Modified antibodies

Abstract

Provided herein are anti-IGF-lR antibodies and compositions and uses thereof.

Description

COMPOSITIONS AND METHODS FOR TREATMENT OF THYROID EYE DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Application No. 63 / 619,034, filed January 9, 2024, the content of which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED), Graves’ ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, dysthyroid ophthalmopathy, and several other terms, is orbitopathy associated with thyroid dysfunction. TAO is divided into two types. Active TAO, which typically lasts 1-3 years, is characterized by an ongoing autoimmune / inflammatory response in the soft tissues of the orbit. Active TAO is responsible for the expansion and remodeling of the ocular soft tissues. The autoimmune / inflammatory response of active TAO spontaneously resolves and the condition transitions into inactive TAO. Inactive TAO is the term used to describe the long-term / permanent sequelae of active TAO. Chronic TAO is a phase of inactive TAO that may be characterized in a subject having received an initial diagnosis of TAO 2-10 years prior to screening, with a Clinical Activity Score (CAS) of <1 in both eyes for at least one year prior to screening or all of the following one year prior to screening, and having no progression in proptosis, no progression in diplopia and no new inflammatory TAO symptoms. The cause of TAO is unknown. TAO is typically associated with Graves’ hyperthyroidism, but can also occur as part of other autoimmune conditions that affect the thyroid gland and produce pathology in orbital and periorbital tissue, and, rarely, the pretibial skin (pretibial myxedema) or digits (thyroid acropachy). TAO is an autoimmune orbitopathy in which the orbital and periocular soft tissues are primarily affected with secondary effects on the eye and vision. In TAO, as a result of inflammation and expansion of orbital soft tissues, primarily eye muscles and adipose, the eyes are forced forward (bulge) out of their sockets, a phenomenon termed proptosis or exophthalmos. Although most cases of TAO do not result in loss of vision, this condition can cause visionthreatening exposure keratopathy, troublesome diplopia (double vision), and compressive dysthyroid optic neuropathy. TAO may precede, coincide with, or follow the systemic complications of dysthyroidism. The ocular manifestations of TAO include upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmosor proptosis), chemosis, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic consequences. Many of the signs and symptoms of TAO, including proptosis and ocular congestion, result from expansion of the orbital adipose tissue and periocular muscles. The adipose tissue volume increases owing in part to new fat cell development (adipogenesis) within the orbital fat. The accumulation of hydrophilic glycosaminoglycans, primarily hyaluronic acid, within the orbital adipose tissue and the perimysial connective tissue between the extraocular muscle fibers, further expands the fat compartments and enlarges the extraocular muscle bodies. Hyaluronic acid is produced by fibroblasts residing within the orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, including IL-lbeta, interferon-gamma, platelet-derived growth factor, thyroid stimulating hormone (TSH) and insulin-like growth factor 1 (IGF-1).

[0003] Antibodies that activate the insulin-like growth factor 1 receptor (IGF-1R) have also been detected and implicated in active TAO. Without being bound to any theory, it is believed that TSHR and IGF-1R form a physical and functional complex in orbital fibroblasts, and that blocking IGF-1R appears to attenuate both IGF-1 and TSH-dependent signaling. It has been suggested that blocking IGF-1R using an antibody antagonist might reduce both TSHR- and IGF-1 -dependent signaling and therefore interrupt the pathological activities of autoantibodies acting as agonists on either receptor.

[0004] IGF-1R is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic function of many cell types. It is a tyrosine kinase receptor comprising two subunits. IGF-IRa contains a ligand-binding domain while IGF-1RP is involved in signaling and contains tyrosine phosphorylation sites.

