years old. In some embodiments, a patient with TED is 35 to 65 years old. In some embodiments, a patient with TED is >65 years old.

[0210] As used herein, the term Clinical Activity Score (CAS) refers to the protocol described and scored according to Table 1. According to this protocol, one point is given for the presence of each of the parameters assessed in the Table below. The sum of all points defines clinical activity and provides the CAS, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy.

[0211] As provided in Table 1, the CAS consists of seven components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, side-to-side, and downward gazes), conjunctival redness, redness of the eyelids, chemosis, swelling of the caruncle / plica, and swelling of the eyelids. Each component is scored as present (1 point) or absent (0 points). The score at each efficacy assessment is the sum of all items present; giving a range of 0-7, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy. A change of ≥2 points is considered clinically meaningful. In some embodiments, the subject’s score improves by at least 2, 3, or 4 points. In some embodiments, the subject’s score improves within 3 weeks of the first dose. In some embodiments, the subject’s score improves within 6 weeks of the first dose. 66 155110240v10Attorney Docket No. VRD-022WO1

[0212] Item 1, spontaneous orbital pain could be a painful, or oppressive feeling on, or behind, the globe. This pain may be caused by the rise in intraorbital pressure, when the orbital tissues volume increases through excess synthesis of extracellular matrix, fluid accumulation, and cellular infiltration and expansion. Item 2, gaze evoked orbital pain, could be pain in the eyes when looking, or attempting to look, up, down or sideways, i.e., pain with upward, downward, or lateral eye movement, or when attempting eye movement. This kind of pain could arise from the stretching of the inflamed muscle(s), especially on attempted upgaze. The `stretching pain` cannot be provoked by digital pressing on the eyeball, as would be expected if it were a manifestation of the raised intraorbital pressure. Both kinds of pain can be reduced after anti-inflammatory treatment. These kinds of pain are therefore considered to be directly related to autoimmune inflammation in the orbit and thus useful in assessing TAO activity.

[0213] Swelling in TAO is seen as chemosis (edema of the conjunctiva), item no.6 in Table 1, and swelling of the caruncle and / or plica semilunaris. Both are signs of TAO activity. Swollen eyelids can be caused by edema, fat prolapse through the orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicative of active TAO include redness and / or pain of the conjunctiva, eyelid, caruncle and / or plica semilunaris.

[0214] In some embodiments, a patient has a baseline CAS of 0-7. In some embodiments, a patient has a baseline CAS of >2. In some embodiments, a patient has a baseline CAS of ≥3. In some embodiments, a patient has a baseline CAS of ≥4. In some embodiments, a patient has a baseline CAS of ≥2 and <4. In some embodiments, a patient has a baseline CAS ≥3 and documented signs or symptoms that began within 15 months of commencing treatment. In some embodiments, a patient has a baseline CAS ≥3 and documented signs or symptoms that began within 12 months of commencing treatment. In some embodiments, a patient has a baseline CAS ≥3 and documented signs or symptoms that began within 9 months of commencing treatment.

[0215] In some embodiments, a patient with TED has proptosis of ≥3 mm above normal values for race and gender at baseline. In some embodiments, a patient with TED has proptosis of ≥20mm at baseline. In some embodiments, a patient with TED has proptosis of <20mm at baseline.

[0216] In some embodiments, a patient with TED has diplopia at baseline. In some embodiments, diplopia is assessed using Gorman Grading of Diplopia. The Gorman 67 155110240v10Attorney Docket No. VRD-022WO1 assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or awakening (intermittent), diplopia at extremes of gaze (inconstant), and continuous diplopia in the primary or reading position (constant). Patients are scored according to which grade of diplopia they are experiencing on the Gorman Subjective Diplopia Score. In some embodiments, diplopia is scored from 0 to 3 (0=no diplopia; 1=intermittent, i.e., diplopia in primary position of gaze, when tired or when first awakening; 2=inconstant, i.e., diplopia at extremes of gaze; 3=constant, i.e., continuous diplopia in primary or reading position). In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is inconstant diplopia. In some embodiments, the diplopia is intermittent diplopia.

[0217] In some embodiments, the present invention provides a method of treating TED in patients with moderate to severe TED. In some embodiments, a patient with moderate to severe TED has proptosis of ≥3 mm above normal values for race and gender at baseline and one or more of: (i) lid retraction of ≥2 mm; (ii) moderate or severe soft tissue involvement; (iii) inconstant or constant diplopia; (iv) spontaneous retrobulbar pain or pain on eye movement; (v) swelling of the conjunctiva, eyelids or plica; or (vi) redness of the eyelids or plica. IGF-1R Antibodies

[0218] The anti-IGF-1R antibodies described below, particularly VRDN-001, VRDN- 002, and VRDN-003 (shown in Tables 2-7) are suitable for treating TED according to methods described in the present invention.

[0219] As used herein, the term “antibody” refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic antibody.

[0220] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e. antibody fragments 68 155110240v10Attorney Docket No. VRD-022WO1 that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.

[0221] In some embodiments, the antibody comprises one or more peptides having the following sequences, or a variant thereof:69 155110240v10Attorney Docket No. VRD-022WO170 155110240v10Attorney Docket No. VRD-022WO171 155110240v10Attorney Docket No. VRD-022WO1

[0222] The VH and the VL sequences can be in any format, including, but not limited to a scFv format where the VH and VL regions are linked with a peptide linker. Examples of peptide linkers that can be used to link various peptides provided for herein include, but are not limited to: (GGGGS)n(SEQ ID NO: 12); (GGGGA)n(SEQ ID NO: 13), or any combination thereof, wherein each n is independently 1-5. In some embodiments, the peptide linker comprises (GGGGS)n(SEQ ID NO: 12), (GGGGA)n(SEQ ID NO: 13), (GSTSGSGKPGSGEGSTKG)n(SEQ ID NO: 26) or any combination thereof, wherein each n is independently 1-8. In some embodiments, the variable regions are not linked with a peptide linker. In some embodiments, the antibody comprises or consists of a polypeptide set forth in SEQ ID NOS: 10 and 11. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOs: 4, 5, 6, 7, 8, and 9. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOs: 27, 28, 6, 29, 30, and 31. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOs: 4, 5, 6, 32, 33, and 9. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOs: 4, 34, 6, 35, 36, and 31. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOs: 18, 19, 20, 21, 22, and 23. In some embodiments, the 72 155110240v10Attorney Docket No. VRD-022WO1 antibody comprises a polypeptide comprising SEQ ID NOs: 37, 28, 20, 38, 39, and 40. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 18, 19, 20, 41, 42, and 23. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 18, 43, 20, 44, 45, and 40.

[0223] In some embodiments, an antibody, or antigen binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the following tables.73 155110240v10Attorney Docket No. VRD-022WO174 155110240v10Attorney Docket No. VRD-022WO1

[0224] In some embodiments, the antibody comprises one or more peptides having the following sequences, or a variant thereof comprising one or more variable domain (italicized) CDRs (italics and bold, according to Kabat numbering scheme) and a human IgG1 / Kappa constant domain (underlined):75 155110240v10Attorney Docket No. VRD-022WO1

[0225] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy or light chain having a sequence of SEQ ID NOs: 10 and 11. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence of SEQ ID NO: 10. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 76 155110240v10Attorney Docket No. VRD-022WO1 comprises the CDRs of SEQ ID NO: 7, 8, and / or 9 as set forth above. In some embodiments, the sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs of SEQ ID NO: 7, 8, and / or 9 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs of SEQ ID NO: 29, 30, and / or 31 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs of SEQ ID NO: 32, 33, and / or 9 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs of SEQ ID NO: 35, 36, and / or 31 as set forth above.

[0226] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having a sequence of SEQ ID NO: 11. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having a sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 In some embodiments, the sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs of SEQ ID NO: 4, 5, and / or 6 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs of SEQ ID NO: 4, 5, and / or 6 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs of SEQ ID NO: 27, 28, and / or 6 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 77 155110240v10Attorney Docket No. VRD-022WO1 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs of SEQ ID NO: 4, 34 and / or 6 as set forth above.

[0227] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 4, 5, or 6. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 7, 8, or 9.

[0228] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 4 the LCDR2 has a sequence of SEQ ID NO: 5 and the LCDR3 has a sequence of SEQ ID NO: 6.

[0229] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 7 the HCDR2 has a sequence of SEQ ID NO: 8 and the HCDR3 has a sequence of SEQ ID NO: 9.

[0230] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 27, 28, or 6. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 29, 30, or 31.

[0231] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 27 the LCDR2 has a sequence of SEQ ID NO: 28 and the LCDR3 has a sequence of SEQ ID NO: 6.

