Compositions and methods for treating thyroid eye disease

Abstract

Provided herein are antibodies and compositions against IGF-1R, and uses thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 266,548, filed January 7, 2022, which is incorporated by reference in its entirety.

[0002] REFERENCE TO ELECTRONICALLY SUBMITTED SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated by reference in its entirety. A copy of this XML, created on January 3, 2023, is named "257635_000702_Seq.XML" and is 247,215 bytes in size. [Background technology]

[0003] Thyroid-associated eye disease (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyrotoxic exophthalmos, thyroid dysfunction eye disease, and several other terms, is an eye disease associated with thyroid dysfunction. TAO is divided into two types. Active TAO, which usually lasts 1-3 years, is characterized by a progressive autoimmune / inflammatory reaction in the soft tissues of the orbit. Active TAO is responsible for the swelling and remodeling of the ocular soft tissues. The autoimmune / inflammatory reaction of active TAO resolves spontaneously and the condition transitions to inactive TAO. Inactive TAO is the term used to describe the long-term / persistent sequelae of active TAO. The cause of TAO is unknown. TAO is usually associated with Grave's hyperthyroidism, but can also occur as part of other autoimmune conditions that affect the thyroid gland and produce pathology in the orbit and periorbital tissues and, rarely, in the pretibial skin (pretibial myxedema) or digits (thyroid clubbed dactyly). TAO is an autoimmune ophthalmopathy in which the orbit and periocular soft tissues are primarily affected, with the eyes and vision secondarily affected. In TAO, the eyeball is pushed forward (bulged) out of the orbit (a phenomenon called proptosis or exophthalmos) as a result of inflammation and swelling of the orbital soft tissues, primarily the eye muscles and fat. Although most cases of TAO do not result in blindness, the condition can cause sight-threatening lagophthalmos, troublesome diplopia (double vision), and compressive hypothyroid optic neuropathy. TAO may precede, occur simultaneously with, or follow the systemic complications of thyroid insufficiency. Ocular manifestations of TAO include upper eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis, and eyeball swelling (proptosis or exophthalmos), conjunctival edema, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic impacts. Many signs and symptoms of TAO, including proptosis and ocular congestion, result from expansion of orbital adipose tissue and periocular muscles. Adipose tissue volume is due, in part, to fat cell growth (adipogenesis) within the orbital fat.Accumulation of hydrophilic glycosaminoglycans (mainly hyaluronic acid) within the orbital adipose tissue and within the perimuscular connective tissue between extraocular muscle fibers further expands the adipose compartment and the extraocular muscle body. Hyaluronic acid is produced by fibroblasts located within the orbital fat and extraocular muscles, and in vitro hyaluronic acid synthesis is stimulated by several cytokines and growth factors, including IL-1β, interferon-γ, platelet-derived growth factor, thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-1).

[0004] Antibodies that activate the insulin-like growth factor I receptor (IGF-IR) have also been detected in active TAO and have been suggested. Without being bound by any theory, it is believed that TSHR and IGF-IR form a physical and functional complex in orbital fibroblasts, and blocking IGF-IR appears to attenuate both IGF-1 and TSH-dependent signaling. It has been suggested that blocking IGF-IR with an antibody antagonist may reduce both TSHR and IGF-I-dependent signaling, thus preventing the pathological activity of autoantibodies that act as agonists at either receptor.

[0005] IGF-IR is a ubiquitously expressed heterotetrameric protein involved in the regulation of growth and metabolic functions in many cell types. IGF-IR is a tyrosine kinase receptor that contains two subunits. IGF-IRα contains the ligand binding domain, while IGF-IRβ is involved in signal transduction and contains a tyrosine phosphorylation site.

[0006] Current treatments for hyperthyroidism due to Graves' disease are incomplete due to the lack of treatments that target the specific pathogenic autoimmune mechanisms underlying the disease. The treatment of moderate to severe active TAO is even more complex. Although the pathogenesis of TAO has become better understood in recent years, TAO remains a therapeutic challenge and a difficult problem. No drugs are approved to treat active TAO. Patients with moderate to severe active TAO have been treated with intravenous glucocorticoids (ivGC) and oral glucocorticoids, but have rarely achieved satisfactory results. Partial responses are frequent and relapse (rebound) after discontinuation of medication is not uncommon. Adverse events are real and many patients eventually require rehabilitative surgery when the condition transitions to inactive TAO. Thus, there remains a need to provide alternative treatments for TAO and its associated conditions. Summary of the Invention

[0007] Provided herein is an antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain selected from the group consisting of SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, and 1731. and a light chain CDR sequence selected from the group consisting of SEQ ID NOs: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, and 207.

[0008] In some embodiments, provided herein is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) sequence selected from the group consisting of SEQ ID NOs: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 61, and 65; and a light chain variable region (VL) sequence selected from the group consisting of SEQ ID NOs: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, and 64.

[0009] In some embodiments, any of the antibodies or antigen-binding fragments provided herein bind to the insulin-like growth factor I receptor (IGF-1R). In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is an scFv antibody.

[0010] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH peptide comprising the amino acid sequence set forth in SEQ ID NO: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, or 64, or any variant thereof.

[0011] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VL peptide comprising the amino acid sequence set forth in SEQ ID NO: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, or 64, or any variant thereof.

[0012] In some embodiments, a heavy chain variable region is provided comprising: (i) a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences, wherein the HCDR1 sequence has the amino acid sequence of SEQ ID NO: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, or 154; the HCDR2 sequence has the amino acid sequence of SEQ ID NO: 155, 156, 157, 158, 159, 160, 161, 162, 163, or 164; and the HCDR3 sequence has the amino acid sequence of SEQ ID NO: 165, 166, 167, 168, 169, 170, 171, 172, or 173, or a variant of any of the foregoing; and (ii) an LCDR1, an LCDR2, or an HCDR3 sequence comprising an LCDR1, an LCDR2, or an HCDR3 sequence comprising an LCDR3, an LCDR4, or an HCDR5 sequence comprising an LCDR5, an LCDR6, or an HCDR7 sequence comprising an LCDR8, an LCDR9, or an HCDR10 sequence comprising an LCDR11, an LCDR12, or an HCDR13 sequence comprising an LCDR14, an LCDR15, an LCDR16, an LCDR17, or an HCDR18 sequence comprising an LCDR19, an LCDR20, an LCDR210, an LCDR22, or an HCDR33 sequence comprising an LCDR31, an LCDR32, or an HCDR34 sequence comprising an LCDR4, an LCDR50, or an HCDR16 sequence comprising an LCDR50, an LCDR610, or an HCDR111 sequence comprising an LCDR12 and a light chain variable region comprising an LCDR1 sequence having the amino acid sequence of SEQ ID NO: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190; an LCDR2 sequence having the amino acid sequence of SEQ ID NO: 191, 192, 193, 194, 195, 196, 197, or 198; and an LCDR3 sequence having the amino acid sequence of SEQ ID NO: 199, 200, 201, 202, 203, 204, 205, 206, or 207, or a variant of any of the foregoing.

[0013] In some embodiments, an antibody or antigen-binding fragment thereof is provided, comprising a VH and VL pair comprising an amino acid sequence of SEQ ID NO: 66-142 or a variant thereof.

[0014] In some embodiments, a method of treating thyroid associated eye disease (TAO) or a symptom of TAO, or reducing the severity of TAO or a symptom of TAO, is provided, comprising administering to a subject any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0015] In some embodiments, provided is a method of reducing exophthalmos in a subject suffering from thyroid associated eye disease (TAO), comprising administering to the subject any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0016] In some embodiments, a method of treating thyroid eye disease in a subject is provided comprising administering to the subject any antibody disclosed herein or any pharmaceutical composition disclosed herein.

[0017] In some embodiments, a method of reducing Thyroid Associated Eye Disease (TAO) Clinical Activity Score (CAS) in a subject is provided, comprising administering to the subject any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0018] In some embodiments, provided is a method of a) reducing exophthalmos by at least 2 mm, and b) lowering Clinical Activity Score (CAS) in a subject suffering from Thyroid Associated Eye Disease (TAO), comprising administering to the subject any antibody disclosed herein or any pharmaceutical composition disclosed herein.

[0019] In some embodiments, provided is a method of treating or reducing the severity of diplopia in a subject suffering from thyroid associated eye disease (TAO), comprising administering to the subject any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0020] In some embodiments, a method is provided for increasing internalization of IGF-1R in a cell, the method comprising contacting the cell with any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0021] In some embodiments, a method of inhibiting IGF-1 stimulated receptor phosphorylation in a cell is provided, the method comprising contacting the cell with any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0022] In some embodiments, a method of treating thyroid eye disease in a subject is provided, the method comprising administering to the subject any antibody disclosed herein or any pharmaceutical composition disclosed herein, wherein the antibody has a serum concentration in the subject of at least or about 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, or 105 μg / mL at least 1, 2, or 3 weeks after administration. [Brief description of the drawings]

[0023] [Figure 1] 1 shows NHP (non-human primate) serum concentrations of various antibodies and embodiments provided herein. [Diagram 2] Various properties of the antibodies provided herein are shown. [Diagram 3] Various properties of the antibodies provided herein are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Provided herein are antibodies that bind to and regulate the activity of IGF-1R. The antibodies can be used, for example, to treat thyroid eye disease.

[0025] As used herein, "thyroid-associated eye disease" (TAO), "thyroid eye disease" (TED), "Graves' eye disease," or "Graves' ophthalmopathy" (GO) refer to the same disorder or condition and are used interchangeably. They all refer to an inflammatory orbital pathology associated with several autoimmune thyroid disorders, most commonly "Graves' disease" (GD), but occasionally with other disorders, such as Hashimoto's thyroiditis.

[0026] The terms "proptosis" and "exophthalmos" (also known as exophthalmos, exophthalmia, or exorbitism) refer to the forward projection, movement, bulging, or protrusion of an organ. As used herein, the term refers to the forward projection, movement, bulging, or protrusion of the eye out of the orbit. Proptosis and exophthalmos are considered by those of skill in the art to have the same meaning and are often used interchangeably, although some have observed slight differences in their meaning. Exophthalmos is used by some to mean severe bulging of the eye; or to mean endocrine-related bulging of the eye. Still others use the term exophthalmos to describe bulging associated with the eye, for example, in subjects with TAO (TED or GO).

[0027] As used herein, "proptosis" and "exophthalmos" are used interchangeably and refer to the forward projection, displacement, bulging, or protrusion of the eye out of the orbit. Because the orbit is a rigid bony structure with only an anterior opening for expansion, any increase in orbital soft tissue content arising from the sides or posterior will force the eye forward. Proptosis or exophthalmos can be the result of several disease processes including infection, inflammation, tumor, trauma, metastasis, endocrine lesions, vascular disease, and extraorbital lesions. TAO (TED or GO) is now recognized as the most common cause of exophthalmos in adults. Exophthalmos can be either bilateral, as is often seen with TAO (TED or GO), or unilateral, as is often seen with orbital tumors.

[0028] Measurement of the degree of exophthalmos can be performed, for example, using an exophthalmometer, an instrument used to measure the forward mobility of the eye. This device allows the measurement of the distance from the lateral orbital margin to the anterior cornea. Computed tomography (CT) scanning and magnetic resonance imaging (MRI) can also be used to measure the degree of exophthalmos or proptosis. CT scanning is an excellent imaging technique for the diagnosis of TAO. In addition to allowing visualization of the enlarged extraocular muscles, CT scans provide the surgeon or clinician with a depiction of the bony anatomy of the orbit when orbital decompression is required. MRI, with its multiplanar and inherent contrast capabilities, provides excellent imaging of the orbital volume without the radiation exposure associated with CT scan studies. MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, while CT scans provide a better view of the bony structure of the orbit. Orbital ultrasound can also be used to diagnose and evaluate TAO, as it can be performed quickly with a high degree of reliability. Hyperreflectivity and hypertrophy of extraocular muscles are easily measured, and serial ultrasound imaging can also be used to monitor the progression or safety of eye disease. Based on currently available technology, or technology that will become available in the future, one skilled in the art can determine the best means to diagnose and monitor proptosis or exophthalmos.

[0029] As used herein, the term "antibody" refers to any form of antibody that exhibits the desired biological activity. Thus, the term 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. A "parent antibody" is an antibody that is obtained by exposing the immune system to an antigen before modifying the antibody for use, e.g., humanizing the antibody for use as a human therapeutic antibody.

[0030] As used herein, unless otherwise specified, "antibody fragment" or "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability to specifically bind to the antigen bound by the full-length antibody, e.g., a fragment that retains one or more CDR regions. Examples of antibody-binding fragments include 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.

[0031] A "Fab fragment" is a fragment that contains one light chain and one heavy chain CH. 1 and a variable region. The heavy chain of a Fab molecule cannot form disulfide bonds with another heavy chain molecule.

[0032] The "Fc" region is the C region of an antibody. H 1 and C H The heavy chain fragments contain two heavy chain fragments each containing two domains. The two heavy chain fragments are connected by two or more disulfide bonds and by a CH 3 The domains are held together by hydrophobic interactions.

[0033] In some embodiments, the antibodies, or antigen fragments herein, comprise an Fc region. In some embodiments, the Fc region comprises a mutation that extends the half-life of the antibody when bound to the Fc region. In some embodiments, the Fc region comprises an S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutation, or any combination thereof. In some embodiments, the Fc region comprises an M252Y, S254T, and T256E mutation. A non-limiting example of an Fc region comprising an M252Y, S254T, and T256E mutation (collectively, "YTE mutations") can be found in the sequence of SEQ ID NO: 89. In some embodiments, an Fc region comprising a YTE mutation comprises the sequence of SEQ ID NO: 90, which differs from SEQ ID NO: 89 in the presence of a C-terminal lysine (K) residue. The numbering of the Fc region can follow the Kabat numbering system for Fc regions.

[0034] In some embodiments, the Fc region comprises S228P and L235E mutations. In some embodiments, the antibody comprises L234F, L235E, and P331S mutations. In some embodiments, the Fc region comprises M252Y, S254T, T256E, S228P, and L235E mutations. In some embodiments, the Fc region comprises S228P, L235E, M428L, and N434S mutations. In some embodiments, the Fc region comprises M428L and N434S mutations. In some embodiments, the Fc region comprises L234F, L235E, P331S, M252Y, S254T, and T256E mutations. Mutations in the Fc region are also described in US2007041972A1, EP2235059B1, U.S. Patent No. 8,394,925, and Mueller et al, Mol Immunol 1997 Apr;34(6):441-52, each of which is incorporated by reference in its entirety. Numbering referenced herein refers to the Kabat numbering system for the Fc region.

[0035] In some embodiments, the Fc region comprises a sequence selected from the following: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 208); APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 209); APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 210); ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 211); ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 212); ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 213); ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 214); or ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (sequence number 215).

[0036] A "Fab' fragment" is a fragment that contains one light chain and one V H Domain and C H 1 domain, as well as C H 1 and C H and a portion or fragment of one heavy chain, which also contains the region between the two domains, and an interchain disulfide bond is formed between the two heavy chains of the two Fab' fragments to form F(ab') 2 It contains so that the molecule can be formed.

[0037] "F(ab') 2The "fragment" consists of two light chains and a C H 1 and C H 2 F(ab') comprises two heavy chains that contain a portion of the constant region between the F(ab') domains, such that interchain disulfide bonds are formed between the two heavy chains. 2 The fragment is composed of two Fab' fragments linked together by disulfide bonds between the two heavy chains.

[0038] The "Fv region" comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0039] The term "single chain Fv" or "scFv" antibody refers to the V H and V L Fv refers to an antibody fragment that contains V domains, which domains are present in a single polypeptide chain. Generally, an Fv polypeptide comprises an Fv polypeptide that enables the scFv to form the desired structure for antigen binding. H and V L The scFv domains further comprise a polypeptide linker between them. For a review of scFvs, see, e.g., Pluckthun (1994) The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315. See also International Patent Application Publication No. 88 / 01649, and U.S. Patent Nos. 4,946,778 and 5,260,203.