[0005] Current therapies for hyperthyroidism due to Graves’ disease are imperfect because therapies targeting the specific underlying pathogenic autoimmune mechanisms of the disease are lacking. Even more complex is the treatment of moderate-to-severe active TAO. Although recent years have witnessed a better understanding of its pathogenesis, TAO remains a therapeutic challenge and dilemma. There are no approved drugs to treat active TAO. Intravenous glucocorticoids (ivGCs) and oral glucocorticoids are used to treat patients with moderate-to-severe active TAO, but results are seldom satisfactory. Partial responses are frequent and relapses (rebound) after drug withdrawal are not uncommon. Adverse events do occur and many patients eventually require rehabilitative surgery conducted when their condition has transitioned to inactive TAO. Accordingly, there is still a need to provide alternativetherapies for TAO and its related symptoms.SUMMARY

[0006] Provided herein are antibodies comprising a variable heavy chain that is at least 90% identical to SEQ ID NO: 1 and a variable light chain that is at least 90% identical to SEQ ID NO: 2. In some embodiments, the variable heavy chain comprises a tyrosine that corresponds to position 32 of SEQ ID NO: 1; an arginine that corresponds to position 98 of SEQ ID NO: 1; a glycine that corresponds to position 99 of SEQ ID NO: 1; a proline that corresponds to position 101 of SEQ ID NO: 1; an aspartate that corresponds to position 102 of SEQ ID NO: 1; a tyrosine that corresponds to position 103 of SEQ ID NO: 1; a tyrosine that corresponds to position 104 of SEQ ID NO: 1; a lysine that corresponds to position 108 of SEQ ID NO: 1; a tryptophane that corresponds to position 109 of SEQ ID NO: 1; or any combination thereof; an arginine that corresponds to position 40 of SEQ ID NO: 1; an isoleucine that corresponds to position 48 of SEQ ID NO: 1; a lysine that corresponds to position 67 of SEQ ID NO: 1; an alanine that corresponds to position 68 of SEQ ID NO: 1; a leucine that corresponds to position 70 of SEQ ID NO: 1; a valine that corresponds to position 72 of SEQ ID NO: 1; a lysine that corresponds to position 74 of SEQ ID NO: 1; an alanine that corresponds to position 79 of SEQ ID NO: 1; a glutamine that corresponds to position 82 of SEQ ID NO: 1; a threonine that corresponds to position 87 of SEQ ID NO: 1; a serine that corresponds to position 91 of SEQ ID NO: 1; and / or a mutation that corresponds to position 30 of SEQ ID NO: 1, such as T30A, T30S, T30K, or T30D; a mutation that corresponds to position 34 of SEQ ID NO: 1, such as M34A, M34S, M34K, or M34D; a mutation that corresponds to position 35 of SEQ ID NO: 1, such as H35A, H35S, H35K, or H35D; a mutation that corresponds to position 54 of SEQ ID NO: 1, such as S54A, S54K, or S54D; a mutation that corresponds to position 106 of SEQ ID NO: 1, such as SI 06 A, S106K, or S106D; a mutation that corresponds to position 111 of SEQ ID NO: 1, such as Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID; or any combination thereof; a mutation that corresponds to position 12 of SEQ ID NO: 1, such as V12K; a mutation that corresponds to position 20 of SEQ ID NO: 1, such as L20V; a mutation that corresponds to position 22 of SEQ ID NO: 1, such as C22A or C22K; a mutation that corresponds to position 38 of SEQ ID NO: 1, such as K38R; a mutation