[0232] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 29 the HCDR2 has a sequence of SEQ ID NO: 30 and the HCDR3 has a sequence of SEQ ID NO: 31.

[0233] In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 32, 33, or 9.

[0234] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 32 the HCDR2 has a sequence of SEQ ID NO: 33 and the HCDR3 has a sequence of SEQ ID NO: 9. 78 155110240v10Attorney Docket No. VRD-022WO1

[0235] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 4, 34, or 6. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 35, 36, or 31.

[0236] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 4 the LCDR2 has a sequence of SEQ ID NO: 34 and the LCDR3 has a sequence of SEQ ID NO: 6.

[0237] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 35 the HCDR2 has a sequence of SEQ ID NO: 36 and the HCDR3 has a sequence of SEQ ID NO: 31.

[0238] The different CDR motifs can be combined in any combination including those not depicted in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0239] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 7; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 8; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9; or variants of any of the foregoing.

[0240] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 27; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 29; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the heavy chain 79 155110240v10Attorney Docket No. VRD-022WO1 CDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing.

[0241] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 32; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 33; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9; or variants of any of the foregoing.

[0242] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 34; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 35; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 36; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing.

[0243] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 80 155110240v10Attorney Docket No. VRD-022WO1 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 7; the heavy chain CDR2 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 8; and the heavy chain CDR3 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 9; or variants of any of the foregoing.

[0244] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 7; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 8; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 9; or variants of any of the foregoing.

[0245] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 27; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 81 155110240v10Attorney Docket No. VRD-022WO1 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 29; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 30; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 31; or variants of any of the foregoing.

[0246] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 32; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical 82 155110240v10Attorney Docket No. VRD-022WO1 to that of SEQ ID NO: 33; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 9; or variants of any of the foregoing.

[0247] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 34; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 35; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 36; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 31; or variants of any of the foregoing.

[0248] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy or light chain having a sequence of SEQ ID NOs: 14 and 15. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence of SEQ ID NO: 14. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14. In some 83 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 7, 8, and / or 9 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 29, 30, and / or 31 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 32, 33, and / or 9 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 35, 36, and / or 31 as set forth above.

[0249] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having a sequence of SEQ ID NO: 15. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 15. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 15 comprises the CDRs of SEQ ID NO: 4, 5, and / or 6 as set forth above.

[0250] In some embodiments, the antibody, or antigen binding fragment thereof, or protein is provided that comprises a peptide having a sequence as set forth in any of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36.

[0251] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy or light chain having a sequence of SEQ ID NOs: 24 and 25. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence of SEQ ID NO: 24. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 84 155110240v10Attorney Docket No. VRD-022WO1 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 21, 22, and / or 23 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 38, 39, and / or 40 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 41, 42, and / or 23 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 44, 45, and / or 40 as set forth above.

[0252] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having a sequence of SEQ ID NO: 25. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25 comprises the CDRs of SEQ ID NO: 18, 19, and / or 20 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25 comprises the CDRs of SEQ ID NO: 37, 28, and / or 20 as set forth above. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25 comprises the CDRs of SEQ ID NO: 18, 43, and / or 20 as set forth above. 85 155110240v10Attorney Docket No. VRD-022WO1

[0253] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 21, 22, or 23.

[0254] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18 the LCDR2 has a sequence of SEQ ID NO: 19 and the LCDR3 has a sequence of SEQ ID NO: 20.

[0255] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21 the HCDR2 has a sequence of SEQ ID NO: 22 and the HCDR3 has a sequence of SEQ ID NO: 23.

[0256] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 21, 22, or 23.

[0257] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 37 the LCDR2 has a sequence of SEQ ID NO: 28 and the LCDR3 has a sequence of SEQ ID NO: 20.

[0258] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 38 the HCDR2 has a sequence of SEQ ID NO: 39 and the HCDR3 has a sequence of SEQ ID NO: 40.

[0259] In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 41, 42, or 23.

[0260] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 41 the HCDR2 has a sequence of SEQ ID NO: 42 and the HCDR3 has a sequence of SEQ ID NO: 23.

[0261] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 18, 43, or 20. In some 86 155110240v10Attorney Docket No. VRD-022WO1 embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 44, 45, or 40.

[0262] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18 the LCDR2 has a sequence of SEQ ID NO: 43 and the LCDR3 has a sequence of SEQ ID NO: 20.

[0263] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 44 the HCDR2 has a sequence of SEQ ID NO: 45 and the HCDR3 has a sequence of SEQ ID NO: 40.

[0264] The different CDR motifs can be combined in any combination including those not depicted in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0265] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 19; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 21; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:22; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23; or variants of any of the foregoing.

[0266] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 38; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:39; and the heavy chain 87 155110240v10Attorney Docket No. VRD-022WO1 CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing.

[0267] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 19; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 41; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:42; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23; or variants of any of the foregoing.

[0268] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 43; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 44; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:45; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing.

[0269] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 19; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 88 155110240v10Attorney Docket No. VRD-022WO1 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 21; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 22; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 23; or variants of any of the foregoing.

[0270] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 37; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 38; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 39; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 40; or variants of any of the foregoing. 89 155110240v10Attorney Docket No. VRD-022WO1

[0271] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 37; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 41; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 42; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 23; or variants of any of the foregoing.

[0272] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 54; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 55; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing. 90 155110240v10Attorney Docket No. VRD-022WO1

[0273] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 43; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 44; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 45; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 40; or variants of any of the foregoing.

[0274] In some embodiments, the antibody, or antigen binding fragment thereof, or protein is provided that comprises a peptide having a sequence as set forth in any of SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 28, 37, 38, 39, 40, 41, 42, 43, 44, or 45.

[0275] In some embodiments, methods described herein comprise use or administration of an anti-IGF-1R antibody, and antigen binding fragments thereof, including any forms, variants, or derivatives thereof of the anti-IGF-1R antibody, and antigen binding fragments.

[0276] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a sequence of, or a variant of any of the foregoing. 91 155110240v10Attorney Docket No. VRD-022WO1

[0277] In some embodiments, the reference anti-IGF-1R antibody is used for comparing the efficacy and safety. In some embodiments, the reference antibody is shown in Table 8.Dosing Regimens 92 155110240v10Attorney Docket No. VRD-022WO1

[0278] The present invention provides, among other things, a more efficacious and safer dosing regimens for treating TED. The dosing regimens disclosed herein result in high diplopia (e.g., ≥ 35%), high proptosis responder rate (e.g., ≥ 50%), and high CAS responder rate (e.g., ≥ 35%), while keeping hearing impairment incidence low (e.g., ≥ 10%). Dose

[0279] In some embodiments, a method comprises administering an IGF-1R to a patient at a therapeutically effective dose.

[0280] In some embodiments, an IGF-1R antibody is administered at a dose of 3-20 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 3-15 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 5-15 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 8-12 mg / kg.

[0281] In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 5 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 10 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 20 mg / kg.

[0282] In some embodiments, an antibody is administered at a dose of 3 mg / kg or less. In some embodiments, an antibody is administered at a dose of 5 mg / kg or less. In some embodiments, an antibody is administered at a dose of 10 mg / kg or less. In some embodiments, an antibody is administered at a dose of 20 mg / kg or less.

[0283] In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 20 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 15 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 5 mg / kg to 15 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 8 mg / kg to 12 mg / kg antibody as a first dose.

[0284] As used herein, the term “first dose” is used interchangeably with “first administration.” In some embodiments, a first dose that is administered intravenously is referred to herein as “the first infusion.” 93 155110240v10Attorney Docket No. VRD-022WO1

[0285] In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 20 mg / kg antibody in subsequent doses. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 15 mg / kg antibody in subsequent doses. In some embodiments, an IGF-1R antibody is administered at a dose of 5 mg / kg to 15 mg / kg antibody in subsequent doses. In some embodiments, an IGF-1R antibody is administered at a dose of 8 mg / kg to 12 mg / kg antibody in subsequent doses. Administration Interval

[0286] In some embodiments, a therapeutically effective dosage regimen comprises administration of one or more doses to a patient (e.g., one or more doses of an antibody as described herein).

[0287] In some embodiments, a therapeutically effective dosage regimen comprises administration of a first dose (e.g., any dose amount of an antibody described herein) to a patient. In some embodiments, a therapeutically effective dosage regimen comprises administration of subsequent dose(s) (e.g., any dose amount of an antibody described herein) to a patient. In some embodiments, a first dose is the same amount as a subsequent dose. In some embodiments, a first dose is different amount as a subsequent dose. In some embodiments, a first dose is a higher amount than a subsequent dose. In some embodiments, a first dose is a lower amount than a subsequent dose.