[0040] A "domain antibody" is an immunologically functional immunoglobulin fragment that contains only the variable region of a heavy chain or the variable region of a light chain. H The two V domains are covalently linked with a peptide linker to create a bivalent domain antibody. H The regions can target the same or different antigens.

[0041] A "bivalent antibody" contains two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody may be bispecific (see below).

[0042] In certain embodiments, the monoclonal antibodies herein also include camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO94 / 04678; WO94 / 25591; U.S. Patent No. 6,005,079. In one embodiment, the present invention relates to a camelized single domain antibody comprising two V-domain antibodies modified to form a single domain antibody. H A single domain antibody comprising the domain is provided.

[0043] As used herein, the term "diabody" refers to small antibody fragments with two antigen-binding sites, which are composed of a light chain variable domain (V L ) connected to a heavy chain variable domain (V H )(V H -V L , or V L -V H ). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains can be paired with complementary domains on another chain to generate two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93 / 11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448. For a review of recombinant antibody variants, see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136.

[0044] Typically, the variant antibodies or antigen-binding fragments of the antibodies provided herein retain at least 10% of their IGF-1R binding activity (compared to the modified parent antibody) when activity is expressed on a molar basis. In some embodiments, the variant antibodies (or antigen-binding fragments thereof) or antigen-binding fragments of the antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the IGF-1R binding affinity of the parent antibody. As described herein, it is also intended that the antibodies or antigen-binding fragments of the present invention can include conservative or non-conservative amino acid substitutions, which can also be referred to as "conservative variants" or "function-conservative variants" of the antibodies, that do not substantially change their biological activity.

[0045] "Isolated antibody" refers to a binding compound in a purified state, and in this context means that the molecule is substantially free of other biological molecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials (such as cellular debris and growth medium). In general, the term "isolated" is not intended to imply the complete absence of such materials, or the absence of water, buffers, or salts, unless present in amounts that would substantially interfere with the experimental or therapeutic uses of the binding compounds described herein.

[0046] As used herein, the term "monoclonal antibody" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence, except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations usually contain a large number of different antibodies, often with different amino acid sequences in the variable domains (especially the CDRs), specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogenous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use according to the invention may be made by the hybridoma method first described by Kohler et al (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using the techniques described in, for example, Clackson et al., Nature 352:624-628 (1991) and Marks et al. (1991) J. Mol. Biol. 222:581-597. See, e.g., Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0047] As used herein, a "chimeric antibody" is an antibody having a variable domain derived from a first antibody and a constant domain derived from a second antibody, where the first and second antibodies are from different species (U.S. Pat. No. 4,816,567, and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81: 6851-6855). Typically, the variable domains are obtained from an antibody derived from a laboratory animal such as a rodent (the "parent antibody"), and the constant domain sequences are obtained from a human antibody, such that the resulting chimeric antibody is less likely to provoke an adverse immune response in a human subject than the parent (e.g., rodent) antibody.

[0048] As used herein, the term "humanized antibody" refers to forms of antibodies that contain sequences derived from both human and non-human (e.g., mouse, rat) antibodies. In general, a humanized antibody will contain substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. The humanized antibody may optionally contain at least a portion of a human immunoglobulin constant region (Fc).

[0049] The term "fully human antibody" refers to an antibody that contains only human immunoglobulin protein sequences. A fully human antibody may contain mouse glycosylation if made in a mouse, a mouse cell, or a hybridoma derived from a mouse cell. Similarly, a "mouse antibody" refers to an antibody that contains only mouse immunoglobulin sequences. Alternatively, a fully human antibody may contain rat glycosylation if made in a rat, a rat cell, or a hybridoma derived from a rat cell. Similarly, a "rat antibody" refers to an antibody that contains only rat immunoglobulin sequences.

[0050] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair comprising one "light chain" (about 25 kDa) and one "heavy chain" (about 50-70 kDa). The amino-terminal portion of each chain comprises a variable region of about 100-110 or more amino acids in length that is primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region that is primarily responsible for effector function. Human light chains are typically classified as kappa and lambda light chains. Human heavy chains are further typically classified as μ, δ, γ, α, or ε, defining the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also comprising a "D" region of about 10 or more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)).

[0051] The variable regions of each light / heavy chain pair form the antibody binding site. Thus, an intact antibody generally has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are generally the same.

[0052] Typically, both heavy and light chain variable domains contain three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FRs). The CDRs are usually aligned by the framework regions, allowing binding to a specific epitope. Generally, from the N-terminus to the C-terminus, both light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignments for each domain generally follow the definitions in Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0053] As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody that are involved in antigen binding. The hypervariable region refers to amino acid residues from the "complementarity determining regions" or "CDRs" (i.e., residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2), and 95-102 (CDRH3) in the heavy chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.), and / or those residues from the "hypervariable loops" (i.e., residues 26-32 (CDRL1), 50-52 (CDRL2), and 91-96 (CDRL3) in the light chain variable domain and 26-32 (CDRH1), 53-55 (CDRH2), and 96-101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917). As used herein, the term "framework" or "FR" refers to variable domain residues other than the hypervariable region residues defined herein as CDR residues. The CDRs provide the majority of contact residues for binding of the antibody to an antigen or epitope. The CDRs of interest can be derived from the variable heavy and light chain sequences of a donor antibody, and also include analogs of naturally occurring CDRs that share or retain the same antigen-binding specificity and / or neutralizing capacity as the donor antibody from which they are derived.

[0054] The antibodies may be any of the following: US patents or patent publications: US7,417,130, US2004 / 132094, US5,831,012, US2004 / 023334, US7,250,297, US6,818,418, US2004 / 209243, US7,838,629, US7,186,524, US6,004,746, US5,475,096, US2004 / 146 938, US2004 / 157209, US6,994,982, US6,794,144, US2010 / 239633, US7,803,907, US2010 / 119446, and / or US7,166,697 (the entire contents of each of which are incorporated herein by reference). The antibody may take the form of a monoclonal antibody (VHH), a single chain antibody (scFv), a shark heavy chain only antibody (VNAR), a microprotein (cysteine ​​knot protein, knottin), a DARPin; a tetranectin; an affibody; a transbody; an anticalin; an adnectin; an affilin; a microbody; a peptide aptamer; an alterase; a plastic antibody; a phylomer; a stradobody; a maxibody; a shrimp body; a finomer, an armadillo repeat protein, a Kunitz domain, an avimer, an atrimer, a probody, an immunobody, a triomab, a troibody; a pepbody; a vaccibody, a unibody; an affimer, a duobody, an Fv, a Fab, a Fab', a F(ab')2, a peptidomimetic molecule, or a synthetic molecule. See also Storz MAbs. 2011 May-Jun; 3(3):310-317, which is incorporated herein by reference.

[0055] The term "antigen" as used herein means any molecule capable of generating or binding to an antibody, either directly or indirectly. The definition of "antigen" includes protein-encoding nucleic acids. "Antigen" can also refer to the binding partner of an antibody. In some embodiments, the antigen is an IGF-1R protein expressed on the cell surface. In some embodiments, the cell is an intact cell. An intact cell is a cell that has not been lysed or broken open with detergent or other reagents. A cell that has been treated with a detergent or other reagent that breaks or creates holes in the cell membrane is not an intact cell. For example, provided herein is a method for generating an antibody that binds to an IGF-1R protein, the method comprising culturing a cell that contains a nucleic acid molecule encoding the IGF-1R antibody.

[0056] As used herein, "specific binding," or "immunospecific binding," or "immunospecifically binds" refers to an antibody that binds to a given antigen (e.g., IGF-1R) or epitope present in an antigen. In some embodiments, the antibody binds to a given antigen (e.g., IGF-1R) or epitope present in an antigen. -7 The following dissociation constant (K D ) and binds to non-specific antigens other than the designated antigen (e.g., BSA, casein, or other non-specific polypeptides) D At least twice as small as Dand binds to a given antigen. The phrases "antibody that recognizes IGF-1R" and "antibody specific for IGF-1R" are used herein interchangeably with the term "antibody that immunospecifically binds to IGF-1R". In the present disclosure, reference may be made to IGF-1R. The degree of specificity required for an anti-IGF-1R antibody may depend on the intended use of the antibody, and in any event is defined by its suitability for use for the intended use. In some embodiments, the antibody or binding compound derived from the antigen-binding site of the antibody of the contemplated method binds to its antigen (IGF-1R) with an affinity that is at least 2-fold greater, at least 10-fold greater, at least 20-fold greater, or at least 100-fold greater than its affinity for any other antigen.

[0057] Methods for measuring mAb specificity and affinity by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993), and Muller, Meth. Enzymol. 92:589 601 (1983), which are incorporated herein by reference in their entireties.

[0058] The term "homolog" refers to a protein sequence having 40% to 100% sequence homology or identity to a reference sequence. The percent identity between two peptide chains can be measured by pairwise alignment using the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carslbad, Calif.) with default settings. In some embodiments, the antibody, or antigen-binding fragment thereof, has at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to a sequence described herein. In some embodiments, the antibody has conservative substitutions compared to the sequences described herein. Exemplary conservative substitutions are shown in Table 1 and are within the scope of the disclosed subject matter. Conservative substitutions can be present in the framework regions or antigen-binding sites as long as they do not adversely affect the properties of the antibody. Substitutions can be made to improve the properties of the antibody, such as stability or affinity. Conservative substitutions produce molecules that have similar functional and chemical properties to the molecule to which such modification is made. Exemplary amino acid substitutions are shown in the table below.

[0059] [Table 1]

[0060] In some embodiments, variants of the proteins and peptides provided herein are provided. In some embodiments, the variants comprise substitutions, deletions, or insertions. In some embodiments, the variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions. The substitutions described herein can be conservative substitutions. In some embodiments, the substitutions are non-conservative. In some embodiments, the variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions. In some embodiments, the variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) insertions. In some embodiments, the substitutions, deletions, or insertions are present in the CDRs provided herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided herein.

[0061] The term "in combination with" as used herein means that the agents described can be administered to an animal or subject together as a mixture, simultaneously as a single agent, or sequentially in any order as a single agent.

[0062] Techniques for enlarging antibodies into small peptide sequences that recognize and bind to these sequences when presented as native sequences in free or conjugated form or in the context of a larger protein are well known in the art. Such antibodies include mouse, mouse-human, and human-human antibodies produced by hybridoma or recombinant techniques known in the art. Antibodies can also be produced in human, mouse, sheep, rat, rabbit, shark, llama, or chicken. In some embodiments, antibodies are produced in chicken. Antibodies can also be produced in or other small animals.

[0063] The term "epitope" is meant to refer to a portion of any molecule that can be recognized and bound by an antibody at one or more of the antigen-binding regions of the Ab. Epitopes usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and have specific three-dimensional structural characteristics as well as specific charge characteristics. Examples of epitopes include, but are not limited to, the residues described herein that form the IGF-1R epitope. In some embodiments, the epitope is present only in non-denatured protein. In some embodiments, the epitope is present only in denatured protein.

[0064] In some embodiments, sources of DNA encoding non-human antibodies include cell lines that produce antibodies, such as hybrid cell lines commonly known as hybridomas.

[0065] Hybrid cells are formed by fusing non-human antibody-producing cells, usually spleen cells of an animal immunized against either natural or recombinant antigen, or peptide fragments of the antigen protein sequence. Alternatively, the non-human antibody-producing cells can be B lymphocytes obtained from the blood, spleen, lymph nodes, or other tissues of an animal immunized with the antigen.

[0066] The second fusion partner, which confers the immortalization function, can be a lymphoblastoid cell or a plasmacytoma or a myeloma cell that is not itself an antibody-producing cell, but is a malignant tumor. Fusion partner cells include, but are not limited to, the hybridoma SP2 / 0-Ag14, abbreviated as SP2 / 0 (ATCC CRL1581), and the myeloma P3X63Ag8 (ATCC TIB9), or derivatives thereof. See, e.g., Ausubel, supra; Harlow, supra; and Colligan, supra, the entire contents of which are incorporated herein by reference.

[0067] Antibodies can be generated according to the examples provided herein. Once the sequence is known, the antibodies can be generated according to known methods. The antibodies can also be converted to a different type, such as to a human IgG. By converting the antibody to a human antibody, the human subject should not recognize the antibody as foreign. Converting non-human IgG antibodies to human IgG antibodies is well known and can be done routinely once the native sequence is known. As discussed herein, the antibodies can be modified according to known methods. Such methods are described, for example, in Riechmann L, Clark M, Waldmann H, Winter G (1988). Reshaping human antibodies for therapy”. Nature 332(6162): 332-323; Tsurushita N, Park M, Pakabunto K, Ong K, Avdalovic A, Fu H, Jia A, Vasquez M, Kumar S. (2004). Antibody-producing cells involving nucleotide sequences encoding the antigen-binding region of a chimeric antibody can also be produced by transformation of non-human, e.g. primate, or human cells. For example, antibody-producing B lymphocytes can be infected with and transformed with a virus such as the Epstein-Barr virus to obtain immortal antibody-producing cells (Kozbor et al., Immunol.Today 4:72). 79 (1983)). Alternatively, B lymphocytes can be transformed by providing a transforming gene or a transforming gene product, as is well known. See, e.g., Ausubel, supra, Harlow, supra, and Colligan, supra, the entire contents of which are incorporated herein by reference. Cell fusion is accomplished by standard procedures well known to those skilled in the art of immunology. Fusion partner cell lines, as well as methods for fusing and selecting hybridomas and screening for mAbs, are well known in the art. See, e.g., Ausubel, supra, Harlow, and Colligan, supra, the entire contents of which are incorporated herein by reference.

[0068] In some embodiments, the antibody is a MAb that binds to IGF-1R, hi some embodiments, the antibody binds to an amino acid of an epitope of IGF-1R.

[0069] In some embodiments, the antibody comprises a sequence provided herein.

[0070] The antibody sequences can be modified to obtain human IgG antibodies. The conversion of the sequences provided herein can be modified to obtain other types of antibodies. The CDRs can also be bound to other antibodies, proteins, or molecules to generate antibody fragments that bind to IGF-1R. This can be in the form of an antibody drug conjugate ("ADC"), a multispecific molecule, or a chimeric antigen receptor. The CDRs and antibody sequences provided herein can be humanized or fully human according to known methods. The sequences can also be made into chimeric antibodies as described herein.

[0071] In some embodiments, the antibody comprises an amino acid sequence comprising a sequence provided herein, or a fragment thereof. In some embodiments, the antibody comprises one or more amino acid sequences provided herein, an antigen-binding fragment thereof, or a human IgG variant thereof. By "human IgG variant thereof" is meant an antibody that has been modified to become a human IgG, if the starting antibody is not a human IgG antibody.

[0072] As described herein, production of antibodies using known sequences is routine and can be done by any method. Thus, in some embodiments, a nucleic acid encoding an antibody or fragment thereof is provided. In some embodiments, the nucleic acid encodes a sequence provided herein. The antibody can also be modified to become a chimeric antibody or a human antibody. The antibody can also be used in an injectable pharmaceutical composition. Also, as described herein, the antibody can be an isolated antibody or a recombinant antibody.

[0073] In some embodiments, "derivatives" of antibodies, fragments, regions, or derivatives thereof (which term includes proteins encoded by truncated or modified genes resulting in molecular species that functionally resemble immunoglobulin fragments) are provided. Modifications include, but are not limited to, the addition of genetic sequences encoding cytotoxic proteins, such as plant and bacterial toxins. Modifications can also include reporter proteins, such as fluorescent or chemiluminescent tags. Fragments and derivatives can be made by any method.

[0074] Identification of these antigen-binding regions and / or epitopes recognized by the Abs described herein provides the information necessary to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility comparable to the embodiments of the present application.