that corresponds to position 76 of SEQ ID NO: 1, such as S76T; and / or a mutation that corresponds to position 23 of SEQ ID NO: 1, such as K23A, provided that the mutation is not K23S or K23D; a mutation that corresponds to position 24 of SEQ ID NO: 1, such as A24S or A24K,provided that the mutation is not A24D; a mutation that corresponds to position 25 of SEQ ID NO: 1, such as S25D, provided that the mutation is not S25A or S25K; a mutation that corresponds to position 26 of SEQ ID NO: 1, such as G26A or G26D, provided that the mutation is not G26S or G26K; a mutation that corresponds to position 27 of SEQ ID NO: 1, such as Y27K, provided that the mutation is not Y27A, Y27S, or Y27D; a mutation that corresponds to position 28 of SEQ ID NO: 1, such as T28S or T28D, provided that the mutation is not T28A or T28K; a mutation that corresponds to position 29 of SEQ ID NO: 1, such as F29A, provided that the mutation is not F29S, F29K, or F29D; a mutation that corresponds to position 31 of SEQ ID NO: 1, such as S31 A or S3 ID, provided that the mutation is not S3 IK; a mutation that corresponds to position 33 of SEQ ID NO: 1, such as W33K, provided that the mutation is not W33A, W33S, or W33D; a mutation that corresponds to position 50 of SEQ ID NO: 1, such as E50A, E50S, or E50D, provided that the mutation is not E50K; a mutation that corresponds to position 51 of SEQ ID NO: 1, such as 151 A, 15 IK, or 15 ID, provided that the mutation is not 15 IS; a mutation that corresponds to position 52 of SEQ ID NO: 1, such as N52A or N52K, provided that the mutation is not N52S or N52D; a mutation that corresponds to position 53 of SEQ ID NO: 1, such as P53S or P53K, provided that the mutation is not P53 A or P53D; a mutation that corresponds to position 55 of SEQ ID NO: 1, such as N55D, provided that the mutation is not N55A, N55S, or N55K; a mutation that corresponds to position 56 of SEQ ID NO: 1, such as G56D, provided that the mutation is not G56A, G56S, or G56K; a mutation that corresponds to position 57 of SEQ ID NO: 1, such as R57A, R57K, or R57D, provided that the mutation is not R57S; a mutation that corresponds to position 58 of SEQ ID NO: 1, such as T58S, T58K, or T58D, provided that the mutation is not T58A; a mutation that corresponds to position 59 of SEQ ID NO: 1, such as N59S or N59K, provided that the mutation is not N59A or N59D; a mutation that corresponds to position 97 of SEQ ID NO: 1, such as A97S or A97D, provided that the mutation is not A97K; a mutation that corresponds to position 100 of SEQ ID NO: 1, such as R100A or R100K, provided that the mutation is not R100S or R100D; a mutation that corresponds to position 105 of SEQ ID NO: 1, such as G105A, provided that the mutation is not G105S, G105K, or G105D; a mutation that corresponds to position 107 of SEQ ID NO: 1, such as S107A, provided that the mutation is not S107K or S107D; a mutation that corresponds to position 110 of SEQ ID NO: 1, such as Y 110S, Y 110K, or Y HOD, provided that the mutation is not Y 110A; a mutation that corresponds to position 112 of SEQ ID NO: 1, such as DI 12S, provided that the mutation is not DI 12A or DI 12K; a mutation that corresponds to position 113 of SEQ ID NO: 1, such asVI 13 A, VI 13S, or VI 13K, provided that the mutation is not VI 13D; or any combination thereof. In some embodiments, the variable light chain comprises:

[0007] a glutamate that corresponds to position 39 of SEQ ID NO: 2; a threonine that corresponds to position 7 of SEQ ID NO: 2; a serine that corresponds to position 14 of SEQ ID NO: 2; an aspartate that corresponds to position 17 of SEQ ID NO: 2; a leucine that corresponds to position 42 of SEQ ID NO: 2; a lysine that corresponds to position 44 of SEQ ID NO: 2; a leucine that corresponds to position 51 of SEQ ID NO: 2; an alanine that corresponds to position 72 of SEQ ID NO: 2; an arginine that corresponds to position 79 of SEQ ID NO: 2; or any combination thereof; and / or a mutation that corresponds to position 24 of SEQ ID NO: 2, such as R24A, R24S R24K, or R24D; a mutation that corresponds to position 26 of SEQ ID NO: 2, such as S26A, S26K, or S26D; a mutation that corresponds to position 28 of SEQ ID NO: 2, such as S28A, S28K, or S28D; a mutation that corresponds to position 33 of SEQ ID NO: 2, such as N33A, N33S, N33K, or N33D; a mutation that corresponds to position 58 of SEQ ID NO: 2, such as N58A, N58S, N58K, or N58D; a mutation that corresponds to position 59 of SEQ ID NO: 2, such as R59A, R59S, R59K, or R59D; a mutation that corresponds to position 102 of SEQ ID NO: 2, such as T102A, T102S, T102K, or T102D; or any combination thereof; a mutation that corresponds to position 41 of SEQ ID NO: 2, such as Y41F; a mutation that corresponds to position 88 of SEQ ID NO: 2, such as L88V; a mutation that corresponds to position 90 of SEQ ID NO: 2, such as I90V; and / or a mutation that corresponds to position 25 of SEQ ID NO: 2, such as S25A, provided that the mutation is not S25K or S25D; a mutation that corresponds to position 27 of SEQ ID NO: 2, such as Q27S or Q27D, provided that the mutation is not Q27A or Q27K; a mutation that corresponds to position 29 of SEQ ID NO: 2, such as I29S, I29K, or I29D, provided that the mutation is not I29A; a mutation that corresponds to position 30 of SEQ ID NO: 2, such as V30S, V30K, or V30D, provided that the mutation is not V30A; a mutation that corresponds to position 32 of SEQ ID NO: 2, such as S32K, or S32D, provided that the mutation is not S32A; a mutation that corresponds to position 34 of SEQ ID NO: 2, such as V34A, V34K, or V34D, provided that the mutation is not V34S; a mutation that corresponds to position 35 of SEQ ID NO: 2, such as N35S, or N35K, provided that the mutation is not N35A or N35D; a mutation that corresponds to position 36 of SEQ ID NO: 2, such as T36S or T36K, provided that the mutation is not T36A or T36D; a mutation that corresponds to position 37 of SEQ ID NO: 2, such as Y37K, provided that the mutation is not Y37A, Y37S, or Y37D; a mutation that corresponds to position 38 of SEQ ID NO: 2, such as L38A, L38K, or L38D, provided that themutation is not L38S; a mutation that corresponds to position 54 of SEQ ID NO: 2, such as Y54A or Y54S, provided that the mutation is not Y54K or Y54D; a mutation that corresponds to position 55 of SEQ ID NO: 2, such as K55S, provided that the mutation is not K55A or K55D; a mutation that corresponds to position 56 of SEQ ID NO: 2, such as V56A, V56K, or V56D, provided that the mutation is not V56S; a mutation that corresponds to position 57 of SEQ ID NO: 2, such as S57A or S57K, provided that the mutation is not S57D; a mutation that corresponds to position 60 of SEQ ID NO: 2, such as F60A, F60S, or F60K, provided that the mutation is not F60D; a mutation that corresponds to position 61 of SEQ ID NO: 2, such as S61 A or S61K, provided that the mutation is not S61D; a mutation that corresponds to position 94 of SEQ ID NO: 2, such as F94A, provided that the mutation is not F94S, F94K, or F94D; a mutation that corresponds to position 95 of SEQ ID NO: 2, such as Q95A, Q95S or Q95D, provided that the mutation is not Q95K; a mutation that corresponds to position 96 of SEQ ID NO: 2, such as G96S, provided that the mutation is not G96A, G96K, or G96D; a mutation that corresponds to position 97 of SEQ ID NO: 2, such as S97A or S97D, provided that the mutation is not S97K; a mutation that corresponds to position 98 of SEQ ID NO: 2, such as H98A, H98K, or H98D, provided that the mutation is not H98S; a mutation that corresponds to position 99 of SEQ ID NO: 2, such as V99A, V99S, or V99D, provided that the mutation is not V99K; a mutation that corresponds to position 100 of SEQ ID NO: 2, such as P100S, P100K, or P100D, provided that the mutation is not P100A; a mutation that corresponds to position 101 of SEQ ID NO: 2, such as P101K, provided that the mutation is not P101A, P101S, or P101D; or any combination thereof.