[0288] In some embodiments, a subsequent dose (e.g., of an antibody as described herein) is administered to a patient once every 1-8 weeks. In some embodiments, a subsequent dose is administered to a patient once every week. In some embodiments, a subsequent dose is administered to a patient once every two weeks. In some embodiments, a subsequent dose is administered to a patient once every three weeks. In some embodiments, a subsequent dose is administered to a patient once every four weeks. In some embodiments, a subsequent dose is administered to a patient once every five weeks. In some embodiments, a subsequent dose is administered to a patient once every six weeks. In some embodiments, a subsequent dose is administered to a patient once every seven weeks. In some embodiments, a subsequent dose is administered to a patient once every eight weeks. In some embodiments, a subsequent dose is administered to a patient once every nine weeks. In some embodiments, a subsequent dose is administered to a patient once every ten weeks. 94 155110240v10Attorney Docket No. VRD-022WO1

[0289] In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 3 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti- IGF-1R antibody to a patient at a dose of 5 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 12 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 15 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 20 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof.

[0290] In some embodiments, an equivalent dosing regimen comprises administering an anti-IGF1R antibody at a dose at an administration interval sufficient to reduce one or more symptoms associated with TED. For example, an equivalent dosing regimen of 10 mg / kg or less every three weeks is 5 mg / kg or less every 10 days, or 20 mg / kg or less every six weeks.

[0291] In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 2 mg / kg or less once every 4 days. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 5 mg / kg or less once every 10 days. In some embodiments, a method comprises administering an anti- IGF-1R antibody to a patient at a dose of 20 mg / kg or less once every six weeks. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 30 mg / kg or less once every nine weeks.

[0292] In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 80 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 70 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 60 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no 95 155110240v10Attorney Docket No. VRD-022WO1 more than 50 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 40 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 30 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 20 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 15 mg / kg according to a dosing regimen. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 10 mg / kg according to a dosing regimen.

[0293] In some embodiments, the total dose is 80 mg / kg. In some embodiments, the total dose is 70 mg / kg. In some embodiments, the total dose is 60 mg / kg. In some embodiments, the total dose is 50 mg / kg. In some embodiments, the total dose is 40 mg / kg.

[0294] In some embodiments, the total dose is administered by a first dose followed by one or more subsequent doses.

[0295] In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and one or more subsequent doses of the anti- IGF-1R antibody at 10 mg / kg every three weeks.

[0296] In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and three subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks. In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and four subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks. In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and five subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks. In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and six subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks. In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and seven subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks. In some embodiments, the dosing regimen comprises administering a first dose of the anti-IGF-1R 96 155110240v10Attorney Docket No. VRD-022WO1 antibody at 10 mg / kg and eight subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks.

[0297] In some embodiments, a total dose of 50 mg is administered by the first dose of 10 mg / kg followed by four subsequent doses of 10 mg / kg every three weeks. In some embodiments, a total dose of 80 mg is administered by the first dose of 10 mg / kg followed by seven subsequent doses of 10 mg / kg every three weeks.

[0298] Doses described herein can be administered according to methods known in the art. Exemplary routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.

[0299] In some embodiments, a dose is administered by infusion, intravenously, or subcutaneously. In some embodiments, a dose is administered intravenously, such as by infusion. Repeat Dosing

[0300] In some embodiments, the method of treating active TED comprises an initial dosing regimen and one or more repeat dosing regimens. In some embodiments, the method of treating TED comprises an initial dosing regimen and one or more repeat dosing regimens, wherein the initial dosing regimen comprises administering an anti-IGF-1R antibody to a patient at a total dose of no more than 80 mg / kg according to a dosing regimen as defined anywhere herein.

[0301] In some embodiments, the initial dosing regimen comprises a first dose of the anti-IGF-1R antibody as defined herein and one or more subsequent doses as defined herein.

[0302] In some embodiments, each of the one or more repeat dosing regimens comprises administering one or more repeat doses, wherein the one or more repeat doses optionally comprises a first repeat dose of the anti-IGF-1R antibody and one or more subsequent doses.

[0303] In some embodiments, a repeat dose is not administered for at least 24 weeks after the first infusion. In some embodiments, a repeat dose is not administered for at least 28 weeks after the first infusion. In some embodiments, a repeat dose is not administered for at least 32 weeks after the first infusion. In some embodiments, a repeat dose is not 97 155110240v10Attorney Docket No. VRD-022WO1 administered for at least 36 weeks after the first infusion. In some embodiments, a repeat dose is not administered for at least 40 weeks after the first infusion. In some embodiments, a repeat dose is not administered for at least 44 weeks after the first infusion. In some embodiments, a repeat dose is not administered for at least 48 weeks after the first infusion. In some embodiments, a repeat dose is not administered for at least 52 weeks after the first infusion.

[0304] In some embodiments, a repeat dose is administered at or after 24 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 28 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 32 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 36 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 40 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 44 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 48 weeks after the first infusion. In some embodiments, a repeat dose is administered at or after 52 weeks after the first infusion. Treatment Period

[0305] The present invention provides, among other things, a method comprising administering an anti-IGF-1R antibody for a treatment period sufficient to result in high diplopia (e.g., ≥ 35%), high proptosis responder rate (e.g., ≥ 50%), high CAS responder rate (e.g., ≥ 35%), while keeping hearing impairment incidence low (e.g., ≥ 10%).

[0306] In some embodiments, a treatment period is therapeutically effective such that the method results in high diplopia (e.g., ≥ 35%), high proptosis responder rate (e.g., ≥ 50%), and high CAS responder rate (e.g., ≥ 35%), while keeping hearing impairment incidence low (e.g., ≥ 10%).

[0307] In some embodiments, a treatment period is sufficient to result in at least 30% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 35% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 40% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 42% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 45% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 48% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 50% diplopia resolution. In some embodiments, a 98 155110240v10Attorney Docket No. VRD-022WO1 treatment period is sufficient to result in at least 55% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 60% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 65% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 70% diplopia resolution.

[0308] In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 16 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 20 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 25 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 35% diplopia resolution for at least 30 weeks.

[0309] In some embodiments, a treatment period is sufficient to result in at least 40 % proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 45 % proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 50 % proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 55 % proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 60 % proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 65 % proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 70 % 99 155110240v10Attorney Docket No. VRD-022WO1 proptosis responder rate. In some embodiments, a treatment period is sufficient to result in at least 75 % proptosis responder rate.

[0310] In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 16 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 20 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 25 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 50% proptosis responder rate for at least 30 weeks.

[0311] In some embodiments, a treatment period is sufficient to result in at least 20% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 25% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 30% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 32% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 35% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 40% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 45% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 48% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 50% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 100 155110240v10Attorney Docket No. VRD-022WO1 55% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 60% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 65% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 70% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 75% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 80% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 85% CAS responder rate. In some embodiments, a treatment period is sufficient to result in at least 90% CAS responder rate.

[0312] In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 16 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 20 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 25 weeks. In some embodiments, a treatment period is sufficient to maintain the at least 30% CAS responder rate for at least 30 weeks.

[0313] In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 20%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 18%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 16%. In some embodiments, a treatment period is sufficient to result in the hearing 101 155110240v10Attorney Docket No. VRD-022WO1 impairment incidence of less than 15%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 12%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 10%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 8%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 6%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 5.5%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 5%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 4%.

[0314] In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain hearing impairment incidence of less than 10% for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 16 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 20 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 25 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 30 weeks.

[0315] In some embodiments, a treatment period is 12 weeks. In some embodiments, a treatment period is 15 weeks. In some embodiments, a treatment period is 18 weeks. In 102 155110240v10Attorney Docket No. VRD-022WO1 some embodiments, a treatment period is 21 weeks. In some embodiments, a treatment period is 24 weeks. In some embodiments, a treatment period is 27 weeks.

[0316] In some embodiments, a treatment period is at least 12 weeks. In some embodiments, a treatment period is at least 15 weeks. In some embodiments, a treatment period is at least 18 weeks. In some embodiments, a treatment period is at least 21 weeks. In some embodiments, a treatment period is at least 24 weeks. In some embodiments, a treatment period is at least 27 weeks.

[0317] In some embodiments, a treatment period is 12 weeks or less. In some embodiments, a treatment period is 15 weeks or less. In some embodiments, a treatment period is 18 weeks. In some embodiments, a treatment period is 21 weeks or less. In some embodiments, a treatment period is 24 weeks. In some embodiments, a treatment period is 27 weeks or less.