[0075] The nucleic acid sequence encoding the antibody described herein can be genomic or cDNA, or RNA (e.g., mRNA) encoding at least one of the variable regions described herein. A convenient alternative to using chromosomal gene fragments as a source of DNA encoding V-region antigen-binding segments is the use of cDNA to construct chimeric immunoglobulin genes, as reported, for example, by Liu et al. (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987)), which are incorporated herein by reference in their entirety. The use of cDNA requires that the gene expression elements appropriate for the host cell be combined with the gene to achieve synthesis of the desired protein. The use of cDNA sequences has an advantage over genomic sequences (containing introns) in that the cDNA sequences can be expressed in bacteria or other hosts that lack a suitable RNA splicing system.

[0076] For example, cDNAs encoding V-region antigen-binding segments capable of detecting, binding to, or neutralizing IGF-1R antigens can be provided using known methods based on the use of the amino acid sequences provided herein. Because the genetic code is degenerate, more than one codon can be used to code for a particular amino acid (Watson, et al. supra). Using the genetic code, two or more different oligonucleotides can be identified, each capable of coding for that amino acid. The probability that a particular oligonucleotide will in fact constitute an actual XXX coding sequence can be estimated by considering unusual base pairing relationships and the frequency with which a particular codon is actually used (to code for a particular amino acid) in a eukaryotic or prokaryotic cell expressing the antibody or fragment. Such "codon usage rules" are disclosed by Lathe, et al., J. Molec. Biol. 183:1 12 (1985). Using the "codon usage rules" of Lathe, a single oligonucleotide, or a series of oligonucleotides, is identified that contains the theoretical "most probable" nucleotide sequence capable of encoding an antibody variable or constant region sequence.

[0077] The variable regions described herein can be combined with any type of constant region, including human or mouse constant regions. Human genes encoding the constant (C) regions of antibodies, fragments, and regions can be obtained from human fetal liver libraries by known methods. Human C region genes can be derived from any human cell, including those that express and produce human immunoglobulins. Human C regions can be derived from any human cell, including those that express and produce human immunoglobulins. H The regions can be derived from any of the known classes or isotypes of human H chains, including gamma, mu, alpha, delta, or epsilon, and their subtypes, e.g., G1, G2, G3, and G4. The H chain isotypes are responsible for the various effector functions of the antibody and therefore are classified according to C. H The choice of region is guided by the desired effector function, such as complement fixation or activity in antibody-dependent cellular cytotoxicity (ADCC). HThe regions are derived from γ1 (IgG1), γ3 (IgG3), γ4 (IgG4), or μ (IgM). L The region can be derived from either the kappa or lambda human light chain isotypes. In some embodiments, the antibody comprises an Fc region domain. In some embodiments, the Fc domain comprises a mutation that extends the half-life of the antibody. In some embodiments, the Fc domain comprises a mutation such as those described in U.S. Pat. No. 7,670,600, which is incorporated herein by reference in its entirety. In some embodiments, the constant region comprises a mutation at amino acid residue 428, which corresponds to the wild-type human IgG constant domain, as numbered according to the EU numbering index of Kabat. Without being bound to any particular theory, an antibody comprising a mutation corresponding to residue 428 may have an increased half-life compared to the half-life of an IgG having a wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of the native residue with threonine, leucine, phenylalanine, or serine. In some embodiments, the antibody further comprises one or more amino acid substitutions compared to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, numbered according to the EU numbering index of Kabat. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is incorporated by reference in its entirety.

[0078] Genes encoding human immunoglobulin C regions can be obtained from human cells by standard cloning techniques (Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) and Ausubel et al., eds. Current Protocols in Molecular Biology (1987 1993)). Human C region genes are readily available from genes containing known clones representing two classes of L chains, five classes of H chains, and their subclasses. F(ab') 2 Chimeric antibody fragments, such as F(ab') and Fab, can be prepared by designing an appropriately truncated chimeric H chain gene. 2 The chimeric gene encoding the H-chain portion of the fragment is 1 The inclusion of a DNA sequence encoding the domain and hinge region followed by a translation stop codon results in a truncated molecule.

[0079] In some embodiments, the antibodies, murine, human, humanized, or chimeric antibodies, antibody fragments, and regions described herein are prepared by cloning DNA segments encoding the heavy and light chain antigen-binding regions of an IGF-1R antigen-specific antibody, and synthesizing these DNA segments as C, ... H and C L These are produced by combining DNA segments encoding these regions to create mouse, human, or chimeric immunoglobulin-encoding genes.

[0080] Thus, in some embodiments, fusion chimeric genes are generated that include a first DNA segment encoding at least an antigen-binding region of non-human origin, such as a functionally rearranged V region with a joining (J) segment, linked to a second DNA segment encoding at least a portion of a human C region.

[0081] Thus, the method for producing cDNA encoding antibody V and C regions, antibodies according to some of the embodiments described herein, involves several steps, as exemplified below: 1. Isolating and screening messenger RNA (mRNA) from a cell line producing an anti-IGF-1R antigen antibody and from an optional additional antibody providing the heavy and light constant regions, and producing cDNA therefrom; 2. Preparation of a full-length cDNA library from the purified mRNA, where appropriate V and / or C region gene fragments of the L and H chain genes can be (i) identified with an appropriate probe, (ii) sequenced, and (iii) matched with C or V gene segments from another antibody to add to the chimeric antibody; 3. Construction of a complete H or L chain coding sequence by combining the cloned specific V region gene fragments with the cloned C region genes described above; 4. Expression and production of the L and H chains in a selected host, including prokaryotic and eukaryotic cells, to provide mouse-mouse, human-mouse, human-human, or human-mouse antibodies.

[0082] Two coding DNA sequences are said to be "operably linked" if the linkage results in a contiguous, translatable sequence without alteration or interruption of the triplet reading frame. A DNA coding sequence is operably linked to a gene expression element if the linkage results in the proper function of the gene expression element and expression of the coding sequence.

[0083] As used herein, and unless otherwise specified, the term "about" is intended to mean ±5% of the value it modifies. Thus, about 100 means from 95 to 105.

[0084] In some embodiments, the antibodies described herein are used to detect the presence of an antigen. The antibodies can be used in any device or method to detect the presence of an antigen.

[0085] The term "purified" when referring to an antibody means an antibody that is substantially free of other materials that are associated with the molecule in its natural environment. For example, a purified protein is substantially free of cellular material or other proteins from the cell or tissue from which it is derived. The term refers to preparations where the isolated protein is sufficiently pure to be analyzed, or at least 70%-80% (w / w) pure, at least 80%-90% (w / w) pure, 90-95% pure; and at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) pure. In some embodiments, an antibody is purified.

[0086] As an alternative to the preparation of monoclonal antibody-secreting hybridomas, monoclonal antibodies against the polypeptides can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptides described herein to isolate immunoglobulin library members that bind to the polypeptides. Techniques and commercially available kits for generating and screening phage display libraries are well known to those skilled in the art. Furthermore, examples of methods and reagents that are particularly suitable for use in generating and screening antibody or antigen-binding protein display libraries can be found in the literature. Thus, the epitopes described herein can be used to screen other antibodies that can be used therapeutically, diagnostically, or as research tools.

[0087] Antibody conjugates The antibodies provided herein can also be conjugated to a chemical moiety. The chemical moiety can be, among others, a polymer, a radionuclide, or a cytotoxic agent. In some embodiments, this may be referred to as an antibody drug conjugate. In some embodiments, the chemical moiety is a polymer that increases the antibody molecule's antibody activity in the subject's body. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa, or 40 kDa), dextran, and monomethoxypolyethylene glycol (mPEG). Lee, et al., (1999) (Bioconj. Chem. 10:973-981) discloses PEG-conjugated single chain antibodies. Wen, et al., (2001) (Bioconj. Chem. 12:545-553) discloses the conjugation of antibodies with PEG linked to a radiometal chelator (diethylenetriaminepentaacetic acid (DTPA)). Examples of chemical moieties include, but are not limited to, antimitotic agents such as calicheamicins (e.g., ozogamicin), monomethyl auristatin E, mertansine, and the like. Other examples include, but are not limited to, biologically active microtubule inhibitors, alkylating agents, and DNA minor groove binders. Other examples are provided herein and below. Chemical moieties can be attached to antibodies via linking groups (aminobenzyl), cleavable linkers, such as cathepsin-cleavable linkers (valine-citrulline), and, in some embodiments, one or more spacers (e.g., p-aminobenzyl carbamate). Without being bound to any particular theory, when the antibody conjugate binds to IGF-1R, the antibody conjugate can be internalized and the chemical moiety can kill the cell or otherwise inhibit proliferation of the cell. In some embodiments, the cell is a thyroid cell.

[0088] The antibodies and antibody fragments of the present invention are 99 Tc, 90 Y, 111 In,32 P, 14 C. 125 I, 3 H, 131 I, 11 C. 15 O. 13 N, 18 F, 35 S, 51 Cr, 57 To, 226 Ra, 60 Co, 59 Fe, 57 Se, 152 EU, 67 CU, 217 Ci, 211 At, 212 Pb, 47 Sc, 109 Pd, 234 Th, and 40 K, 157 Gd, 55 Mn, 52 Tr, and 56 It is also possible to conjugate with a label such as Fe.

[0089] Antibodies and antibody fragments include rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescamine, 152 It is also possible to conjugate with fluorescent or chemiluminescent labels, including fluorophores such as Eu, dansyl, umbelliferone, luciferin, luminal labels, isoluminal labels, aromatic acridinium ester labels, imidazole labels, acridinium salt labels, oxalate ester labels, aequorin labels, 2,3-dihydrophthalazinedione, biotin / avidin, spin labels, as well as stable free radicals.

[0090] The antibody molecule can also be conjugated to cytotoxic factors such as diphtheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dianthin proteins, Phytoiacca americana proteins PAPI, PAPII, and PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogenin, restrictocin, phenomycin, and enomycin.

[0091] Any method known in the art can be used for conjugating the antibody molecules of the present invention to various moieties, including those described by Hunter, et al., (1962) Nature 144:945; David, et al., (1974) Biochemistry 13:1014; Pain, et al., (1981) J. Immunol. Meth. 40:219; and Nygren, J., (1982) Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are conventional and very well known in the art.

[0092] Chimeric Antigen Receptor The antibodies provided herein can also be incorporated into chimeric antigen receptors ("CARs") that can be used, for example, in CAR-T cells. In some embodiments, the extracellular domain of the CAR can be an antibody provided herein. In some embodiments, the antibody is in scFv format. CAR-T cells are a type of treatment in which a patient's T cells are modified to attack cells that express IGF-1R. Cells are taken from the patient's blood. Special receptors are then added in the laboratory that bind to specific proteins on the patient's cells. In some embodiments, the receptors bind to IGF-1R using the binding region of an antibody provided herein. CAR-T cells containing IGF-1R antibodies can then be used to treat conditions such as those provided herein.

[0093] In some embodiments, an antibody (e.g., an anti-IGF-1R antibody) is provided herein. In some embodiments, the antibody is a recombinant antibody that binds to IGF-1R protein. In some embodiments, the IGF-1R protein is a human IGF-1R protein. In some embodiments, the IGF-1R protein recognized by the antibody is in its native (non-denatured) conformation. In some embodiments, the antibody does not specifically bind to denatured IGF-1R protein. As used herein, the term "recombinant antibody" refers to an antibody that does not occur in nature. In some embodiments, the term "recombinant antibody" refers to an antibody that is not isolated from a human subject.

[0094] In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain has the following sequence: QVQLVQSGAEVVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPSNGRTNYNQKFQGKATLTVDKSSSTAYMQLSSLTSEDSAVYYFARGRPDYYGSSKWYFDVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA and the light chain comprises the following sequence: DVVMTQTPLSLPVSLGDPASISCRSSQSIVHSNVNTYLEWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGAGTDFTLRISRVEAEDLGIYYCFQGSHVPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (sequence number 219).

[0095] In some embodiments, the heavy chain of SEQ ID NO:216 comprises a C-terminal lysine residue added to the C-terminus of SEQ ID NO:216.

[0096] In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain has the following sequence: QVQLVQSGAEVVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPSNGRTNYNQKFQGKATLTVDKSSSTAYMQLSSLTSEDSAVYYFARGRPDYYGSSKWYFDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 217), and the light chain comprises the sequence of SEQ ID NO: 219.

[0097] In some embodiments, the heavy chain of SEQ ID NO:217 comprises a C-terminal lysine residue added to the C-terminus of SEQ ID NO:217.

[0098] In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain has the following sequence: QVQLVQSGAEVVKPGASVKLSSKASGYTFTSYWMHWVKQRPGQGLEWIGEINPSNGRTNYNQKFQGKATLTVDKSSSTAYMQLSSLTSEDSAVYYFARGRPDYYGSSKWYFDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 218), and the light chain comprises the sequence of SEQ ID NO: 219.

[0099] In some embodiments, the heavy chain of SEQ ID NO:218 comprises a C-terminal lysine residue added to the C-terminus of SEQ ID NO:218.

[0100] In some embodiments, the antibody may comprise a heavy chain (HC) or light chain (LC) sequence, or a combination of HC and LC sequences, or variants thereof, as provided in the table below:

[0101] [Table 2-1]

[0102] [Table 2-2]

[0103] [Table 2-3]

[0104] [Table 2-4]

[0105] [Table 2-5]

[0106] [Table 2-6]

[0107] [Table 2-7]

[0108] In some embodiments, an antibody may comprise a heavy chain variable region (VH) or light chain variable region (VL) sequence, or a combination or variant of a VH and VL sequence, as provided in the table below:

[0109] [Table 3-1]

[0110] [Table 3-2]

[0111] [Table 3-3]

[0112] [Table 3-4]

[0113] [Table 3-5]

[0114]

Table 3-6

[0115]

Table 3-7

[0116]

Table 3-8

[0117]

Table 3-9

[0118]

Table 3-10

[0119]

Table 3-11

[0120]

Table 3-12

[0121]

Table 3-13

[0122]

Table 3-14

[0123]

Table 3-15

[0124]

Table 3-16

[0125]

Table 3-17

[0126]

Table 3-18

[0127]

Table 3-19

[0128]

Table 3-20

[0129]

Table 3-21

[0130]

Table 3-22

[0131]

Table 3-23

[0132]

Table 3-24

[0133]

Table 3-25

[0134]

Table 3-26

[0135]

Table 3-27

[0136]

Table 3-28

[0137]

Table 3-29

[0138]

Table 3-30

[0139]

Table 3-31

[0140]

Table 3-32

[0141]

Table 3-33

[0142]

Table 3-34

[0143]

Table 3-35

[0144]

Table 3-36

[0145] [Table 3-37]

[0146] [Table 3-38]

[0147] As provided herein, the heavy chain can be linked to an Fc region, including those with mutations that can affect the half-life of the antibody. Non-limiting mutations of the Fc region are provided herein.

[0148] In some embodiments, the LC and HC can be combined with the VH and VL domains provided herein, with or without constant regions. The constant regions can be replaced as provided herein. The VH and VL regions can be used to form the antibodies provided herein. The VH and VL sequences can be in any format, including but not limited to, an scFv format in which the VH and VL regions are linked by a peptide linker. An example of a peptide linker that can be used to link the various peptides provided herein is (GGGGS) n (SEQ ID NO: 220); (GGGGA) n (SEQ ID NO: 221), or any combination thereof, where each n is independently 1 to 5. In some embodiments, the variable regions are not linked by a peptide linker.

[0149] In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the table below: In some embodiments, the CDRs of the VH and VL regions are provided from the table below.

[0150] [Table 4-1]

[0151] [Table 4-2]

[0152] In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a heavy chain variable region and corresponding heavy chain variable region CDRs provided in the table below.

[0153] [Table 5]

[0154] In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a light chain variable region and corresponding light chain variable region CDRs as provided in the table below.

[0155] [Table 6]

[0156] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) sequence selected from the group consisting of SEQ ID NOs: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 61, and 65.

[0157] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) sequence selected from the group consisting of SEQ ID NOs: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, and 64.

[0158] In some embodiments, the antibody or antibody binding fragment thereof is selected from the group consisting of SEQ ID NOs: 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 300, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 09, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, or 142 amino acid sequence or a variant thereof.

[0159] In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:1 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:3 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:4 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:5 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:6 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:7 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:8 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:9 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:10 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 11 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 12 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 13 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 14 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 15 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 17 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 19 and a VL sequence of SEQ ID NO: 2.In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:20 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:21 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:22 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:23 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:24 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:25 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:26 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:27 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO:28 and a VL sequence of SEQ ID NO:2. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 61 and the VL sequence of SEQ ID NO: 2. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 65 and the VL sequence of SEQ ID NO: 2.

[0160] In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 31. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 32. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 33. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 34. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 35. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 36. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 37. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 38. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 39. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 40. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 41. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 42. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 43. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 44. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 45. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 46. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 47. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 48.In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 49. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 50. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 51. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 52. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 53. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 54. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 55. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 56. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 57. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 1 and the VL sequence of SEQ ID NO: 58. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 1 and the VL sequence of SEQ ID NO: 59. In some embodiments, the antibody or antibody binding fragment thereof comprises the VH sequence of SEQ ID NO: 1 and the VL sequence of SEQ ID NO: 60.

[0161] In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 33. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 33. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 23 and a VL sequence of SEQ ID NO: 33. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 54. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 54. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 23 and a VL sequence of SEQ ID NO: 54. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 58. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 58. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 23 and a VL sequence of SEQ ID NO: 58. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 59. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 59. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 23 and a VL sequence of SEQ ID NO: 59. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 61 and a VL sequence of SEQ ID NO: 62. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 61 and a VL sequence of SEQ ID NO: 63. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 61 and a VL sequence of SEQ ID NO: 64. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 65 and a VL sequence of SEQ ID NO: 62. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 65 and a VL sequence of SEQ ID NO: 63. In some embodiments, the antibody or antibody binding fragment thereof comprises a VH sequence of SEQ ID NO: 65 and a VL sequence of SEQ ID NO: 64.

[0162] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH complementarity determining region (CDR) sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, and 173.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VLCDR sequence selected from the group consisting of SEQ ID NOs: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, and 207.

[0164] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the HCDR1 sequence has the amino acid sequence of SEQ ID NO: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, or 154; the HCDR2 sequence has the amino acid sequence of SEQ ID NO: 155, 156, 157, 158, 159, 160, 161, 162, 163, or 164; and the HCDR3 sequence has the amino acid sequence of SEQ ID NO: 165, 166, 167, 168, 169, 170, 171, 172, or 173, or a variant of any of the foregoing.

[0165] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the LCDR1 sequence has the amino acid sequence of SEQ ID NO: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190; the LCDR2 sequence has the amino acid sequence of SEQ ID NO: 191, 192, 193, 194, 195, 196, 197, or 198; and the LCDR3 sequence has the amino acid sequence of SEQ ID NO: 199, 200, 201, 202, 203, 204, 205, 206, or 207, or a variant of any of the foregoing.

[0166] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 144, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 145, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 146, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 147, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 148, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 149, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 150, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 151, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 152, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 153, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 154, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.

[0167] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 156, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 157, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 159, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 161, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 162, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 163, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 164, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.

[0168] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 167, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 168, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 169, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 170, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 171, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 172, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 173, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.

[0169] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 176, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 177, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 178, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 179, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 180, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 181, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 182, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 184, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 185, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 185, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 187, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 188, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 189, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 190, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.

[0170] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 192, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 193, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 193, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 195, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 196, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 198, and CDR3 of SEQ ID NO: 199.

[0171] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 200. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 201. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 202. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 203. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 204. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 205. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 206.In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 207.

[0172] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 178, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 178, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 178, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 199.

[0173] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 201. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 201. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 201.

[0174] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 205. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 205. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 205.

[0175] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 206. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 165, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 206. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 155, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 206.

[0176] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 178, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 201. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 205. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 158, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 206.

[0177] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 178, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 201. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 205. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain variable region comprising CDR1 of SEQ ID NO: 143, CDR2 of SEQ ID NO: 160, and CDR3 of SEQ ID NO: 166, and a light chain variable region comprising CDR1 of SEQ ID NO: 174, CDR2 of SEQ ID NO: 191, and CDR3 of SEQ ID NO: 206.

[0178] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH peptide comprising the amino acid sequence set forth in SEQ ID NO: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 61, or 65, or any variant thereof.

[0179] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VL peptide comprising the amino acid sequence set forth in SEQ ID NO: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, or 64, or any variant thereof.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof comprises a sequence that is at least at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to the sequence of SEQ ID NOs: 1-65. In some embodiments, the antibody or antigen-binding fragment thereof comprises a sequence that is at least at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to the sequence of SEQ ID NOs: 66-142. In some embodiments, the antibody or antigen-binding fragment thereof comprises a sequence that is at least at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to the sequence of SEQ ID NOs: 143-174 and 176-207.

[0181] In addition to these specific combinations, V H Peptides and V L Any of the peptides can be combined with each other.

[0182] In addition to these specific combinations, any of the HC and LC peptides can be combined with each other.

[0183] In some embodiments, the antibody comprises the sequence of ATCC clone PTA-7444, or an antigen-binding fragment thereof. The sequence of the antibody produced by ATCC clone PTA-7444 is incorporated herein by reference, including antigen-binding fragments thereof.

[0184] Additionally, as provided herein, an antibody can be a multispecific antibody, in that the antibody has multiple binding regions that target different proteins or the same protein at different epitopes. In some embodiments, the antibody is a bispecific antibody.

[0185] As provided herein, the different peptides described herein (V H or V L) may be linked by a peptide linker or may instead be a contiguous sequence without being linked by a peptide linker. In some embodiments, the peptide linker has the following sequence: (GGGGS) n (SEQ ID NO: 220); (GGGGA) n (SEQ ID NO: 221), or any combination thereof, where each n is independently 1 to 5. H -ZV L or V L -ZV H In some embodiments, Z is represented by the formula: n (SEQ ID NO: 200); (GGGGA) n (SEQ ID NO: 221), or any combination thereof (wherein each n is independently 1 to 5).

[0186] As provided herein, antibodies or antigen-binding fragments thereof can be sequence variants.

[0187] Other examples of antibodies include those described in US20160096894A1, EP1399483B1, EP2194067B1, US20040202651A1, US20110229933A1, US8137933B2, US8951790B2, US20190270820A1, US7572897B2, US20090275126A1, EP1959014B1, US20080014203A1, US20080226635A1, US20120076778A1, US20190153071A1, WO2011161119A1, US1 0611825B2, US20120237507A1, EP2681240B1, US9982036B2, US20180312573A1, EP2681239B1, US20160151487A1, US20190225696A1, WO2017011773A2, US20200023076A1, US20190153471A1, US20190194713A1, WO2020006486A1, US20080112888A1, US20150168424A1, EP2032989B2, US9045536B2.Other examples of antibodies include those described in US8153121B2, EP1469879B1, WO2016064716A1, US20190270820A1, US20180280527A1, US20190225696A1, US7998681B2, US20040202651A1, US20 050136063A1, US20090285824A1, US20150274829A1, EP2322550B1, US20060286103A1, US20070 071675A1, US20100047239A1, US20130004416A1, US20080112888A1, US20150168424A1, US20100 143340A1, US20110014117A1, US20100260668A1, US20100074900A1, US20150017168A1, US2011 0044980A1, US20130330323A1, US20120263722A1, US20120201746A1, US10519245B2, US2018024 3432A1, US20170218091A1, US20200115460A1, US20100104645A1, US20120065380A1, EP2970433B1, US20160289341A1, US20160289343A1, US20190293656A1.

[0188] Pharmaceutical Compositions In some embodiments, to prepare pharmaceutical or sterile compositions of anti-IGF-1R antibodies, or other proteins provided herein, the antibodies or antigen-binding fragments thereof, or other proteins provided herein, are mixed with a pharma- ceutically acceptable carrier or excipient.See, e.g., Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0189] Formulations of the therapeutic and diagnostic agents can be prepared, for example, by mixing with an acceptable carrier, excipient, or stabilizer in the form of a lyophilized powder, a slurry, an aqueous solution, or a suspension (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: (See, for example, Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY; Weiner and Kotkoskie (2000) Excipient Forms: Disperse Systems, Marcel Dekker, NY). In some embodiments, the antibody is diluted to an appropriate concentration in sodium acetate solution (pH 5-6) with NaCl or sucrose added for tonicity. Additional agents such as polysorbate 20 or polysorbate 80 can be added to improve stability.

[0190] The toxicity and therapeutic efficacy of the antibody composition administered alone or in combination with another agent may be determined, for example, by the LD 50 (the dose lethal to 50% of the population), and ED 50 The dose ratio between toxic and therapeutic effects is called the therapeutic index (LD50 / ED 50 In certain embodiments, antibodies that exhibit large therapeutic indices are desirable. The data obtained from these cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within the range of ED 50 The dosage may vary within this range, depending on the dosage form employed and the route of administration.

[0191] In some embodiments, the compositions of the present invention are administered to a subject in accordance with the Physician's Guide 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0192] The method of administration can be varied. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral, intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, aspiration, inhalation, topical, dermal, transdermal, or intraarterial.

[0193] In some embodiments, the antibody or antigen-binding fragment thereof can be administered by an invasive route, such as injection. In some embodiments, the antibody or antigen-binding fragment thereof, or pharmaceutical composition thereof, is administered intravenously, subcutaneously, intramuscularly, intraarterially, intraarticularly (e.g., into an arthritic joint), or by inhalation, aerosol delivery. Administration by non-invasive routes (e.g., orally, e.g., in a pill, capsule, or tablet) is also within the scope of this embodiment.

[0194] In some embodiments, the antibody or antigen-binding fragment thereof can be administered directly to the eye, the anterior chamber of the eye, the vitreous chamber of the eye, the suprachoroidal space, or the retroorbital space. In some embodiments, administration to the eye, the anterior chamber of the eye, the vitreous chamber of the eye, the suprachoroidal space, or the retroorbital space is by injection. In some embodiments, the injection is an intravitreal injection, an intraorbital injection, a retroorbital injection, a suprachoroidal injection, or an intracavitary injection. In some embodiments, the injection is an intravitreal injection. In some embodiments, the injection is an intraorbital injection. In some embodiments, the injection is a retroorbital injection. In some embodiments, the injection is a suprachoroidal injection. In some embodiments, the injection is an intracavitary injection.

[0195] In some embodiments, the anti-IGF-1R antibody, or antigen-binding fragment thereof, is administered in combination with at least one additional therapeutic agent, such as, but not limited to, any therapeutic agent used to treat thyroid eye disease. For example, in some embodiments, the anti-IGF-1R antibody, or antigen-binding fragment thereof, is administered in combination with at least one additional therapeutic agent, such as, but not limited to, a therapeutic agent used to treat thyroid eye disease or a condition associated with thyroid eye disease. Examples of such therapeutic agents and agents include antithyroid medications, diabetes medications, beta blockers, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, regular insulin, insulin aspart, insulin glulisine, insulin lispro, insulin isophane, insulin degludec, insulin detemir, insulin glargine, acarbose, miglitol, acarbose, thiazolidinediones ... These include, but are not limited to, sebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol, sotalol, timolol, tomolol, ophthalmic solutions, sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0196] Compositions can be administered using medical devices known in the art. For example, pharmaceutical compositions of the invention can be administered by injection using a hypodermic needle, including, for example, a prefilled syringe or an autoinjector.

[0197] The pharmaceutical compositions may also be administered using a needleless hypodermic injection device, such as those devices disclosed in U.S. Pat. Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824, or 4,596,556.

[0198] Pharmaceutical compositions can also be administered by infusion. Examples of well-known implants and module forms for administering pharmaceutical compositions include U.S. Pat. No. 4,487,603, which discloses an implantable micro infusion pump for dispensing drugs at a controlled rate; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses an implantable infusion device with variable flow for continuous drug delivery; and U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system with multiple chamber compartments. Many other such implants, delivery systems and modules are known to those skilled in the art.

[0199] Alternatively, the antibody can be administered locally rather than systemically, for example by injecting the antibody, often in a depot or sustained release formulation, directly into the arthritic joint or into a pathogen-induced lesion identified by immunopathology. Additionally, the antibody can be administered in a targeted drug delivery system, for example in liposomes coated with tissue-specific antibodies that target the arthritic joint or into a pathogen-induced lesion identified by immunopathology. The liposomes are targeted to and selectively taken up by the affected tissue.

[0200] Dosing regimens vary depending on multiple factors, including the serum or tissue turnover rate of the therapeutic antibody, the severity of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of target cells within the biological matrix. Preferably, the dosing regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesirable side effects. Thus, the amount of biologic agent delivered will vary, in part, depending on the particular therapeutic antibody and the severity of the disease state being treated. Guidance for selecting appropriate doses of therapeutic antibodies is available (e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert, et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973; Slamon et al. (2001) New Engl.J.Med.344:783-792;Beniaminovitz et al.(2000)New Engl.J.Med.342:613-619;Ghosh et al.(2003)New Engl.J.Med.348:24-32;Lipsky et al.(2000)New Please refer to Engl.J.Med.343:1594-1602).

[0201] The determination of the appropriate dose is made by the clinician, for example, using parameters or factors known or suspected in the art to affect treatment. Generally, the dose is started at a dose somewhat below the optimal dose, and then increased by small increments until a desired or optimal effect is achieved, relative to any negative side effects. Important diagnostic indicators include, for example, indicators of inflammatory symptoms, or the amount of inflammatory cytokines produced. In general, it is desirable that the biological agent used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. For human subjects, for example, chimeric, humanized, and fully human antibodies may be desirable.

[0202] The antibody or antigen-binding fragment thereof can be provided by continuous infusion or by doses administered, for example, 1-7 times per week, once per week, once per two weeks, once per month, once every two months, once every three months, once every six months, once every year, etc. The doses can be provided, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or by inhalation. In some embodiments, the antibody is administered every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. In some embodiments, the antibody is administered every 4 weeks. In some embodiments, the antibody is administered every 5 weeks. In some embodiments, the antibody is administered every 7 weeks. In some embodiments, the antibody is administered every 6 weeks. In some embodiments, the antibody is administered every 8 weeks. In some embodiments, the antibody is administered for at least 21-52 weeks, or more. In some embodiments, the antibody is administered on such a schedule for at least 21 weeks. In some embodiments, the antibody is administered on such a schedule for at least 24 weeks. In some embodiments, the antibody is administered on such a schedule for at least 32 weeks. In some embodiments, the antibody is administered on such a schedule for at least 36 weeks. In some embodiments, the antibody is administered on such a schedule for at least 40 weeks. In some embodiments, the antibody is administered on such a schedule for at least 42 weeks. In some embodiments, the antibody is administered once (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered twice (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered three times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered four times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered five times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered six times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered seven times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered eight times (e.g., by infusion or continuous injection).In some embodiments, the antibody is administered 9 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 10 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 11 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 12 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 13 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 14 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 15 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 16 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 17 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 18 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 19 times (e.g., by infusion or continuous injection). In some embodiments, the antibody is administered 20 times (e.g., by infusion or continuous injection). When the antibody is administered more than once, the antibody can be administered according to a schedule, such as the schedules provided herein.

[0203] The total weekly dose can be as provided herein. In some embodiments, the total weekly dose is at least 0.05 μg / kg body weight, more typically at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / kg, 0.25 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 5.0 mg / mL, 10 mg / kg, 25 mg / kg, 50 mg / kg, or more (see, e.g., Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji, et al. (20003) Cancer (See Immunol. Immunother. 52:133-144.) Doses can also be provided to achieve a predetermined target concentration of antibody in the subject's serum, e.g., 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / mL.