[0318] In some embodiments, a patient is administered 5 doses of an anti-IGF-1R antibody. In some embodiments, a patient is administered 6 doses of an anti-IGF-1R antibody. In some embodiments, a patient is administered 7 doses of an anti-IGF-1R antibody. In some embodiments, a patient is administered 8 doses of an anti-IGF-1R antibody. In some embodiments, a patient is administered 9 doses of an anti-IGF-1R antibody. In some embodiments, a patient is administered 10 doses of an anti-IGF-1R antibody.

[0319] In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 12 weeks. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 15 weeks. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 18 weeks. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 21 weeks. In some embodiments, a method comprises administering an anti-IGF- 1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 24 weeks. 103 155110240v10Attorney Docket No. VRD-022WO1

[0320] In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 12 weeks or less. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 15 weeks or less. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 18 weeks or less. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 21 weeks or less. In some embodiments, a method comprises administering an anti-IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 24 weeks or less.

[0321] In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 3 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 4 infusions or less. In some embodiments, an anti- IGF-1R antibody is intravenously administered to a patient for 5 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 6 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 7 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 8 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 9 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient for 10 infusions or less.

[0322] In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 3 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 4 infusions or less. In some embodiments, an anti-IGF- 1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 5 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 6 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 7 infusions or less. In some embodiments, an anti-IGF- 104 155110240v10Attorney Docket No. VRD-022WO1 1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 8 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 9 infusions or less. In some embodiments, an anti-IGF-1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 10 infusions or less. Clinical Efficacy Metrics / Endpoints

[0323] TED is an autoimmune condition characterized by inflammation, and enlargement of extraocular muscles, orbital fat and connective tissue. These changes lead to pain, redness and swelling of the eyelids and conjunctiva, as well as eye bulging (proptosis), double vision (diplopia), and these symptoms and signs form the basis of clinically relevant efficacy endpoints

[0324] In some embodiments, the clinical efficacy metrics achieved are placebo- adjusted rates. Those skilled in the art will appreciate that a placebo adjusted rate adjusts the efficacy results based on a placebo response rate.

[0325] In some embodiments, a method comprises a primary endpoint analysis performed at week 15, and additional efficacy and safety follow-ups performed at 24 weeks (Week 24), 36 weeks (Week 36), and 52 weeks (Week 52) after the first infusion. In some embodiments, an endpoint (e.g., primary or secondary) “maintained” through 24 weeks (Week 24), 36 weeks (Week 36), and / or 52 weeks (Week 52) refers to being the endpoint being maintained for that time period after the first infusion. Diplopia

[0326] In some embodiments, diplopia resolution is a reduction in Gorman Subjective Diplopia Score to 0 from baseline for participants with baseline Gorman Subjective Diplopia Score >0. In some embodiments, diplopia responder is a decrease of >=1 from baseline for participants with baseline Gorman Subjective Diplopia Score >0.

[0327] In one aspect, the present invention provides, among other things, a method of treating TED comprising alleviating diplopia in a patient with TED. In some embodiments, a patient has a baseline Gorman Subjective Diplopia Score of >0, 1, 2, or 3.

[0328] In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score. In some embodiments, a method comprises achieving a reduction 105 155110240v10Attorney Docket No. VRD-022WO1 in Gorman Subjective Diplopia Score of at least 1. In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score of at least 2. In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score of at least 3.

[0329] In some embodiments, a method comprises achieving diplopia resolution. In some embodiments, diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline. In some embodiments, a method achieves at least 30% diplopia resolution rate. In some embodiments, a method results in at least 35% diplopia resolution rate. In some embodiments, a method results in at least 40% diplopia resolution rate. In some embodiments, a method results in at least 40% diplopia resolution rate. In some embodiments, a method results in at least 42% diplopia resolution rate. In some embodiments, a method results in at least 45% diplopia resolution rate. In some embodiments, a method results in at least 48% diplopia resolution rate. In some embodiments, a method results in at least 50% diplopia resolution rate. In some embodiments, a method results in at least 55% diplopia resolution rate. In some embodiments, a method results in at least 60% diplopia resolution rate. In some embodiments, a method results in at least 65% diplopia resolution rate. In some embodiments, a method results in at least 70% diplopia resolution rate.

[0330] In some embodiments, a method achieves diplopia resolution within 3 weeks from the first administration. In some embodiments, a method achieves diplopia resolution within 6 weeks from the first administration. In some embodiments, a method achieves diplopia resolution within 9 weeks from the first administration. In some embodiments, diplopia resolution is maintained for at least 15 weeks. In some embodiments, diplopia resolution is maintained for at least 24 weeks. In some embodiments, diplopia resolution is maintained for at least 36 weeks. In some embodiments, diplopia resolution is maintained for at least 52 weeks. In some embodiments, diplopia resolution rate is maintained for at least 15 weeks. In some embodiments, diplopia resolution rate is maintained for at least 24 weeks. In some embodiments, diplopia resolution rate is maintained for at least 36 weeks. In some embodiments, diplopia resolution rate is maintained for at least 52 weeks.

[0331] In some embodiments, a method comprises achieving a diplopia response. In some embodiments, a method comprises achieving a diplopia responder rate. In some embodiments, a diplopia response is a reduction of >=1 from baseline for participants with 106 155110240v10Attorney Docket No. VRD-022WO1 baseline Gorman Subjective Diplopia Score >0. In some embodiments, a method results in at least 30% diplopia responder rate. In some embodiments, a method results in at least 35% diplopia responder rate. In some embodiments, a method results in at least 40% diplopia responder rate. In some embodiments, a method results in at least 40% diplopia responder rate. In some embodiments, a method results in at least 42% diplopia responder rate. In some embodiments, a method results in at least 45% diplopia responder rate. In some embodiments, a method results in at least 48% diplopia responder rate. In some embodiments, a method results in at least 50% diplopia responder rate. In some embodiments, a method results in at least 55% diplopia responder rate. In some embodiments, a method results in at least 60% diplopia responder rate. In some embodiments, a method results in at least 65% diplopia responder rate. In some embodiments, a method results in at least 70% diplopia responder rate.

[0332] In some embodiments, a method achieves diplopia response within 3 weeks from the first administration. In some embodiments, a method achieves diplopia response within 6 weeks from the first administration. In some embodiments, a method achieves diplopia response within 9 weeks from the first administration. In some embodiments, diplopia responder rate is maintained for at least 15 weeks. In some embodiments, diplopia responder rate is maintained for at least 24 weeks. In some embodiments, diplopia responder rate is maintained for at least 36 weeks. In some embodiments, diplopia responder rate is maintained for at least 52 weeks.

[0333] In some embodiments, a diplopia responder rate of at least 35% is maintained for at least 15 weeks. In some embodiments, a diplopia responder rate of at least 35% is maintained for at least 24 weeks. In some embodiments, a diplopia responder rate of at least 35% is maintained for at least 36 weeks. In some embodiments, a diplopia responder rate of at least 35% is maintained for at least 52 weeks.

[0334] In some embodiments, at least 90% of diplopia responders at week 15 maintained a diplopia response at week 24. In some embodiments at least 85% of diplopia responders at week 15 maintained a diplopia response at week 36. In some embodiments at least 70% of diplopia responders at week 15 maintained a diplopia response at week 52. In some embodiments at least 75% of diplopia responders at week 15 maintained a diplopia response at week 52. In some embodiments at least 70% of diplopia responders at week 15 maintained a diplopia response at week 52. In some embodiments at least 65% of diplopia 107 155110240v10Attorney Docket No. VRD-022WO1 responders at week 15 maintained a diplopia response at week 52. In some embodiments at least 60% of diplopia responders at week 15 maintained a diplopia response at week 52. In some embodiments at least 55% of diplopia responders at week 15 maintained a diplopia response at week 52. In some embodiments at least 50% of diplopia responders at week 15 maintained a diplopia response at week 52.

[0335] In some embodiments, at least 65% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. In some embodiments, at least 60% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. In some embodiments, at least 55% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. In some embodiments, at least 50% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. In some embodiments, at least 45% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. In some embodiments, at least 40% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. In some embodiments, at least 35% of week 15 patients who had diplopia resolution maintained diplopia resolution at week 52. Proptosis

[0336] As used herein, the term “proptosis” refers to the forward projection, displacement, bulging, or protrusion of the eye anteriorly out of the orbit. Owing to the rigid bony structure of the orbit with only anterior opening for expansion, any increase in orbital soft tissue contents taking place from the side or from behind will displace the eyeball forward. inflammations, tumors, trauma, metastases, endocrine lesions, vascular diseases & extra orbital lesions.

[0337] In some embodiments, a method comprises achieving a proptosis response. In some embodiments, a proptosis responder is a reduction of proptosis of ≥ 2 mm from baseline in the study eye (without a corresponding increase of ≥ 2 mm in the fellow eye) as measured by exophthalmometer. In some embodiments, a proptosis responder is a reduction of proptosis of ≥ 2 mm from baseline in the study eye (without a corresponding increase of ≥ 2 mm in the fellow eye) as measured by MRI / CT.