[0204] In some embodiments, the antibody has a serum concentration in the subject of at least or about 10 μg / mL, or 20 μg / mL, 50 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, or 105 μg / mL at least 1, 2, or 3 weeks after administration.

[0205] In some embodiments, a dose of 20 mg / kg IV is administered. In some embodiments, a dose is used to provide a Cmin of 133 ug / mL after about 5 weeks. In some embodiments, a dose of antibody is administered to provide a Cmin of 102 ug / mL after 6 weeks. In some embodiments, the dose of antibody is as provided herein, such as a loading dose of 10 mg / mg with subsequent doses equal to or less than the loading dose. In some embodiments, the antibody is administered at a dose as provided herein to achieve a Cmin of at least, or about, 100 ug / mL.

[0206] As used herein, "inhibit" or "treat" or "treatment" includes slowing the progression of symptoms associated with a disorder and / or reducing the severity of symptoms of such a disorder. These terms further include alleviating existing, uncontrolled, or undesirable symptoms, preventing further symptoms, and preventing the underlying causes of such symptoms. Thus, these terms refer to the production of a beneficial outcome in a vertebrate subject having a disorder, disease, or condition, or at risk of developing such a disorder, disease, or condition.

[0207] As used herein, the terms "therapeutically effective amount", "therapeutically effective dose" and "effective amount" refer to an amount of an antibody or antigen-binding fragment thereof that is effective when administered alone or together with an additional therapeutic agent to a cell, tissue, or subject to cause a measurable improvement in one or more symptoms of a disease or condition, or in the progression of such a disease or condition. A therapeutically effective dose further refers to an amount of the binding compound sufficient to cause at least partial relief of a symptom, e.g., treatment, cure, prevention, or relief of an associated medical condition, or an increase in the rate of treatment, cure, prevention, or relief of such a condition. When applied to an individual active ingredient administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to the combined amount of the active ingredients that results in a therapeutic effect, whether the combination is sequential or simultaneous. An effective amount of a therapeutic agent results in an improvement in a diagnostic indicator or parameter of at least 10%; usually at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably at least 50%. An effective amount can also result in an improvement in subjective indicators, where subjective indicators are used to assess the severity of the disease. In some embodiments, an amount is a therapeutically effective amount if it is an amount that can be used to treat or alleviate a condition provided herein.

[0208] The term "subject" as used throughout includes any living organism, such as mammals (e.g., rats, mice, dogs, cats, rabbits), and animals, including, for example, humans. A subject can also be referred to as a patient. In some embodiments, a subject is a subject in need. A subject "in need" means a subject who has been identified as needing treatment for a condition in need of treatment, and who is being treated for the specific purpose of treating such condition. The condition can be, for example, any of the conditions described herein.

[0209] On the other hand, the isolated antibodies bind to an epitope of the IGF-1R protein or other proteins described herein and exhibit IGF-1R inhibitory or therapeutic activity in vitro and / or in vivo, and the antibodies or antigen-binding fragments thereof capable of inhibiting IGF-1R function are suitable as therapeutic agents for treating IGF-1R-related conditions in both humans and animals. These conditions include thyroid eye disease. Accordingly, methods of treating such conditions are also provided, the methods comprising administering the antibody or antigen-binding fragment thereof to a subject having such a condition.

[0210] In some embodiments, the methods include administering a therapeutically or prophylactically effective amount of one or more monoclonal antibodies or antigen-binding fragments of the antibodies described herein to a subject who is susceptible or exhibits a condition for which IGF-1R is known or suspected to be the cause of the observed condition. Any active form of the antibody can be administered, including, but not limited to, scFv, Fab, and F(ab')2 fragments, as well as other forms of the antibody provided herein.

[0211] As used herein, an IGF-1R-associated condition refers to a condition caused by the regulation of IGF-1R, including, but not limited to, thyroid eye disease and other conditions provided herein.

[0212] In some embodiments, the antibodies used are compatible with the recipient species such that an immune response against the MAb does not result in an unacceptably short circulating half-life or elicit an immune response against the MAb in the subject.

[0213] Treatment of an individual may include administering a therapeutically effective amount of the antibody described herein. The antibody can be provided in a kit such as those provided herein. The antibody can be used or administered alone or in combination with another therapeutic, analgesic, or diagnostic agent such as those provided herein. When providing a patient with an antibody or fragment thereof capable of binding to IGF-1R, or an antibody capable of protecting against IGF-1R being a pathology in a recipient patient, the dose of the agent administered will vary depending on factors such as the patient's age, weight, height, sex, general condition, and previous medical history.

[0214] Antibodies capable of treating a condition associated with IGF-1R activity or usable to treat an IGF-1R-related condition can be provided to a subject in an amount sufficient to affect a reduction, amelioration, or alleviation in an IGF-1R-related symptom or condition, such as thyroid eye disease.

[0215] Thus, in some embodiments, a method for treating a subject suffering from an IGF-1R mediated disorder is provided. In some embodiments, the method comprises administering a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof provided herein. In some embodiments, the disorder is thyroid eye disease. As provided herein, the antibody or antigen-binding fragment thereof can be administered together with other therapeutic agents. These can be administered simultaneously or sequentially.

[0216] In some embodiments, the antibodies or antigen-binding fragments thereof can be used to treat thyroid eye disease. In some embodiments, the antibodies or antigen-binding fragments thereof can be used to treat or reduce the severity of, or symptoms of, thyroid associated eye disease (TAO).

[0217] In some embodiments, there is provided a method or use for reducing exophthalmos in the eye in a subject suffering from Thyroid Associated Eye Disease (TAO).

[0218] In some embodiments, the subject has been previously treated with an antibody different from those provided herein.

[0219] In some embodiments, the method or use provides for a Clinical Activity Score (CAS) in a subject having or suspected of having Thyroid Associated Eye Disease (TAO).

[0220] In some embodiments a method or use is provided for a) reducing exophthalmos by at least 2 mm, and b) lowering the Clinical Activity Score (CAS).

[0221] As used herein, the term Clinical Activity Score (CAS) refers to the scoring procedure described in Table 2. According to this procedure, the presence of each of the parameters described in the table below is awarded one point. The sum of all the points defines the clinical activity and provides the CAS, where 0 or 1 constitutes inactive disease and 7 constitutes severe active eye disease.

[0222] [Table 7]

[0223] As shown in Table 2, the CAS consists of seven components: spontaneous retrobulbar pain, pain when trying to move the eye (gazing up, side-to-side, and down; sometimes called "gazing-induced orbital pain"), conjunctival redness, eyelid redness, caruncle / fold swelling, and eyelid swelling. Each component is scored as present (1 point) or absent (0 point). The score on each efficacy assessment is the sum of all items present, giving a range of 0 to 7, with 0 or 1 constituting inactive disease and 7 severe active eye disease. A change of more than 2 points is considered clinically significant.

[0224] Item 1, spontaneous orbital pain, can be pain or pressure in or behind the eye. This pain can be caused by increased intraorbital pressure when the volume of the orbital tissue increases due to excess synthesis of extracellular matrix, fluid accumulation, and cellular infiltration and swelling. Item 2, gaze-induced orbital pain, can be pain in the eye when looking or trying to look up, down, or to the side, i.e., pain with upward, downward, or horizontal eye movements or when trying to move the eye. This type of pain can be caused by the stretching of the inflamed muscle(s), especially when trying to gaze upward. The "stretching pain" may not be caused by pressing the eye with a finger, as it would be expected to be a sign of increased intraorbital pressure. Both types of pain may not be relieved after anti-inflammatory treatment. These pains are therefore directly related to autoimmune inflammation in the orbit and therefore may be useful in assessing TAO activity.

[0225] Swelling of TAO is seen as chemosis (edema of the conjunctiva), item 6 of Table 1, and swelling of the caruncle and / or semilunar folds. Both are signs of TAO activity. Swollen eyelids can be caused by edema, fat herniation through the orbital septum, or fibrous degeneration. In addition to swelling, other symptoms indicative of active TAO include redness and / or pain of the conjunctiva, eyelids, caruncle, and / or semilunar folds.

[0226] In some embodiments, the subject being treated has a reduction in exophthalmos of at least 2 mm. In some embodiments, the subject being treated has a reduction in exophthalmos of at least 3 mm. In some embodiments, the subject being treated has a reduction in exophthalmos of at least 4 mm.

[0227] In some embodiments, the treated subject's Clinical Activity Score (CAS) is reduced by at least 2 points. In some embodiments, the subject's Clinical Activity Score (CAS) is reduced to (1). In some embodiments, the subject's Clinical Activity Score (CAS) is reduced to zero (0).

[0228] In some embodiments, methods are provided for treating thyroid associated eye disease (TAO) or reducing the severity of TAO in a subject, wherein treatment with the antibody (i) reduces exophthalmos in the eye by at least 2 mm; (ii) is not accompanied by a worsening of 2 mm or more in the other (i.e., fellow) eye; and (iii) reduces CAS in the subject to (1) or zero (0).

[0229] In some embodiments, methods are provided for improving quality of life in a subject with Thyroid Associated Eye Disease (TAO, also known as Graves' Eye Disease / Graves' Ophthalmopathy). In some embodiments, quality of life is measured by the Graves' Eye Disease Quality of Life (GO-QoL) survey or either the visual functioning or appearance subscales thereof. In some embodiments, treatment results in an 8 point or greater improvement in the GO-QoL. In some embodiments, treatment results in an improvement in the functioning subscale of the GO-QoL. In some embodiments, treatment results in an improvement in the appearance subscale of the GO-QoL.

[0230] In some embodiments, methods are provided for treating diplopia or reducing the severity of thyroid associated eye disease (TAO) in a subject. In some embodiments, the diplopia is stationary diplopia. In some embodiments, the diplopia is non-stationary diplopia. In some embodiments, the diplopia is intermittent diplopia. In some embodiments, the improvement or reduction in the severity of diplopia is sustained for at least 20 weeks after discontinuing antibody administration. In some embodiments, the improvement or reduction in the severity of diplopia is sustained for at least 50 weeks after discontinuing antibody administration.

[0231] Disease severity can be measured in the following non-limiting embodiments: For example, for eyelid opening, the distance between the eyelid margins is measured (in mm) with the patient looking in primary eye position, in a relaxed sitting position, and with distant fixation. For eyelid swelling, the indicator / rating is either "absent / indeterminate", "moderate", or "severe". Eyelid redness is either absent or present. Conjunctival redness is either absent or present. In some embodiments, chemosis is either absent or present. In some embodiments, inflammation of the caruncle or fold is either absent or present. Exophthalmos is measured in millimeters using the same Hertel exophthalmometer and the same canthus distance for each individual patient. Subjective diplopia is scored from 0 to 3 (0=no diplopia; 1=intermittent, i.e., diplopia in the first position of gaze when tired or when first getting up; 2=variable, i.e., diplopia in extreme gaze; 3=constant, i.e., continuous diplopia in the first or reading position). For ocular muscle involvement, the twitching is measured in degrees. Corneal involvement is either absent / patchy or keratopathy / ulcer. For optic nerve involvement, i.e., most forced visual acuity, color vision, optic disc, relative afferent pupillary defect, pathology is either absent or present. In addition, if optic nerve compression is suspected, the visual field is checked. In some embodiments, patients can be classified according to the following severity classifications: For example, visual field-threatening thyroid eye disease: thyroid dysfunction-induced optic neuropathy (DON), and / or corneal breaks. This category allows for immediate intervention. Moderate to severe thyroid eye disease: Patients without vision-threatening disease whose eye disease sufficiently impacts daily life to justify the risk of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe thyroid eye disease usually have one of the following: eyelid retraction ≥2mm, moderate or severe soft tissue involvement, exophthalmos ≥3mm greater than normal for race and sex, and variable or constant diplopia.Mild thyroid eye disease: Patients whose features of thyroid eye disease have only minimal impact on daily life, insufficient to justify immunosuppression or surgical treatment. These patients usually have only one or more of the following: slight eyelid retraction (<2 mm), mild soft tissue involvement, exophthalmos less than 3 mm greater than normal for race and sex, transient diplopia or absence of diplopia, and corneal exposure responsive to lubricants.

[0232] In some embodiments, patients can be characterized by Graves' Eye Disease Quality of Life (GO-QoL) score. In addition to exophthalmos (or proptosis) and CAS, quality of life is also investigated using the GO Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to measure improved quality of life after treatment with the methods disclosed herein. In some embodiments, the questionnaire can measure the reduction or absence of side effects after treatment with an antibody, or antigen-binding fragment thereof, according to the methods disclosed herein compared to treatment with glucocorticoids. The GO-QoL is a 16-item self-administered questionnaire that is divided into two subsets and is used to assess the perceived effect of TED by the subject on (i) their daily physical activity (as this activity is related to visual function) and (ii) psychosocial function. Quality of life is investigated using the GO QoL questionnaire. The GO-QoL questionnaire [CBTerwee et al, 1998] is completed on day 1, and at weeks 6, 12, and 24 (or PW) during the treatment period, and at months 7 and 12 (or PW) during the follow-up period. The GO-QoL is a 16-item self-administered questionnaire divided into two self-assessment subscales; one covering the impact of visual function on daily activities, and the other investigating the impact on self-perceived appearance. The visual function subscale covers activities such as driving a car, walking outdoors, reading, and watching television. The appearance subscale asks the subject questions such as whether the eye disease has changed the subject's appearance; whether it has caused others to react negatively towards the subject; whether it has caused social isolation; and whether it has caused the subject to hide his or her appearance. Each subscale has eight questions that can be answered with "yes (very much)", "yes (slightly)", or "no (not at all)". Each is scored from 0 to 2, and the raw total score is then mechanically converted to a 0 to 100 scale, with 0 representing the most negative impact on quality of life and 100 representing no impact. A change of 8 points or more on the 0 to 100 scale has been shown to be clinically significant.The combined score utilizes the raw scores from both subscales and again converts these to a single 0-100 scale. The questionnaire has two self-rating subscales. Each subscale has eight questions answered with (i) "yes (very much agree)", (ii) "yes (slightly)", or (iii) "no (not at all)". Each is scored from 0 to 2, and then the raw total score is mechanically converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact. A change of more than 8 points on the 0-100 scale is considered clinically significant. The combined score utilizes the raw scores from both subscales and again converts these to a single 0-100 scale.

[0233] Patients can also be assessed for the presence or absence of a Gorman grading of diplopia. The Gorman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or awake (intermittent), diplopia on extreme fixation (variable), and continuous diplopia in primary or reading position (constant). Patients are scored according to the grade of diplopia they are experiencing. An improvement of 1 grade or greater is considered clinically significant.

[0234] In some embodiments, the method includes administering an antibody such as those provided herein. In some embodiments, the antibody is administered at a dosage of about 1 mg / kg to about 5 mg / kg of antibody as a first dose. In some embodiments, the antibody is administered at a dosage of about 5 mg / kg to about 10 mg / kg of antibody as a first dose. In some embodiments, the antibody is administered at a dosage of about 5 mg / kg to about 20 mg / kg of antibody as a subsequent dose. In some embodiments, the antibody is administered in the following amounts: about 10 mg / kg of antibody as a first dose; and about 20 mg / kg of antibody in the subsequent dose. In some embodiments, the subsequent doses are administered every three weeks for at least 21 weeks.

[0235] In some embodiments, the antibody is administered in a pharmaceutical composition such as those provided herein. In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutical active compounds for the treatment of TAO. In some embodiments, the pharmaceutical composition further comprises a corticosteroid; rituximab or other anti-CD20 antibody; tocilizumab or other anti-IL-6 antibody; or selenium, infliximab or other anti-TNFα antibody, or a thyroid stimulating hormone receptor (TSHR) inhibitor.

[0236] In some embodiments, the methods provided herein include administering to a subject an antibody, or antigen-binding fragment thereof, that specifically binds to and inhibits IGF-IR. In some embodiments, the antibody is as provided herein.

[0237] A kit useful for carrying out the embodiments described herein is also provided. The kit includes a first container that contains or is packaged with the antibody described above. The kit may also include another container that contains or is packaged with related solutions that are necessary or convenient for carrying out the embodiments. The container can be made of glass, plastic, or foil, and can be a vial, bottle, pouch, tube, bag, etc. The kit can also contain written information, such as instructions or analytical information for carrying out the embodiments, such as the amount of reagent contained in the first container means. The container can be in another container device, such as a box or bag, together with the written information.

[0238] In yet another aspect of the present specification, a kit for detecting IGF-1R protein in a biological sample is provided. The kit includes a container that holds one or more antibodies that bind to an epitope of the IGF-1R protein, and instructions for using the antibodies to bind to the IGF-1R protein to form an immunological complex, and detecting the formation of the immunological complex, such that the presence or absence of the immunological complex correlates with the presence or absence of the IGF-1R protein in the sample. An example of the container is a multi-well plate, which allows for the simultaneous detection of IGF-1R protein in multiple samples.

[0239] In some embodiments, an antibody is provided that binds to IGF-1R protein. In some embodiments, the antibody is isolated. In some embodiments, the antibody specifically binds. In some embodiments, the antibody binds to properly folded IGF-1R protein. In some embodiments, the antibody is specific for a particular IGF-1R conformational state (open or closed). In some embodiments, the antibody binds to IGF-1R protein in a cell membrane. In some embodiments, the antibody binds to IGF-1R protein in the cell membrane in an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of IGF-1R protein. As used herein, the term "neutralize" means that the activity or function of the protein is inhibited. The inhibition can be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The inhibition rate can be based on the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits IGF-1R-facilitated glucose transport. In some embodiments, the antibody inhibits internalization of IGF-1R protein.

[0240] In some embodiments, the antibody comprises a sequence provided herein, or an antigen-binding fragment thereof. In some embodiments, the antibody comprises a heavy chain CDR described herein, or an antigen-binding fragment thereof. The heavy chain can be one or more of the heavy chains described herein. In some embodiments, the antibody comprises a light chain described herein, or an antigen-binding fragment thereof.

[0241] In some embodiments, a method for treating, inhibiting, or alleviating a condition associated with IGF-1R is provided. In some embodiments, the method comprises administering to a subject an antibody described herein or a pharmaceutical composition described herein to treat, inhibit, or alleviate a condition associated with IGF-1R. In some embodiments, the condition is as described herein.

[0242] In some embodiments, a method for detecting the presence or absence of IGF-1R in a sample is provided, the method comprising contacting the sample with one or more antibodies described herein and detecting binding of the antibody to an IGF-1R antigen. In some embodiments, detected binding indicates the presence of an IGF-1R antigen, or no detected binding to an IGF-1R antigen indicates the absence of an IGF-1R antigen. Detection can be performed using any known method, such as biosensors, ELISA, sandwich assays, and the like. However, in some embodiments, the method comprises detecting the presence of a protein under non-denaturing conditions. Using non-denaturing conditions, the protein of interest can be detected in its native or properly folded form.

[0243] In some embodiments, a method is provided for identifying a test antibody that binds to an epitope on an IGF-1R protein, the method comprising contacting a test antibody with an epitope on an IGF-1R protein and detecting whether the test antibody binds to the epitope. In some embodiments, detecting comprises detecting whether the test antibody binds to the protein and is competitively inhibited by an antibody comprising a sequence provided herein. In some embodiments, detecting comprises mutating one or more residues of the epitope or protein and measuring binding of the test antibody to the mutated epitope, where the test antibody is considered to bind to the epitope if the mutation reduces binding of the test antibody compared to the non-altered epitope.

[0244] In some embodiments, a method is provided for monitoring the internalization of IGF-1R from the surface of a cell. In some embodiments, the method includes contacting a cell with an anti-IGF-1R antibody provided herein and detecting the presence of IGF-1R in the cell or at the surface of the cell. The difference in expression at the cell surface can be measured and internalization can be monitored and measured. This can be used to measure the effect of another molecule, such as a test agent, to regulate the internalization of IGF-1R protein. Thus, the antibodies provided herein can be used to identify test agents that regulate (increase or decrease) the internalization of IGF-1R protein. Test molecules that increase internalization, as measured by a decrease in binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface, can be identified according to the methods provided herein. Test molecules that decrease internalization, as measured by an increase in binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface, can be identified according to the methods provided herein. Surface expression can be measured by fluorescence, which can be achieved by a secondary antibody that recognizes the IGF-1R antibody or by labeling the anti-IGF-1R antibodies provided herein.

[0245] In some embodiments, a method for inhibiting IGF-1 stimulated receptor phosphorylation in a cell is provided. In some embodiments, the method includes contacting the cell with an antibody provided herein or a pharmaceutical composition comprising the antibody. In some embodiments, the contacting includes administering the antibody or a pharmaceutical composition comprising the antibody to a subject. In some embodiments, the cell is an intraocular cell. In some embodiments, the subject has or is at risk for thyroid eye disease (TED). In some embodiments, the antibody has an IC50 of about 0.2 nm, 0.15 nm, 0.10 nm, 0.09 nm or less. In some embodiments, the IC50 is measured in an in vitro assay, such as the assay provided herein, such as those shown in the Examples. In some embodiments, the IC50 is measured in a cell that is an A549 cell or a HOCF cell.

[0246] In some embodiments, there is provided a method of treating thyroid eye disease in a subject, the method comprising treating the subject with an antibody provided herein or a pharmaceutical composition comprising the antibody, wherein the antibody has a serum concentration in the subject of at least or about 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, or 105 μg / mL at least 1, 2, or 3 weeks after administration. In some embodiments, the serum concentration is measured after 1, 2, or 3 administrations of the antibody or pharmaceutical composition comprising the antibody to the subject.

[0247] In some embodiments, methods are provided for inhibiting IGF-1-induced receptor autophosphorylation by at least 95%, 96%, 97%, 98%, or 99%, or 100% in a subject in need thereof. In some embodiments, the methods include administering to the subject an antibody provided herein, or a pharmaceutical composition comprising the antibody. In some embodiments, IGF-1-induced receptor autophosphorylation is inhibited in the eye or orbital region of the subject. In some embodiments, inhibiting IGF-1-induced receptor autophosphorylation treats thyroid eye disease in a subject or ameliorates a symptom described herein.

[0248] Enumerated Embodiments In some embodiments, the embodiments provided herein include, but are not limited to, the following: 1. A heavy chain complementarity determining region (HCDR) sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, and 173; and a light chain CDR (LCDR) sequence selected from the group consisting of SEQ ID NOs: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, and 207. 2. A heavy chain variable region (VH) sequence selected from the group consisting of SEQ ID NOs: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 61, and 65; and a light chain variable region (VL) sequence selected from the group consisting of SEQ ID NOs: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, and 64. 3. The antibody or antigen-binding fragment thereof of any one of embodiments 1 or 2, wherein the antibody binds to the insulin-like growth factor I receptor (IGF-1R). 4. The antibody of any one of embodiments 1 to 3, wherein the antibody is a monoclonal antibody. 5. The antibody of any one of embodiments 1 to 4, wherein the antibody is a humanized antibody. 6. The antibody of any one of embodiments 1 to 5, wherein the antibody is an scFv antibody. 7. The antibody of any one of embodiments 1-6, wherein the antibody or antigen-binding fragment thereof comprises a VH peptide comprising the amino acid sequence set forth in SEQ ID NO: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 61, or 65, or any variant thereof. 8. The antibody of any one of embodiments 1-7, wherein the antibody or antigen-binding fragment thereof comprises a VL peptide comprising the amino acid sequence set forth in SEQ ID NO: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, or 64, or any variant thereof. 9. An antibody or antigen-binding fragment thereof, comprising: (i) a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences, wherein the HCDR1 sequence has the amino acid sequence of SEQ ID NO: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, or 154; the HCDR2 sequence has the amino acid sequence of SEQ ID NO: 155, 156, 157, 158, 159, 160, 161, 162, 163, or 164; and the HCDR3 sequence has the amino acid sequence of SEQ ID NO: 165, 166, 167, 168, 169, 170, 171, 172, or 173, or a variant of any of the foregoing. and (ii) a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the LCDR1 sequence has the amino acid sequence of SEQ ID NO: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190; the LCDR2 sequence has the amino acid sequence of SEQ ID NO: 191, 192, 193, 194, 195, 196, 197, or 198; and the LCDR3 sequence has the amino acid sequence of SEQ ID NO: 199, 200, 201, 202, 203, 204, 205, 206, or 207, or a variant of any of the foregoing. 10. An antibody or antigen-binding fragment thereof, comprising a VH and VL pair comprising an amino acid sequence of SEQ ID NO: 66 to 142 or a variant thereof. 11. The antibody of any one of embodiments 1 to 10, wherein the heavy chain variable region and the light chain variable region are not linked by a linker. 12. The antibody of any one of embodiments 1 to 10, wherein the heavy chain variable region and the light chain variable region are linked by a peptide linker. 13. The peptide linker has the following sequence: (GGGGS) n (SEQ ID NO: 220), (GGGGA) n (SEQ ID NO: 221), or any combination thereof (wherein each n is independently 1 to 5). 14. The antibody of any one of embodiments 1 to 13, wherein the variant has 1 to 10 substitutions, deletions, or insertions. 15. The antibody of any one of embodiments 1 to 14, wherein the variant has 1 to 10 conservative substitutions. 16. The antibody of any one of embodiments 1 to 15, wherein the variant has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology to the sequences of SEQ ID NOs: 1 to 65. 17. The antibody of any one of embodiments 1 to 15, wherein the variant has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology to the sequences of SEQ ID NOs: 66 to 142. 18. The antibody of any one of embodiments 1 to 15, wherein the variant has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the sequences of SEQ ID NOs: 143 to 174 and 176 to 207. 19. The antibody of any one of embodiments 1 to 18, wherein the antibody is an scFv antibody. 20. The antibody of any one of embodiments 1 to 19, wherein the antibody is a monoclonal antibody. 21. The antibody of any one of embodiments 1 to 20, wherein the antibody is a humanized antibody. 22. The antibody of any one of embodiments 1 to 21, wherein the antibody comprises an Fc region. 23. The antibody of embodiment 22, wherein the Fc region is selected from the group consisting of SEQ ID NOs: 208, 209, 210, 211, 212, 213, 214, and 215. 24. The antibody of any one of embodiments 1 to 23, wherein the Fc region comprises a mutation that extends the half-life of the antibody when linked to the Fc region. 25. The antibody of embodiment 24, wherein the Fc region comprises an S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutation, or any combination thereof. 26. The antibody of embodiment 24, wherein the Fc region comprises M252Y, S254T, and T256E mutations. 27. The antibody of embodiment 24, wherein the Fc region comprises S228P and L235E mutations. 28. The antibody of embodiment 24, wherein the Fc region comprises L234F, L235E, and P331S mutations. 29. The antibody of embodiment 24, wherein the Fc region comprises M252Y, S254T, T256E, S228P and L235E mutations. 30. The antibody of embodiment 24, wherein the Fc region comprises S228P, L235E, M428L, and N434S mutations. 31. The antibody of embodiment 24, wherein the Fc region comprises M428L and N434S mutations. 32. The antibody of embodiment 24, wherein the Fc region comprises the following mutations: L234F, L235E, P331S, M252Y, S254T, and T256E. 33. The antibody of any one of embodiments 1 to 32, wherein the antibody is an isolated antibody. 34. A nucleic acid molecule encoding an antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 33. 35. A vector comprising the nucleic acid molecule of embodiment 34. 36. A cell comprising a nucleic acid comprising a nucleic acid molecule according to embodiment 34 or a vector according to embodiment 35. 37. A pharmaceutical composition comprising an antibody according to any one of embodiments 1 to 33 or a nucleic acid molecule encoding said antibody. 38. The pharmaceutical composition according to embodiment 37, wherein the composition is an injectable pharmaceutical composition. 39. The pharmaceutical composition according to embodiment 37 or 38, wherein the pharmaceutical composition is administered intravenously or subcutaneously. 40. A method for treating thyroid associated eye disease (TAO) or a symptom of TAO, or reducing the severity of TAO or a symptom of TAO, comprising administering to a subject an antibody described in any one of embodiments 1 to 33 or a pharmaceutical composition described in any one of embodiments 37 to 39. 41. A method for reducing exophthalmos in a subject suffering from thyroid associated eye disease (TAO), comprising administering to the subject an antibody according to any one of embodiments 1 to 33 or a pharmaceutical composition according to any one of embodiments 37 to 39. 42. A method for treating thyroid eye disease in a subject, comprising administering to the subject an antibody according to any one of embodiments 1 to 33 or a pharmaceutical composition according to any one of embodiments 37 to 39. 43. A method for reducing a Clinical Activity Score (CAS) of Thyroid Associated Eye Disease (TAO) in a subject, the method comprising administering to the subject an antibody described in any one of embodiments 1 to 33 or a pharmaceutical composition described in any one of embodiments 37 to 39. 44. A method for a) reducing exophthalmos by at least 2 mm and b) lowering Clinical Activity Score (CAS) in a subject suffering from Thyroid Associated Eye Disease (TAO), comprising administering to the subject an antibody according to any one of embodiments 1 to 33 or a pharmaceutical composition according to any one of embodiments 37 to 39. 45. The method of any one of embodiments 40-44, wherein exophthalmos is reduced by at least 2 mm. 46. ​​The method of any one of embodiments 40-44, wherein exophthalmos is reduced by at least 3 mm. 47. The method of any one of embodiments 40-44, wherein exophthalmos is reduced by at least 4 mm. 48. The method of any one of embodiments 40-44, wherein the subject's Clinical Activity Score (CAS) is reduced by at least 2 points. 49. The method of any one of embodiments 40-44, wherein the subject's Clinical Activity Score (CAS) is reduced to (1). 50. The method of any one of embodiments 40-44, wherein the subject's Clinical Activity Score (CAS) is reduced to zero (0). 51. A method for treating thyroid associated eye disease (TAO) or reducing the severity of TAO in a subject, comprising administering to the subject an antibody according to any one of embodiments 1-33 or a pharmaceutical composition according to any one of embodiments 36-38, wherein treatment with the antibody (i) reduces exophthalmos in the eye by at least 2 mm; (ii) is not accompanied by a worsening of the other (i.e., fellow eye) by 2 mm or more; and (iii) reduces CAS in the subject to (1) or zero (0). 52. A method for improving the quality of life in a subject suffering from thyroid associated eye disease (TAO, also known as Graves' eye disease / Graves' ophthalmopathy), comprising administering to the subject an antibody described in any one of embodiments 1 to 33 or a pharmaceutical composition described in any one of embodiments 37 to 39. 53. The method of embodiment 52, wherein said quality of life is measured by the Graves' Eye Disease Quality of Life (GO-QoL) survey, or either its visual functioning or appearance subscales. 54. The method of embodiment 53, wherein the treatment results in an improvement of 8 or more points in GO-QoL. 55. The method of embodiment 53, wherein said treatment results in an improvement in the functioning subscale of the GO-QoL. 56. The method of embodiment 53, wherein said treatment results in an improvement in the appearance subscale of the GO-QoL. 57. A method for treating diplopia or reducing the severity of diplopia in a subject suffering from thyroid associated eye disease (TAO), comprising administering to the subject an antibody described in any one of embodiments 1 to 33 or a pharmaceutical composition described in any one of embodiments 37 to 39. 58. The method of embodiment 57, wherein the diplopia is stationary diplopia. 59. The method of embodiment 57, wherein the diplopia is non-stationary diplopia. 60. The method of embodiment 57, wherein the diplopia is intermittent diplopia. 61. The method of embodiment 57, wherein the improvement or reduction in the severity of diplopia persists for at least 20 weeks after administration of the antibody is discontinued. 62. The method of embodiment 57, wherein the improvement or reduction in the severity of diplopia persists for at least 50 weeks after administration of the antibody is discontinued. 63. The method of any one of embodiments 40-62, wherein the antibody is administered at a dosage of about 1 mg / kg to about 5 mg / kg of antibody as a first dose. 64. The method of any one of embodiments 40-62, wherein the antibody is administered at a dosage of about 5 mg / kg to about 10 mg / kg of antibody as a first dose. 65. The method of any one of embodiments 40-62, wherein the antibody is administered at a dosage of about 5 mg / kg to about 20 mg / kg of antibody in subsequent doses. 66. The method of any one of embodiments 40-62, wherein the antibody is administered in the following amounts: about 10 mg / kg of antibody as a first dose; and about 20 mg / kg of antibody in subsequent doses. 67. The method of embodiment 66, wherein said subsequent doses are administered every 3 weeks for at least 21 weeks. 68. The method of any one of embodiments 40 to 67, wherein the antibody or antigen-binding fragment thereof is a human antibody, a monoclonal antibody, a human monoclonal antibody, a purified antibody, a diabody, a single-chain antibody, a multispecific antibody, Fab, Fab', F(ab')2, Fv or scFv. 69. The method of any one of embodiments 40 to 68, wherein the antibody or antigen-binding fragment thereof is administered in a pharmaceutical composition additionally comprising a pharma- ceutically acceptable diluent or excipient or carrier. 70. The method of embodiment 69, wherein the pharmaceutical composition further comprises one or more pharma- ceutical active compounds for the treatment of TAO. 71. The method of embodiment 69 or 70, wherein the pharmaceutical composition further comprises a corticosteroid; rituximab or other anti-CD20 antibody; tocilizumab or other anti-IL-6 antibody; or selenium, infliximab, or other anti-TNFα antibody, or a thyroid-stimulating hormone receptor (TSHR) inhibitor. 72. The method of any one of embodiments 4 to 71, wherein the antibody or antigen-binding fragment thereof is administered directly to the eye, the anterior chamber of the eye, the vitreous chamber of the eye, the suprachoroidal space, or the retroorbital space. 73. The method of embodiment 72, wherein the antibody or antigen-binding fragment thereof is administered by injection. 74. The method of embodiment 73, wherein the injection is an intravitreal injection, an intraorbital injection, a retroorbital injection, a suprachoroidal injection, or an intracavitary injection. 75. A method for increasing internalization of IGF-1R in a cell, the method comprising contacting the cell with an antibody described in any one of embodiments 1 to 33 or a pharmaceutical composition described in any one of embodiments 37 to 39. 76. The method of embodiment 74, wherein the contacting comprises administering to the subject an antibody of any one of embodiments 1 to 33 or a pharmaceutical composition of any one of embodiments 37 to 39. 77. The method of embodiment 76, wherein the subject has or is at risk for thyroid eye disease (TED). 78. A method for inhibiting IGF-1 stimulated receptor phosphorylation in a cell, the method comprising contacting the cell with an antibody described in any one of embodiments 1 to 33 or a pharmaceutical composition described in any one of embodiments 37 to 39. 79. The method of embodiment 78, wherein the contacting comprises administering to the subject an antibody of any one of embodiments 1 to 33 or a pharmaceutical composition comprising any one of embodiments 36 to 38. 80. The method of embodiment 79, wherein the subject has or is at risk for thyroid eye disease (TED). 81. The method of any one of embodiments 78-80, wherein the antibody has an IC50 of about 0.2 nm, 0.15 nm, 0.10 nm, 0.09 nm or less. 82. The method of embodiment 81, wherein the IC50 is measured in an in vitro assay, such as the assay provided herein. 83. The method of any one of embodiments 78 to 82, wherein the cells are A549 cells or HOCF cells. 84. A method for treating thyroid eye disease in a subject, the method comprising administering to the subject an antibody of any one of embodiments 1-33, or a pharmaceutical composition of any one of embodiments 37-39, wherein the antibody has a serum concentration in the subject of at least or about 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, or 105 μg / mL at least 1, 2, or 3 weeks after administration. 85. The method of embodiment 84, wherein the antibody or pharmaceutical composition is administered intravenously. 86. The method of any one of embodiments 84-85, wherein the antibody or pharmaceutical composition is administered at a dose of about 20 mg / kg. 87. The method of any one of embodiments 84-86, wherein the antibody or pharmaceutical composition is administered at least, or approximately, once per week, once every two weeks, once every three weeks, or once every four weeks. 88. A method for inhibiting IGF-1-induced receptor autophosphorylation in a cell by at least 95%, 96%, 97%, 98%, or 99% or 100%, said method comprising contacting said cell with an antibody according to any one of embodiments 1 to 33, or a pharmaceutical composition according to any one of embodiments 37 to 39. 89. The method of embodiment 88, wherein the inhibition of IGF-1-induced receptor autophosphorylation is measured relative to induced receptor autophosphorylation in the absence of the antibody or pharmaceutical composition. 90. The method of embodiment 88 or 89, wherein the contacting comprises administering to the subject the antibody or a pharmaceutical composition comprising the antibody. 91. The method of embodiment 90, wherein the subject has or is at risk for thyroid eye disease (TED). 92. A method for inhibiting IGF-1-induced receptor autophosphorylation by at least 95%, 96%, 97%, 98%, or 99% or 100% in a subject in need thereof, the method comprising administering to the subject an antibody according to any one of embodiments 1 to 33, or a pharmaceutical composition according to any one of embodiments 37 to 39. 93. The method of embodiment 92, wherein the subject has or is at risk for thyroid eye disease (TED). 94. The method of any one of embodiments 92 or 93, wherein the antibody or pharmaceutical composition is administered intravenously. 95. The method of any one of embodiments 88 to 94, wherein the antibody comprises the CDRs of VRDN-1100. 96. The method of any one of embodiments 88 to 95, wherein the antibody comprises the CDRs of an antibody of VRDN-1100 or the CDRs of VRDN-2700.