[0338] In some embodiments, a patient had baseline proptosis of ≥ 16 mm. In some embodiments, a patient had baseline proptosis of ≥ 20 mm. In some embodiments, a patient had baseline proptosis of <20 mm. 108 155110240v10Attorney Docket No. VRD-022WO1

[0339] In some embodiments, a method results in at least 40% proptosis responder rate. In some embodiments, a method results in at least 45% proptosis responder rate. In some embodiments, a method results in at least 50% proptosis responder rate. In some embodiments, a method results in at least 55% proptosis responder rate. In some embodiments, a method results in at least 60% proptosis responder rate. In some embodiments, a method results in at least 65% proptosis responder rate. In some embodiments, a method results in at least 70% proptosis responder rate. In some embodiments, a method results in at least 75% proptosis responder rate.

[0340] In some embodiments, a method achieves proptosis response within 3 weeks from the first administration. In some embodiments, a method achieves proptosis response within 6 weeks from the first administration. In some embodiments, a method achieves proptosis response within 9 weeks from the first administration.

[0341] In some embodiments, proptosis responder rate is maintained for at least 15 weeks. In some embodiments, proptosis responder rate is maintained for at least 24 weeks. In some embodiments, proptosis responder rate is maintained for at least 36 weeks. In some embodiments, proptosis responder rate is maintained for at least 52 weeks.

[0342] In some embodiments, a method comprises achieving a reduction in proptosis as compared to baseline. In some embodiments, a reduction in proptosis as compared to a baseline is measured using a least squared mean method. In some embodiments, a method results in a reduction in proptosis of at least 2 mm. In some embodiments, a method results in a reduction in proptosis of at least 2.5 mm. In some embodiments, a method results in a reduction in proptosis of at least 3 mm. In some embodiments, a method results in a reduction in proptosis of at least 3.5 mm. In some embodiments, a method results in a reduction in proptosis of at least 4 mm. In some embodiments, a method achieves a reduction in proptosis within 3 weeks from the first administration. In some embodiments, a method achieves a reduction in proptosis within 6 weeks from the first administration. In some embodiments, a method achieves a reduction in proptosis within 9 weeks from the first administration. In some embodiments, proptosis reduction is maintained for at least 15 weeks. In some embodiments, proptosis reduction is maintained for at least 24 weeks. In some embodiments, proptosis reduction is maintained for at least 36 weeks. In some embodiments, proptosis reduction is maintained for at least 52 weeks. 109 155110240v10Attorney Docket No. VRD-022WO1

[0343] In some embodiments, at least 30% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 35% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 40% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 45% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 50% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 55% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 60% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 65% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 75% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, at least 85% of week 15 proptosis responders maintained a proptosis response at week 52.

[0344] In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 55% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 60% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 35% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 40% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 45% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 55% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 60% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 65% of week 15 proptosis responders maintained a proptosis response at week 52. In some 110 155110240v10Attorney Docket No. VRD-022WO1 embodiments, the proptosis responder rate at week 15 is at least 50% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 75% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 85% of week 15 proptosis responders maintained a proptosis response at week 52. In some embodiments, the proptosis responder rate at week 15 is at least 50% and at least 90% of week 15 proptosis responders maintained a proptosis response at week 52.

[0345] In some embodiments, proptosis recurrence was measured throughout the 52- week follow-up period. In some embodiments, proptosis recurrence was defined as no worsening or recurrence. In some embodiments, no worsening was defined as <2 mm increase in proptosis from Week 15. In some embodiments, recurrence was defined as experiencing an increase in proptosis of ≥2 mm from Week 15. In some embodiments, proptosis response in the study eye was defined as a reduction of proptosis of ≥2 mm from baseline in the study eye (without a corresponding increase of ≥2 mm in the other eye) as measured by exophthalmometer.

[0346] In some embodiments, at least 90% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 85% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 80% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 75% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 70% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 65% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 60% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 55% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 50% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 45% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 40% of week 15 proptosis responders experienced no worsening at week 52. In some embodiments, at least 35% of week 15 proptosis responders experienced no worsening at week 52. 111 155110240v10Attorney Docket No. VRD-022WO1 Clinical Activity Score (CAS)

[0347] The Clinical Activity Score (CAS) was devised as a measure of disease activity and a potential predictor of response to anti-inflammatory treatment. The CAS is based on seven components. Each component is scored as present or absent (scored as 1 or 0, respectively), and the CAS is given as the sum of the scores (range, 0 to 7, with higher scores indicating greater level of inflammation).

[0348] Clinical Activity Responder Rate in the study eye is a reduction in Clinical Activity Score (CAS) ≥ 2 points from baseline in the study eye (without a corresponding increase of ≥ 2 points in the fellow eye).

[0349] In some embodiments, change from baseline is the post-baseline value – baseline value.

[0350] In some embodiments, a method comprises achieving a CAS response. In some embodiments, a CAS response is a reduction in CAS score by ≥2. In some embodiments, a method results in at least 20% CAS responder rate. In some embodiments, a method results in at least 25% CAS responder rate. In some embodiments, a method results in at least 30% CAS responder rate. In some embodiments, a method results in at least 32% CAS responder rate. In some embodiments, a method results in at least 35% CAS responder rate. In some embodiments, a method results in at least 40% CAS responder rate. In some embodiments, a method results in at least 45% CAS responder rate. In some embodiments, a method results in at least 48% CAS responder rate. In some embodiments, a method results in at least 50% CAS responder rate. In some embodiments, a method results in at least 55% CAS responder rate. In some embodiments, a method results in at least 60% CAS responder rate. In some embodiments, a method results in at least 65% CAS responder rate. In some embodiments, a method results in at least 70% CAS responder rate. In some embodiments, a method results in at least 75% CAS responder rate. In some embodiments, a method results in at least 80% CAS responder rate. In some embodiments, a method results in at least 85% CAS responder rate. In some embodiments, a method results in at least 90% CAS responder rate. In some embodiments, a method results in a CAS responder rate within 3 weeks of the first administration. In some embodiments, a method results in a CAS responder rate within 6 weeks of the first administration. In some embodiments, a method results in a CAS responder rate within 9 weeks of the first administration. In some embodiments, CAS response is maintained for at least 15 weeks. In some embodiments, CAS response is 112 155110240v10Attorney Docket No. VRD-022WO1 maintained for at least 24 weeks. In some embodiments, CAS response is maintained for at least 36 weeks. In some embodiments, CAS response is maintained for at least 52 weeks.

[0351] In some embodiments, a method comprises reducing CAS score as compared to baseline. In some embodiments, a method results in a reduction of CAS of ≥1. In some embodiments, a method results in a reduction of CAS of ≥2. In some embodiments, a method results in a reduction of CAS of ≥3. In some embodiments, a method results in a reduction of CAS of ≥4. In some embodiments, a method results in a reduction in CAS within 3 weeks of the first administration. In some embodiments, a method results in a reduction in CAS within 6 weeks of the first administration. In some embodiments, a method results in a reduction in CAS within 9 weeks of the first administration. In some embodiments, CAS reduction is maintained for at least 15 weeks. In some embodiments, a method results in a CAS score of 0 or 1, wherein the patient at baseline has a CAS score of >1.

[0352] In some embodiments, at least 85% of week 15 CAS responders maintained a CAS response at week 24. In some embodiments, at least 75% of week 15 CAS responders maintained a CAS response at week 36. In some embodiments, at least 80% of week 15 CAS responders maintained a CAS response at week 36. In some embodiments, at least 75% of week 15 CAS responders maintained a CAS response at week 52. In some embodiments, at least 80% of week 15 CAS responders maintained a CAS response at week 52. Overall Responder Rate

[0353] In some embodiments, a method comprises achieving an overall response. Overall response rate (ORR) in the study eye comprises proptosis responder rate in the study eye and clinical activity responder rate in the study eye. In some embodiments, overall response comprises a reduction of proptosis of ≥2 mm from baseline and a reduction in CAS ≥2 points from baseline. In some embodiments, overall response comprises a reduction of proptosis of ≥2 mm from baseline as measured by exophthalmometer and a reduction in CAS ≥2 points from baseline. In some embodiments, overall response comprises a reduction of proptosis of ≥2 mm from baseline as measured by MRI / CT and a reduction in CAS ≥2 points from baseline. In some embodiments, overall response comprises a reduction of proptosis of ≥2 mm from baseline as measured by MRI and a reduction in CAS ≥2 points from baseline. In some embodiments, overall response comprises a reduction of proptosis of ≥2 mm from 113 155110240v10Attorney Docket No. VRD-022WO1 baseline as measured by CT and a reduction in CAS ≥2 points from baseline. In some embodiments, overall response rate comprises a reduction of proptosis of ≥2 mm from baseline in the study eye without a corresponding increase of ≥2 mm in the fellow eye and a reduction in CAS ≥2 points from baseline in the study eye without a corresponding increase of ≥2 points in the fellow eye. In some embodiments, overall response rate comprising proptosis response in the study eye (i.e., reduction of proptosis of ≥2 mm from baseline in the study eye [without a corresponding increase of ≥2 mm in the fellow eye] as measured by exophthalmometer) and clinical activity response in the study eye (i.e., reduction in CAS ≥2 points from baseline in the study eye [without a corresponding increase of ≥2 points in the fellow eye]).