[0249] The subject matter will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the claims should not be interpreted as being limited to these examples, but rather as encompassing any and all modifications that become evident as a result of the teachings provided herein. Those skilled in the art will readily recognize that there are various non-critical parameters that can be changed or modified to produce essentially similar results. EXAMPLES

[0250] Example 1: IGF-1R antibodies block IGF-1 stimulation. Blockade of IGF-1 stimulation is measured by secretion of hyaluronan in the presence of IGF-1R antibodies VRDN-2700, VRDN-03100, VRDN-02100, VRDN-02200, VRDN-02300, VRDN-02400, and VRDN-02500, all of which are disclosed herein. Immunoglobulins are purified from serum of patients with Graves' eye disease (GO) and tested for their ability to activate TSHR and / or IGF-1R antibodies, as well as TSHR / IGF-1R crosstalk in primary cultures of GO fibroblasts. Cells are treated with M22 or GO-Ig with or without IGF-1R inhibitory antibodies, such as those provided herein, including but not limited to VRDN-2700, VRDN-03100, VRDN-02100, VRDN-02200, VRDN-02300, VRDN-02400, and VRDN-02500, all of which are disclosed herein. Hyaluronan (hyaluronic acid; HA) secretion is measured as the primary biological response to GO fibroblast stimulation. IGF-1R autophosphorylation is used as an indicator of direct IGF-1R activation. TSHR activation is measured by the production of cyclic AMP (cAMP). IGF-1R antibodies disclosed herein are found to effectively block HA secretion and thus IGF stimulation.

[0251] Example 2: Treatment of patients with thyroid eye disease and clinical evaluation of IGF-1R antibodies in thyroid eye disease. Subjects are provided with an infusion of an IGF-1R inhibitory antibody, such as those provided herein, including but not limited to VRDN-2700, VRDN-03100, VRDN-02100, VRDN-02200, VRDN-02300, VRDN-02400, and VRDN-02500, all of which are disclosed herein. The number of infusions is individualized for each subject and is based on the clinical judgment of the investigator. The day 1 visit occurs within 14 days of the last visit of the previous trial. The visit window is ±1 day for weeks 1 and 4, and ±3 days for weeks 3, 6, 9, 12, 15, 18, 21, and 24. The follow-up period is only for subjects who were exophthalmos non-responders in the previous trial; subjects who relapsed in the previous trial did not participate in the follow-up period. The visit window during the follow-up period is ±7 days.

[0252] The treatment period is 24 weeks (6 months), during which time teprotumumab will be administered by infusion eight times.

[0253] Subjects who are exophthalmos non-responders will participate in a 6-month follow-up period in this extension study; subjects who relapse in the lead-in trial and are retreated in this extension study will not participate in the follow-up period.

[0254] Efficacy assessments will be performed on both eyes at each evaluation. The "study eye" (i.e., the more severely affected eye) will remain the same as that identified at the baseline (Day 1) visit of the previous study. Both eyes will be evaluated for efficacy, but the study eye will be used to assess the primary outcome measure.

[0255] Efficacy will be assessed by exophthalmos (measured as an exophthalmos rating on the Clinical Scale of Severity using a Heteroscopy instrument for consistency in measurement), CAS (7-item scale), diplopia (measured as part of the Clinical Scale of Severity), and the Clinical Scale of Severity (including a mobility limitation rating).

[0256] Quality of life will be assessed using the GO-QoL questionnaire.

[0257] Safety will be assessed by AE and concomitant medication monitoring, immunogenicity studies, physical and ophthalmologic examinations, vital signs, clinical safety laboratory assessments (complete blood count, chemistry (including thyroid panel and HbA1C), and urinalysis), pregnancy testing (if applicable), and electrocardiogram (ECG). The study will also be monitored by a Data Safety Monitoring Board (DSMB).

[0258] Exophthalmos assessments will be performed using a Hereter exophthalmometer, and for consistency in measurements, the same Hereter device and the same observer will be used for each assessment throughout the duration of the study (unless strictly unavoidable). Furthermore, the same intercanthal distance (ICD) will be used in each case.

[0259] Exophthalmos will be measured in each eye on Day 1 and at Weeks 6, 12, 18, and 24 (or early withdrawal (PW)) during the treatment period, and at Months 7, 9, and 12 (or PW) during the follow-up period. Measurements will be recorded under Exophthalmos in the Clinical Measures of Severity eCRF.

[0260] The antibodies are also found to be effective in treating thyroid eye disease and improving quality of life as provided herein.

[0261] Example 3: Antibodies with increased pK Cynomolgus monkeys were administered an antibody containing the CDR of VRDN-2700 with a YTE mutation in the Fc domain at 10 mg / kg, either intravenously or subcutaneously, and samples were collected at 0.5, 2, and 8 hours, as well as on days 1, 3, 7, 10, 14, 21, and 28, for PK analysis by ELISA. Teprotumumab was also administered at 10 mg / kg IV as a comparator. The results, shown in Figure 1, indicate that the antibody had significantly higher PK compared to teprotumumab. This result indicates that the antibody containing the CDR of VRDN-2700 is likely to be administered at a lower dose compared to teprotumumab, even when administered subcutaneously. These results could not have been predicted previously.

[0262] Example 4: VRDN-2700 VRDN-2700, which has M252Y, S254T, and T256E mutations in the Fc domain, is a novel anti-IGF-1R antibody incorporating half-life extending modifications in its Fc region, as described herein, which can be used to treat thyroid eye disease (TED). The pharmacokinetic (PK) parameters of VRDN-2700 containing such Fc mutations were measured in cynomolgus monkeys against the marketed IGF-1R antibody, teprotumumab, and a PK model was constructed for potential human dosing regimen projects.

[0263] TED is an autoimmune condition most commonly associated with Graves' disease and hyperthyroidism, but may also be found in euthyroid or hypothyroid patients. Ophthalmopathy in TED is driven by thyroid-stimulating hormone receptor (TSHR) agonist autoantibodies and crosstalk between TSHR and IGF-1R. Pathological remodeling of the orbital and periorbital tissues results in a variety of symptoms that may include dry eye, increased lacrimation, local inflammation, eyelid retraction and eventual exophthalmos, diplopia, and optic nerve compression, leading to subsequent blindness.

[0264] The pathology underlying TED is mainly the activation of the inflammatory cascade in the orbit, with the recruitment of fibrocytes and immune cells. Overexpression of IGF-1R has been shown in the orbit of TED patients, and it has been speculated that IGF-1R blocking antibodies may disrupt the crosstalk between IGF-1R and TSHR and impair the inflammatory cascade. Indeed, antagonism of IGF-1R has been shown to dramatically reduce much of the inflammatory syndrome affecting TED patients.

[0265] VRDN-2700 is a monoclonal antibody that inhibits IGF-1-mediated signaling through the IGF-1R with sub-nanomolar potency and incorporates clinically validated Fc modifications (M252Y, S254T, and T256E) to extend half-life. The antibody was discovered to have a more favorable PK profile than traditional IgG therapeutic antibodies, with the potential for a less burdensome treatment paradigm for patients.

[0266] VRDN-2700 with Fc mutation was administered to cynomolgus monkeys at 2, 10, and 50 mg / kg by 30-minute intravenous (IV) injection and at 2 and 10 mg / kg by subcutaneous (SC) injection. Teprotumumab at 10 mg / kg was also administered by 30-minute IV injection. Serum concentrations of VRDN-2700 and teprotumumab were measured using a human IgG-specific ELISA assay. Data were analyzed using a WinNonlin noncompartmental model. A semi-mechanistic model incorporating target-mediated drug disposition was constructed using available human and cynomolgus monkey data. Data are presented below.

[0267] The table and graph in Figure 2 show a more favorable PK profile.

[0268] The table shows PK parameters ± SD. Evidence of target-mediated drug disposition (TMDD) was observed at the 2 mg / kg but not at the 10 and 50 mg / kg doses, consistent with teprotumumab and other IGF-1R antibodies that reported saturation of TMDD at higher doses.

[0269] Modifications that extend the half-life of VRDN-2700 extend exposure. At equal doses, SC administered VRDN-2700 with the YTE mutation achieves greater exposure than intravenous infusion of teprotumumab, achieving approximately twice the half-life in NHPs compared to SC administration with a pre-discovery formulation with an estimated bioavailability (F) of 62%. Parameters are estimated ± SD as shown in Figure 3.

[0270] Model stimulation predicts that VRDN-2700 administered at 10mg / kg every 3 weeks or 20mg / kg every 6 weeks will result in a Cmin of over 100ug / mL, similar to the approved teprotumour regimen (1st dose 10mg / kg followed by seven doses of 20mg / kg q3w). The 10mg / kg·q3w regimen will result in lower Cmax values. The smaller dose and lower Cmax values ​​may mitigate toxicity, while a longer dosing interval would increase patient convenience and reduce cost of treatment. Furthermore, the model predicts that a fixed dose of 300mg subcutaneously administered VRDN-2700 weekly may achieve a steady-state Cmin of approximately 130ug / mL, allowing for self-administration at home. Where lower Cmin values ​​are beneficial, a fixed dose of 300 mg subcutaneously administered every other week of VRDN-2700 is expected to achieve steady-state Cmin levels of approximately 50 ug / mL. In summary, the extended half-life of VRDN-2700 is expected to offer patients a greater range of options for more convenient dosing intervals and routes of administration.

[0271] During investigation of the antibody, the expression of VRDN-2700 was compared to other antibodies with mutations in the Fc domain, such as the L / S mutations described herein. Unexpectedly, the yield for the antibody with the YTE mutation in the Fc domain (VRDN2700) was approximately 80% higher than the yield of a similar antibody except for the one with the L / S mutation. This was surprising and unexpected, since other antibodies tested targeting IGF-1R with YTE or LS mutations had similar expression regardless of Fc mutation. The YTE version had fewer low molecular weight species compared to the LS version. Thus, indicating a more homogenous composition with fewer impurities in the YTE antibody, which provides an advantage over antibodies with LS mutations. This was also unexpected, since another antibody investigated showed the opposite effect on such species. Furthermore, during purification, it was found that the LS mutant formed more aggregates when purified on a cation exchange column compared to VRDN-2700. Aggregation of the LS mutant causes major manufacturing issues that were not observed with VRDN-2700. Thus, this difference in the Fc variants to this antibody could not have been anticipated or predicted, and confers a significant and unexpected advantage to the antibody referred to herein as VRDN-2700.