[0354] In some embodiments, a method results in at least 10% overall responder rate. In some embodiments, a method results in at least 15% overall responder rate. In some embodiments, a method results in at least 20% overall responder rate. In some embodiments, a method results in at least 25% overall responder rate. In some embodiments, a method results in at least 30% overall responder rate. In some embodiments, a method results in at least 35% overall responder rate. In some embodiments, a method results in at least 40% overall responder rate. In some embodiments, a method results in at least 45% overall responder rate. In some embodiments, a method results in at least 50% overall responder rate. In some embodiments, a method results in at least 55% overall responder rate. In some embodiments, a method results in at least 60% overall responder rate. In some embodiments, a method results in at least 65% overall responder rate. In some embodiments, a method results in at least 70% overall responder rate. In some embodiments, a method results in at least 75% overall responder rate. In some embodiments, a method results in at least 80% overall responder rate. In some embodiments, a method results in at least 85% overall responder rate. In some embodiments, a method results in at least 90% overall responder rate. In some embodiments, a method results in at least 95% overall responder rate.

[0355] In some embodiments, a method achieves an overall response within 3 weeks from the first administration. In some embodiments, a method achieves an overall response within 6 weeks from the first administration. In some embodiments, a method achieves an overall response within 9 weeks from the first administration.

[0356] In some embodiments, an overall response is maintained for at least 15 weeks. In some embodiments, an overall response is maintained for at least 24 weeks. In some 114 155110240v10Attorney Docket No. VRD-022WO1 embodiments, an overall response is maintained for at least 36 weeks. In some embodiments, an overall response is maintained for at least 52 weeks. In some embodiments, overall response rate is maintained for at least 15 weeks. In some embodiments, overall response rate is maintained for at least 24 weeks. In some embodiments, overall response rate is maintained for at least 32 weeks. In some embodiments, overall response rate is maintained for at least 52 weeks.

[0357] In some embodiments, a method comprises achieving an overall responder rate. In some embodiments, at least 30% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 35% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 40% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 45% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 50% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 55% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 60% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 65% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 70% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 75% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 80% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 85% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 90% of week 15 overall responders maintained an overall response at week 52. In some embodiments, at least 95% of week 15 overall responders maintained an overall response at week 52.

[0358] In some embodiments, at least 30% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 35% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 40% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 45% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 50% of week 15 patients who had an overall response maintained the overall response 115 155110240v10Attorney Docket No. VRD-022WO1 at week 52. In some embodiments, at least 55% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 60% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 65% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 70% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 75% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 80% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 85% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 90% of week 15 patients who had an overall response maintained the overall response at week 52. In some embodiments, at least 95% of week 15 patients who had an overall response maintained the overall response at week 52.

[0359] In some embodiments, the overall responder rate at week 15 is at least 50% and at least 70% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 55% and at least 70% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 60% and at least 70% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 35% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 40% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 45% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 55% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 60% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 65% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 70% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the 116 155110240v10Attorney Docket No. VRD-022WO1 overall responder rate at week 15 is at least 50% and at least 75% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 85% of week 15 overall responders maintained the overall response at week 52. In some embodiments, the overall responder rate at week 15 is at least 50% and at least 90% of week 15 overall responders maintained the overall response at week 52.

[0360] Orbital Fat

[0361] Orbital fat volume can be measured by imaging of the head to facilitate three- dimensional volumetric calculations. Images can be taken at baseline and various timepoints post treatment to assess the change in volume. Imaging may utilize T1 / T2 high resolution with 1 mm slices and thickness of orbits, face and ears without contrast. In some embodiments, orbital fat is measured from MRI and CT scans. In some embodiments, orbital fat is measured from an MRI. In some embodiments, orbital fat is measured from CT scans.

[0362] In some embodiments, administrating an anti-IGF-1R antibody results in an improvement in orbital fat volume as compared to a baseline.

[0363] In some embodiments, the orbital fat volume is reduced by 100-15,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by 100- 15,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by 2,000-15,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by 5,000-10,000 µL as compared to a baseline.

[0364] In some embodiments, the orbital fat volume is reduced by at least 100 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 150 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 190 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 200 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 300 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 400 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 600 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 700 µL as 117 155110240v10Attorney Docket No. VRD-022WO1 compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 800 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 900 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 1,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 1,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 6,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 6,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9,000 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9,500 µL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 10,000 µL as compared to a baseline.

[0365] In some embodiments, an improvement in orbital fat volume is a reduction in volume as compared to baseline. In some embodiments, a method results in at least a 5% reduction in orbital fat volume. In some embodiments, a method results in at least a 10% reduction in orbital fat volume. In some embodiments, a method results in at least a 15% reduction in orbital fat volume. In some embodiments, a method results in at least a 20% reduction in orbital fat volume. In some embodiments, a method results in at least a 25% reduction in orbital fat volume. In some embodiments, a method results in at least a 30% 118 155110240v10Attorney Docket No. VRD-022WO1 reduction in orbital fat volume. In some embodiments, a method results in at least a 35% reduction in orbital fat volume. In some embodiments, a method results in at least a 40% reduction in orbital fat volume. In some embodiments, a method results in at least a 45% reduction in orbital fat volume. In some embodiments, a method results in at least a 50% reduction in orbital fat volume. In some embodiments, a method results in at least a 55% reduction in orbital fat volume. In some embodiments, a method results in at least a 60% reduction in orbital fat volume. In some embodiments, a method results in at least a 65% reduction in orbital fat volume. In some embodiments, a method results in at least a 70% reduction in orbital fat volume. In some embodiments, a method results in at least a 75% reduction in orbital fat volume. In some embodiments, a method results in at least a 80% reduction in orbital fat volume. In some embodiments, a method results in at least a 85% reduction in orbital fat volume. In some embodiments, a method results in at least a 90% reduction in orbital fat volume. In some embodiments, a method results in at least a 95% reduction in orbital fat volume.

[0366] In some embodiments, a reduction in orbital fat volume is achieved within 3 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, a reduction in orbital fat volume is achieved within 6 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, a reduction in orbital fat volume is achieved within 9 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, a reduction in orbital fat volume is achieved within 12 weeks from the first administration of the anti-IGF-1R antibody. In some embodiments, a reduction in orbital fat volume is achieved within 15 weeks from the first administration of the anti-IGF-1R antibody.

[0367] In some embodiments, a reduction in orbital fat volume is maintained for at least 6 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 9 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 12 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 15 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 18 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 21 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 24 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 27 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at 119 155110240v10Attorney Docket No. VRD-022WO1 least 30 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 36 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 52 weeks.

[0368] In some embodiments, a reduction in orbital fat volume of at least 900 µL is maintained for at least 24 weeks. In some embodiments, a reduction in orbital fat volume of at least 500 µL is maintained for at least 36 weeks. In some embodiments, a reduction in orbital fat volume of at least 150 µL is maintained for at least 52 weeks. In some embodiments, a reduction in orbital fat volume of at least 190 µL is maintained for at least 52 weeks. Extraocular Muscles

[0369] Proptosis caused by expansion of extraocular muscles is type 2 orbitopathy. Extraocular muscle volume can be measured by imaging of the head to facilitate three- dimensional volumetric calculations. Images can be taken at baseline and various timepoints post treatment to assess the change in volume. Imaging may utilize T1 / T2 high resolution with 1 mm slices and thickness of orbits, face and ears without contrast. In some embodiments, extraocular muscle volume is assessed as the total rectus muscle volumes. In some embodiments, extraocular muscles are measured from MRI and CT scans. In some embodiments, extraocular muscles are measured from an MRI. In some embodiments, extraocular muscles are measured from CT scans.

[0370] In some embodiments, administrating an anti-IGF-1R antibody results in an improvement in extraocular muscle volume as compared to a baseline.

[0371] In some embodiments, the extraocular muscle volume is reduced by 1,000- 5,000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by 1,500-3,000 µL as compared to a baseline.

[0372] In some embodiments, the extraocular muscle volume is reduced by at least 500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 900 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1,000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1,200 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1,500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is 120 155110240v10Attorney Docket No. VRD-022WO1 reduced by at least 2,000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 2,500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3,000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3,500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4,000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4,500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5,000 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5,500 µL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 6,000 µL as compared to a baseline.

[0373] In some embodiments, a method results in at least a 5% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 10% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 15% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 20% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 25% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 30% reduction in extraocular muscle volume. In some embodiments, a method results in at leas...

Claims

Attorney Docket No. VRD-022WO1 CLAIMS 1. A method of treating active thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a total dose of no more than 80 mg / kg according to a dosing regimen, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6.

2. The method of claim 1, wherein the dosing regimen comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and one or more subsequent doses of the anti- IGF-1R antibody at 10 mg / kg every three weeks.

3. The method of claim 1 or 2, wherein the total dose is 50 mg / kg.

4. The method of claim 1 or 2, wherein the total dose is 15 mg / kg.

5. The method of claim 3 or 4, wherein the method comprises administering four subsequent doses.

6. The method of claim 1 or 2, wherein the total dose is 80 mg / kg.

7. The method of claim 6, wherein the method comprises administering seven subsequent doses.

8. The method of any one of the preceding claims, wherein the method results in at least 35% diplopia resolution, wherein diplopia resolution is determined by a reduction in Gorman subjective diplopia score to 0 from baseline for participants with baseline Gorman subjective diplopia score >0. 162 155110240v10Attorney Docket No. VRD-022WO1 9. The method of claim 8, wherein the at least 35% diplopia resolution is achieved within 3 weeks of the first administration.

10. The method of any one of the preceding claims, wherein the method results in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye.

11. The method of claim 10, wherein the at least 50% proptosis responder rate is achieved within 3 weeks of the first administration.

12. The method of any one of the preceding claims, wherein the method results in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye.

13. The method of claim 11, wherein the at least 30% CAS responder rate is achieved within 3 weeks of the first administration.

14. The method of any one of the preceding claims, wherein the method results in the hearing impairment incidence of less than 10%.

15. The method of any one of the preceding claims, wherein the method results in a reduction in orbital fat volume as compared to a baseline.

16. The method of claim 15, wherein the orbital fat volume is determined using MRI or CT.

17. The method of any one of the preceding claims, wherein the method results in a reduction in extraocular muscle volume as compared to a baseline.

18. The method of claim 17, wherein the extraocular muscle volume is determined using MRI or CT. 163 155110240v10Attorney Docket No. VRD-022WO1 19. A method of treating thyroid eye disease (TED) comprising administering an anti- IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 35% diplopia resolution, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6.

20. The method of any one of claims 8-19, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline.

21. The method of any one of the preceding claims, wherein the treatment results in at least 40% diplopia resolution.

22. The method of any one of the preceding claims, wherein the diplopia resolution is achieved within 3 weeks from the first administration.

23. The method of any one of the preceding claims, wherein the diplopia resolution is achieved within 6 weeks from the first administration.

24. The method of any one of the preceding claims, wherein the diplopia resolution is maintained for at least 12 weeks.

25. The method of any one of the preceding claims, wherein the diplopia resolution is maintained for at least 15 weeks.

26. The method of any one of the preceding claims, wherein the diplopia resolution is maintained for at least 52 weeks. 164 155110240v10Attorney Docket No. VRD-022WO1 27. The method of any one of the preceding claims, wherein the percentage diplopia resolution is a placebo-adjusted value.

28. The method of any one of the preceding claims, wherein the patient has a baseline Gorman Subjective Diplopia Score of >0, 1, 2, or 3.

29. A method of treating thyroid eye disease (TED) comprising administering an anti- IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 50% proptosis responder rate, wherein the proptosis responder is determined by a reduction of proptosis of ≥ 2 mm from baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6.

30. The method of any one of claims 10-18 and 20-29, wherein the treatment results in at least 60% proptosis responder rate.

31. The method of claim 29 or 30, wherein the proptosis responder rate is achieved within 3 weeks of the first administration.

32. The method of any one of claims 10-18 and 20-31, wherein the proptosis responder rate is maintained for at least 12 weeks.

33. The method of any one of claims 10-18 and 17-32, wherein the proptosis responder rate is maintained for at least 15 weeks. 165 155110240v10Attorney Docket No. VRD-022WO1 34. The method of any one of claim 10-18 and 20-33, wherein the method results in at least 70% proptosis responder rate.

35. The method of any one of claims 10-18 and 20-34, wherein the proptosis responder rate is maintained for at least 52 weeks.

36. The method of claim 35, wherein the proptosis responder rate of at least 70% is maintained for at least 52 weeks.

37. The method of any one of claims 29-36, wherein at least 70% of week 15 proptosis responders maintained a proptosis response at week 52.

38. The method of claim 37, wherein the proptosis responder rate at week 15 is at least 50%, and at least 40%, at least 50%, at least 60%, or at least 70% of week 15 proptosis responders maintained a proptosis response at week 52 39. The method of claim 37, wherein the proptosis responder rate at week 15 is at least 60% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52.

40. The method of claim 37, wherein the proptosis responder rate at week 15 is at least 70% and at least 70% of week 15 proptosis responders maintained a proptosis response at week 52.

41. The method of any one of claims 10-18 and 20-40, wherein the percentage proptosis responder rate is a placebo-adjusted value.

42. The method of any one of claims 10-18 and 20-40, wherein the baseline is the proptosis measurement prior to the first administration.

43. The method of any one of the preceding claims. wherein the patient had a baseline proptosis of ≥ 16 mm. 166 155110240v10Attorney Docket No. VRD-022WO1 44. The method of any one of the preceding claims, wherein the patient had a baseline proptosis of ≥ 20 mm.

45. The method of any one of the preceding claims, wherein the treatment results in the reduction of proptosis of ≥2.5 mm from baseline.

46. The method of any one of claims 10-18 and 20-45, wherein proptosis is measured by exophthalmometer.

47. The method of claim 46, wherein the exophthalmometer is a hertel exophthalmometer.

48. The method of any one of claims 10-18 and 40-45, wherein proptosis is measured by imaging.

49. The method of claim 48, wherein the imaging is magnetic resonance imaging (MRI) or computed tomography (CT).

50. A method of treating thyroid eye disease (TED), comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in at least 30% CAS responder rate, wherein the CAS responder is determined by a reduction in CAS of ≥ 2 points from a baseline in the study eye, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6. 167 155110240v10Attorney Docket No. VRD-022WO1 51. The method of claim 50, wherein the at least 30% CAS responder rate is achieved within 3 weeks of the first administration.

52. The method of any one of claims 12-18, 20-28, and 30-51, wherein the CAS responder rate is maintained for at least 52 weeks.

53. The method of any one of the preceding claims, wherein the treatment results in a reduction of CAS of ≥2.5 from a baseline in the study eye.

54. The method of any one of the preceding claims, wherein the treatment results in a reduction of CAS of ≥3 from a baseline in the study eye.

55. The method of claim 54, wherein the reduction of CAS of ≥2.5 from a baseline in the study eye is maintained for at least 52 weeks.

56. The method of claim 54, wherein the reduction of CAS of ≥3 from a baseline in the study eye is maintained for at least 52 weeks.

57. The method of any one of claims 19-56, wherein the patient has a baseline CAS of 0- 7.

58. The method of any one of the preceding claims, wherein the patient has the baseline CAS of ≥ 2.

59. The method of any one of the preceding claims, wherein the treatment results in hearing impairment incidence of less than 10%.

60. The method of claim 59, wherein the hearing impairment incidence of less than 10% is maintained for the treatment period.

61. The method of claim 59, wherein the hearing impairment incidence of less than 10% is maintained for at least 15 weeks. 168 155110240v10Attorney Docket No. VRD-022WO1 62. The method of claim 59, wherein the hearing impairment incidence of less than 10% is maintained for at least 52 weeks.

63. The method of any one of claims 14 and 59-62, wherein the treatment results in hearing impairment incidence of less than 8%.

64. The method of any one of the preceding claims, wherein the treatment results in hearing impairment incidence of less than 6%.

65. The method of any one of the preceding claims, wherein the treatment does not result in hearing impairment incidence.

66. The method of any one of claims 14 and 59-65, wherein the percentage of hearing impairment incidence is a placebo-adjusted value.

67. A method of treating thyroid eye disease (TED) comprising administering to a patient an anti-IGF-1R antibody at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to reduce one or more symptoms associated with TED, wherein the administering of the anti-IGF-1R antibody results in the hearing impairment incidence of less than 10%, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6.