[0272] The extended half-life of VRDN-2700 (YTE) indicates that it can be used as a convenient SC injection or as an IV infusion requiring less therapeutic doses and / or less frequent doses than conventional therapeutic IgG antibodies, and has superior properties compared to other Fc variant versions of the same antibody (same variable region).

[0273] Example 5: Variant IGF-1R antibodies block IGF-1 stimulation (hypothesis). Blockade of IGF-1 stimulation is measured by secretion of hyaluronan in the presence of IGF-1R antibodies comprising VH and VL sequences of SEQ ID NOs: 67-142, all of which are disclosed herein. Immunoglobulins are purified from serum of patients with Graves' eye disease (GO) and tested for their ability to activate TSHR and / or IGF-1R antibodies, as well as TSHR / IGF-1R crosstalk in primary cultures of GO fibroblasts. Cells are treated with M22 or GO-Ig with or without IGF-1R inhibitory antibodies, such as those provided herein, including but not limited to antibodies comprising VH and VL sequences of SEQ ID NOs: 66-142, all of which are disclosed herein. Secretion of hyaluronan (hyaluronic acid; HA) is measured as the primary biological response to GO fibroblast stimulation. IGF-1R autophosphorylation is used as an indicator of direct IGF-1R activation. TSHR activation is measured by the production of cyclic AMP (cAMP). The IGF-1R antibodies disclosed herein are found to effectively block HA secretion and therefore IGF stimulation.

[0274] Example 6: Treatment of patients with thyroid eye disease and clinical evaluation of IGF-1R antibodies in thyroid eye disease (Hypothesis). Subjects are provided with an infusion of an IGF-1R inhibitory antibody, such as those provided herein, including but not limited to antibodies comprising VH and VL sequences of SEQ ID NOs: 67-142, all of which are disclosed herein. The number of infusions is individualized for each subject and is based on the clinical judgment of the investigator. The day 1 visit occurs within 14 days of the last visit of the previous trial. The visit window is ±1 day for weeks 1 and 4, and ±3 days for weeks 3, 6, 9, 12, 15, 18, 21, and 24. The follow-up period is only for subjects who were exophthalmos non-responders in the previous trial; subjects who relapsed in the previous trial did not participate in the follow-up period. The visit window during the follow-up period is ±7 days.

[0275] The treatment period is 24 weeks (6 months), during which time teprotumumab will be administered by infusion eight times.

[0276] Subjects who are exophthalmos non-responders will participate in a 6-month follow-up period in this extension study; subjects who relapse in the lead-in trial and are retreated in this extension study will not participate in the follow-up period.

[0277] Efficacy assessments will be performed on both eyes at each evaluation. The "study eye" (i.e., the more severely affected eye) will remain the same as that identified at the baseline (Day 1) visit of the previous study. Both eyes will be evaluated for efficacy, but the study eye will be used to assess the primary outcome measure.

[0278] Efficacy will be assessed by exophthalmos (measured as an exophthalmos rating on the Clinical Scale of Severity using a Heteroscopy instrument for consistency in measurement), CAS (7-item scale), diplopia (measured as part of the Clinical Scale of Severity), and the Clinical Scale of Severity (including a mobility limitation rating).

[0279] Quality of life will be assessed using the GO-QoL questionnaire.

[0280] Safety will be assessed by AE and concomitant medication monitoring, immunogenicity studies, physical and ophthalmologic examinations, vital signs, clinical safety laboratory assessments (complete blood count, chemistry (including thyroid panel and HbA1C), and urinalysis), pregnancy testing (if applicable), and electrocardiogram (ECG). The study will also be monitored by a Data Safety Monitoring Board (DSMB).

[0281] Exophthalmos assessments will be performed using a Hereter exophthalmometer, and for consistency in measurements, the same Hereter device and the same observer will be used for each assessment throughout the duration of the study (unless strictly unavoidable). Furthermore, the same intercanthal distance (ICD) will be used in each case.

[0282] Exophthalmos will be measured in each eye on Day 1 and at Weeks 6, 12, 18, and 24 (or early withdrawal (PW)) during the treatment period, and at Months 7, 9, and 12 (or PW) during the follow-up period. Measurements will be recorded under Exophthalmos in the Clinical Measures of Severity eCRF.

[0283] The antibodies are also found to be effective in treating thyroid eye disease and improving quality of life as provided herein.

[0284] Example 7: Antibodies with increased pK (hypothetical). Cynomolgus monkeys are administered antibodies comprising VH and VL sequences of SEQ ID NOs: 67-142, all of which are disclosed herein, at 10 mg / kg, either intravenously or subcutaneously, and samples are collected at 0.5 hours, 2 hours, 8 hours, and at days 1, 3, 7, 10, 14, 21, and 28 for PK analysis by ELISA. VRDN-02700 and SEQ ID NO: 66 are also administered at 10 mg / kg IV as comparator assays. Antibodies comprising VH and VL sequences of SEQ ID NOs: 67-142 are shown to have significantly higher PK compared to controls.

[0285] Example 8: Binding Affinity of IGF-1R Antibodies The binding affinity of IGF-1R antibodies was determined by surface plasmon resonance (SPR). SPR measurements were performed at 25°C on a Biacore 8K+ instrument (Cytiva). In all Biacore experiments, HBS-EP+ (Cytiva) and NaOH 10 mM were used as running and regeneration buffers, respectively. For antibody capture, anti-huIgG (Fcγ specific) monoclonal antibodies were immobilized on CM5 Series S Biacore chips. Immobilization was performed using an amine coupling kit according to the method provided by Biacore. After chip activation, the capture antibody was injected, resulting in a surface density of approximately 10,000 resonance units (RU). Anti-IGF-1R antibodies were injected at a concentration of 10 nM diluted in 1xHBS-EP+ assay buffer at a flow rate of 30 μL / min for 1 min, followed by stabilization for 1 min. Association of recombinant human His-tagged IGF 1R extracellular domain protein was determined in a single cycle analysis by injecting five consecutive concentrations ranging from 6.3 to 100 nM by two-fold serial dilution in 1xHBS-EP+pH 7.4 at 30 μL / min for 1 min. Dissociation in HBS pH 7.4 or pH 6 buffer was then monitored for 10 min. The flow cell surface was regenerated by two injections of 1 mM glycine (pH 1.5) at 30 μL / min. Kinetic parameter analysis was performed using Biacore Insight Evaluation software (Cytiva) using a 1:1 binding kinetics fitting model. The results are shown in the following table:

[0286] [Table 8-1]

[0287] [Table 8-2]

[0288] [Table 8-3]

[0289] Each of these examples and embodiments provided herein demonstrates that the antibodies provided herein can be used to treat TED and its associated conditions.

[0290] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent was specifically and individually indicated and incorporated by reference. This statement of incorporation of references is intended by the applicants to relate to each and every individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent, each of which is expressly identified in compliance with 37 CFR § 1.57(b)(1), even if such citation is not immediately adjacent to the dedicated statement of incorporation by reference, in compliance with 37 CFR § 1.57(b)(2). The inclusion within this specification of a dedicated statement of incorporation by reference, if any, does not in any way weaken this general statement of incorporation by reference. The citation of references herein is not intended as an admission that the references refer to pertinent prior art, nor is it an admission of any kind as to the contents or date of those publications or documents.

[0291] The present embodiments are not limited in scope by the specific embodiments described herein. Indeed, various modifications in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to be included within the scope of the embodiments and any appended claims.

[0292] The specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. Various modifications, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and will fall within the scope of the present disclosure and any appended claims.

Claims

1. An antibody or antigen-binding fragment thereof that binds to insulin-like growth factor I receptor (IGF-1R): (i) a heavy chain complementarity determining region (HCDR) sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, and 173; a light chain CDR (LCDR) sequence selected from the group consisting of SEQ ID NOs: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, and 207; contains, or (ii) a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences, wherein the HCDR1 sequence has the amino acid sequence of SEQ ID NO: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, or 154; the HCDR2 sequence has the amino acid sequence of SEQ ID NO: 155, 156, 157, 158, 159, 160, 161, 162, 163, or 164; and the HCDR3 sequence has the amino acid sequence of SEQ ID NO: 165, 166, 167, 168, 169, 170, 171, 172, or 173, or a variant of any of the foregoing; a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the LCDR1 sequence has the amino acid sequence of SEQ ID NO: 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190; the LCDR2 sequence has the amino acid sequence of SEQ ID NO: 191, 192, 193, 194, 195, 196, 197, or 198; and the LCDR3 sequence has the amino acid sequence of SEQ ID NO: 199, 200, 201, 202, 203, 204, 205, 206, or 207; or a variant of any of the foregoing. An antibody or antigen-binding fragment thereof comprising: (i) a heavy chain variable region (VH) sequence selected from the group consisting of SEQ ID NOs: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 61, and 65; a light chain variable region (VL) sequence selected from the group consisting of SEQ ID NOs: 2, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, and 64; contains, or (ii) a VH and VL pair comprising an amino acid sequence selected from SEQ ID NOs: 66 to 142, or a variant thereof; An antibody or antigen-binding fragment thereof comprising:

3. The antibody (i) a monoclonal antibody, and / or a humanized antibody, and / or an scFv antibody, or (ii) a human antibody, a monoclonal antibody, a human monoclonal antibody, a purified antibody, a diabody, a single-chain antibody, a multispecific antibody, a Fab, a Fab', a F(ab')2, a Fv, or a scFv; or (iii) variants thereof containing 1 to 10 substitutions, deletions, or insertions, optionally wherein the variant has 1 to 10 conservative substitutions and / or has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology to a sequence of SEQ ID NOs: 1-65, or to a sequence of SEQ ID NOs: 66-142, or to a sequence of SEQ ID NOs: 143-174 and 176-207. The antibody of claim 1, 4. The antibody of claim 1, wherein (i) the heavy chain variable region and the light chain variable region are not linked by a linker, or (ii) the heavy chain variable region and the light chain variable region are linked by a peptide linker, and optionally the peptide linker comprises the following sequence: (GGGGS) n (SEQ ID NO:220), (GGGGA) n (SEQ ID NO:221), or any combination thereof, where each n is independently 1 to 5.

5. the antibody comprises an Fc region and optionally (i) the Fc region is selected from the group consisting of SEQ ID NOs: 208, 209, 210, 211, 212, 213, 214, and 215; and / or (ii) the Fc Region comprises a mutation that increases the half-life of the antibody when linked to the Fc Region, and optionally the Fc Region comprises a S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutation, or any combination thereof; The antibody described in claim 1.

6. A nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.

7. A vector comprising the nucleic acid molecule of claim 6.

8. A cell comprising the nucleic acid molecule of claim 6 or a vector comprising the same.

9. An injectable pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 5, or a nucleic acid molecule encoding same, optionally comprising: (i) intravenous or subcutaneous administration, or (ii) directly into the eye, the anterior chamber of the eye, the vitreous chamber of the eye, the suprachoroidal space, or the retro-orbital space; and optionally, the injection is an intravitreal injection, an intraorbital injection, a retroorbital injection, a suprachoroidal injection, or an intracameral injection.

10. An agent for treating thyroid associated eye disease (TAO) or the symptoms of TAO, or reducing the severity of TAO or the symptoms of TAO, comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, or a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof, or a nucleic acid molecule encoding same, wherein said treatment or reduction is achieved by: (i) resulting in a reduction in the Clinical Activity Score (CAS) of Thyroid Associated Eye Disease (TAO), such as a reduction in the Clinical Activity Score (CAS) of at least 2 points, or a reduction in the Clinical Activity Score (CAS) to 1, or a reduction in the Clinical Activity Score (CAS) to 0; or (ii) resulting in an 8-point or greater improvement in the Graves' Eye Disease Quality of Life (GO-QoL) survey, or an improvement in the functioning subscale of the GO-QoL, or an improvement in the appearance subscale of the GO-QoL; or (iii) results in a reduction in exophthalmos of the eye in a subject, optionally resulting in a reduction in exophthalmos of at least 2 mm, 3 mm, or 4 mm; or (iv) resulting in a reduction in the severity of diplopia in a subject with thyroid-associated eye disease (TAO), wherein optionally the diplopia is steady, non-steady, or intermittent diplopia, and optionally the improvement or reduction in the severity of diplopia persists for at least 20 weeks or at least 50 weeks after discontinuing antibody administration. An agent comprising:

11. A therapeutic agent for thyroid eye disease, comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, or a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof, or a nucleic acid molecule encoding same, and optionally (i) the antibody has a serum concentration in the subject of at least 1, 2, or 3 weeks after administration of at least or about 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, or 105 μg / mL, and optionally, the antibody or pharmaceutical composition is administered intravenously, and optionally, the antibody or pharmaceutical composition is administered at a dose of about 20 mg / kg, and optionally, the antibody or pharmaceutical composition is administered at least or about once a week, once every two weeks, once every three weeks, or once every four weeks; or (ii) the antibody is administered at a dosage of about 1 mg / kg to about 5 mg / kg, or about 5 mg / kg to about 10 mg / kg of antibody as a first dose; or (iii) the antibody is administered at a dose of about 5 mg / kg to about 20 mg / kg of antibody in subsequent doses; or (iv) the antibody is administered in the following amounts: about 10 mg / kg of antibody as a first dose; and about 20 mg / kg of antibody in subsequent doses, optionally wherein the subsequent doses are administered every three weeks for at least 21 weeks.

12. The pharmaceutical composition further comprises a pharmaceutically acceptable diluent or excipient or carrier, and optionally the pharmaceutical composition (i) one or more pharmaceutically active compounds for the treatment of TAO, and / or (ii) Corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFα antibodies, or thyroid-stimulating hormone receptor (TSHR) inhibitors. The agent according to claim 10, further comprising:

13. The pharmaceutical composition further comprising a pharmaceutically acceptable diluent or excipient or carrier, and optionally the pharmaceutical composition (i) one or more pharmaceutically active compounds for the treatment of TAO, and / or (ii) Corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFα antibodies, or thyroid-stimulating hormone receptor (TSHR) inhibitors. The agent according to claim 11, further comprising:

14. An agent for increasing the internalization of IGF-1R on cells in a subject, comprising an antibody or antigen-binding fragment thereof described in any one of claims 1 to 5, or a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof, or a nucleic acid molecule encoding same, wherein said cells are contacted with said antibody or pharmaceutical composition, and optionally said subject has or is at risk of having thyroid eye disease (TED).

15. An inhibitor of IGF-1 stimulated receptor phosphorylation on cells in a subject, comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, or a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof, or a nucleic acid molecule encoding same, wherein said cells are contacted with said antibody or pharmaceutical composition, and optionally said subject has thyroid eye disease (TED), and further optionally: (i) the antibody has an IC50 of about 0.2 nM, 0.15 nM, 0.10 nM, 0.09 nM or less, optionally wherein the IC50 is measured in an in vitro assay, such as the assay provided herein; and / or (ii) The agent, wherein the cells are A549 cells or HOCF cells.

16. An agent for inhibiting IGF-1-induced receptor autophosphorylation in a subject's cells by at least 95%, 96%, 97%, 98%, or 99% or 100%, comprising an antibody or antigen-binding fragment thereof described in any one of claims 1 to 5, or a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof or a nucleic acid molecule encoding same, wherein said cells are contacted with said antibody or pharmaceutical composition, and said inhibition of IGF-1-induced receptor autophosphorylation is measured relative to induced receptor autophosphorylation in the absence of said antibody or pharmaceutical composition, and optionally said subject has thyroid eye disease (TED).

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