68. The method of claim 67, wherein the hearing impairment incidence is less than the 8%. 169 155110240v10Attorney Docket No. VRD-022WO1 69. The method of claim 67 or 68, wherein the hearing impairment incidence is less than the 6%.

70. The method of any one of claims 67-69, wherein the hearing impairment incidence of less than 10% is maintained for the treatment period.

71. The method of any one of claims 67-70, wherein the hearing impairment incidence of less than 10% is maintained for at least 15 weeks.

72. The method of any one of claims 67-71, wherein the hearing impairment incidence of less than 10% is maintained for at least 52 weeks.

73. The method of any one of claims 67-72, wherein the percentage of hearing impairment incidence is a placebo-adjusted value.

74. The method of any one of the preceding claims, wherein the treatment results in at least 40% clinical activity responder rate.

75. The method of any one of the preceding claims, wherein the treatment results in at least 25% diplopia responder rate within 3 weeks of the first administration.

76. The method of claim 75, wherein the treatment results in at least 30%, at least 40%, at least 50%, at least 55%, or at least 60% diplopia responder rate in diplopia resolution.

77. The method of claim 75 or 76, wherein the diplopia responder rate is maintained for at least 15 weeks.

78. The method of any one of claims 75-77, wherein the diplopia responder rate is maintained for at least 52 weeks.

79. The method of any one of the preceding claims, wherein the treatment results in at least 1.5 mm reduction from baseline in proptosis within 3 weeks of the first administration. 170 155110240v10Attorney Docket No. VRD-022WO1 80. The method of claim 79, wherein the administering of the anti-IGF-1R antibody results in at least 2.5 mm reduction from baseline in proptosis within 9 weeks of the first administration.

81. The method of any one of the preceding claims, wherein the treatment results in CAS of 0 or 1 in the study eye.

82. The method of any one of the preceding claims, wherein the treatment period is at least 9 weeks, at least 12 weeks.

83. The method of claim 82, wherein the treatment period is at least 15 weeks.

84. The method of claim of 82 or 83, wherein the treatment period is no more than 24 weeks.

85. The method of any one of the preceding claims, wherein the patient does not have hearing impairment prior to the treatment.

86. The method of any one of the preceding claims, wherein the patient has hearing impairment prior to treatment.

87. The method of any one of the preceding claims, wherein the patient, prior to treatment, had proptosis of ≥3 mm above normal values for race and gender.

88. The method of any one of the preceding claims, wherein the patient had a CAS of ≥3 prior to treatment.

89. The method of any one of the preceding claims, wherein the patient, prior to treatment, had lid retraction of ≥2 mm.

90. The method of any one of the preceding claims, wherein the patient, prior to treatment, had moderate or severe soft tissue involvement. 171 155110240v10Attorney Docket No. VRD-022WO1 91. The method of any one of the preceding claims, wherein the patient, prior to treatment, had periodic or constant diplopia.

92. The method of any one of the preceding claims, wherein the patient has had documented signs and symptoms of TED for no longer than 15 months.

93. The method of any one of the preceding claims, wherein the treatment results in substantially no incidence of anti-drug antibody (ADA) as compared to placebo.

94. The method of any one of the preceding claims, wherein the anti-IGF-1R antibody comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3, and a light chain variable region (VL) having an amino acid sequence of SEQ ID NO:

2.

95. The method of any one of the preceding claims, wherein the anti-IGF-1R antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO: 10, and a light chain having an amino acid sequence of SEQ ID NO:

11.

96. The method of any one of the claims 1-94, wherein the anti-IGF-1R antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO: 14, and a light chain having an amino acid sequence of SEQ ID NO:

15.

97. The method of any one of the preceding claims, wherein the patient is at least 18 years of age or older.

98. The method of any one of the preceding claims, wherein the patient had not received prior treatment with another anti-IGF-1R therapy.

99. The method of any one of claims 1-97, wherein the patient has received prior treatment with another anti-IGF-1R therapy. 172 155110240v10Attorney Docket No. VRD-022WO1 100. The method of any one of the preceding claims, wherein the patient, prior to the treatment, did not have a compressive optic neuropathy of TED that is expected to require surgical decompression in the immediate future.

101. The method of any one of the preceding claims, wherein the patient, prior to the treatment, did not have corneal decompensation in the study eye unresponsive to medical management.

102. The method of any one of the preceding claims, wherein the patient did not have a decrease in CAS of ≥2 points in the study eye between screening assessment and Day -1.

103. The method of any one of the preceding claims, wherein the patient did not a decrease in proptosis of ≥2 mm in the study eye between screening assessment and Day -1.

104. The method of any one of the preceding claims, wherein the patent, prior to the treatment, have not had previous orbital irradiation or decompression surgery involving excision of fat for TED to the study eye’s orbit.

105. The method of any one of the preceding claims, wherein administering an anti-IGF- 1R antibody results in an improvement in orbital fat volume and / or extraocular muscle volume.

106. A method of treating thyroid eye disease (TED) comprising administering an anti- IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to result in a reduction in orbital fat volume and / or extraocular muscle volume as compared to a baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6. 173 155110240v10Attorney Docket No. VRD-022WO1 107. The method of claim 105 or 106, wherein the orbital fat volume is reduced by at least 3000 µL as compared to a baseline.

108. The method of any one of claims 105-107, wherein the orbital fat volume is reduced by at least 7000 µL as compared to a baseline.

109. The method of any one of claims 105-108, wherein the extraocular muscle volume is reduced by at least 1500 µL as compared to a baseline.

110. The method of any one of claims 105-109, wherein the extraocular muscle volume is reduced by at least 2500 µL as compared to a baseline.

111. The method of any one of claims 105-110, wherein the extraocular muscle volume is determined using MRI or CT.

112. The method of any one of claims 105-111, wherein the orbital fat volume is determined using MRI or CT.

113. The method of any one of claims 105-112, wherein the baseline is a value prior to the administration of the anti-IGF-1R antibody.

114. The method of any one of claims 105-112, wherein the baseline is a patient without the administration of the anti-IGF-1R antibody.

115. The method of any one of claims 105-112, wherein the baseline is a historical data of the same disease condition.

116. The method of any one of claims 19-115, wherein the method comprises administering the anti-IGF-1R antibody at a first dose of 10 mg / kg and at least four subsequent doses of 10 mg / kg every three weeks. 174 155110240v10Attorney Docket No. VRD-022WO1 117. The method of claim 116, wherein the method comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and four subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks.

118. The method of any one of claims 19-117, wherein the method comprises administering the anti-IGF-1R antibody to the patient at a total dose of 50 mg / kg.

119. The method of any one of claims 19-116, wherein the method comprises administering a first dose of the anti-IGF-1R antibody at 10 mg / kg and seven subsequent doses of the anti-IGF-1R antibody at 10 mg / kg every three weeks.

120. The method of any one of claims 19-116 and 119, wherein the method comprises administering the anti-IGF-1R antibody to the patient at a total dose of 80 mg / kg.

121. The method of any one of the preceding claims, wherein the method further comprises administering magnesium to the subject.

122. The method of claim 121, wherein the magnesium is administered prior to, during, or after the administration of the anti-IGF-1R antibody.

123. The method of claim 121, wherein the magnesium is administered 1-2 days prior to subsequent administration of the anti-IGF-1R antibody.

124. The method of any one of claims 121-123, wherein the magnesium is administered at a dose of 200-600 mg.

125. The method of claim 124, wherein the magnesium is administered at a dose of 400 mg.

126. The method of any one of claims 121-125, wherein the magnesium is administered orally. 175 155110240v10Attorney Docket No. VRD-022WO1 127. The method of any one of the preceding claims, wherein the treatment results in an improvement in Graves’ Orbitopathy-Quality of Life (GO-QOL) score.

128. The method of claim 127, wherein the treatment results in an at least 8 point improvement in GO-QOL score.

129. A method of treating thyroid eye disease (TED) comprising administering an anti- IGF-1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for a treatment period sufficient to at least 8 point improvement in GO-QOL score as compared to baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO:

6.

130. The method of any one of claims 127-129, wherein the improvement in GO-QOL score is in GO-QOL combined score.

131. The method of any one of claims 127-129, wherein the improvement in GO-QOL score is in GO-QOL activity subscale score.

132. The method of any one of claims 127-129, wherein the improvement in GO-QOL score is in GO-QOL appearance subscale score.

133. The method of any one of claims 127-132, where the improvement in GO-QOL score is maintained for at least 24 weeks.

134. The method of any one of claims 127-133, where the improvement in GO-QOL score is maintained for at least 36 weeks. 176 155110240v10Attorney Docket No. VRD-022WO1 135. The method of any one of claims 127-134, where the improvement in GO-QOL score is maintained for at least 52 weeks. 177 155110240v10

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