[0008] Provided herein are antibodies antibody comprises a variable heavy chain that is at least 90% identical to SEQ ID NO: 1 and a variable light chain that is at least 90% identical to SEQ ID NO: 2, wherein the SEQ ID NO: 1 does not comprise a mutation at position 32, such as Y32A, Y32S, Y32K, or Y32D, a mutation at position 98, such as R98A, R98S, R98K, or R98D, a mutation at position 99, such as G99A, G99S, G99K, or G99D, a mutation at position 101, such as P101A, P101S, P101K, or P101D, a mutation at position 102, such as D102A, D102S, or D102K, a mutation at position 103, such as Y103A, Y103S, Y103K, or Y103D, a mutation at position 104, such as Y104A, Y104S, Y104K, or Y104D, a mutation at position 108, such as K108A, K108S, K108K, or K108D, or a mutation at position 109, such as W109A, W109S, W109K, or W109D; a mutation at position 40 such as R40A, a mutation at position 48 such as I48M, a mutation at position 67 such as K67R, a mutation at position 68 such as A68V, a mutation at position 70 such as L70M, a mutation at position 72 such asV72R, a mutation at position 74 such as K74T, a mutation at position 79 such as A79V, a mutation at position 82 such as Q82E, a mutation at position 87 such as T87R, a mutation at position 91 such as S91T, and SEQ ID NO: 2 does not comprise a mutation at position 39, such as a E39A, E39S, E39K, or E39D, a mutation at position 7, such as T7S, a mutation at position 14, such as S14T, a mutation at position 17, such as D17Q, a mutation at position 42, such as L42Q, a mutation at position 44, such as K44R, a mutation at position 51, such as L51R, a mutation at position 72, such as A72S, a mutation at position 79, such as R79K. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 30 of SEQ ID NO: 1, such as T30A, T30S, T30K, or T30D; a mutation that corresponds to position 34 of SEQ ID NO: 1, such as M34A, M34S, M34K, or M34D; a mutation that corresponds to position 35 of SEQ ID NO: 1, such as H35A, H35S, H35K, or H35D; a mutation that corresponds to position 54 of SEQ ID NO: 1, such as S54A, S54K, or S54D; a mutation that corresponds to position 106 of SEQ ID NO: 1, such as SI 06 A, S106K, or S106D; a mutation that corresponds to position 111 of SEQ ID NO: 1, such as Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID; a mutation that corresponds to position 12 of SEQ ID NO: 1, such as V12K; a mutation that corresponds to position 20 of SEQ ID NO: 1, such as L20V; a mutation that corresponds to position 22 of SEQ ID NO: 1, such as C22A or C22K; a mutation that corresponds to position 38 of SEQ ID NO: 1, such as K38R; a mutation that corresponds to position 76 of SEQ ID NO: 1, such as S76T; or any combination thereof; and / or a mutation that corresponds to position 23 of SEQ ID NO: 1, such as K23A, provided that the mutation is not K23S or K23D; a mutation that corresponds to position 24 of SEQ ID NO: 1, such as A24S or A24K, provided that the mutation is not A24D; a mutation that corresponds to position 25 of SEQ ID NO: 1, such as S25D, provided that the mutation is not S25A or S25K; a mutation that corresponds to position 26 of SEQ ID NO: 1, such as G26A or G26D, provided that the mutation is not G26S or G26K; a mutation that corresponds to position 27 of SEQ ID NO: 1, such as Y27K, provided that the mutation is not Y27A, Y27S, or Y27D; a mutation that corresponds to position 28 of SEQ ID NO: 1, such as T28S or T28D, provided that the mutation is not T28A or T28K; a mutation that corresponds to position 29 of SEQ ID NO: 1, such as F29A, provided that the mutation is not F29S, F29K, or F29D; a mutation that corresponds to position 31 of SEQ ID NO: 1, such as S31 A or S3 ID, provided that the mutation is not S3 IK; a mutation that corresponds to position 33 of SEQ ID NO: 1, such as W33K, provided that the mutation is not W33A, W33S, or W33D; a mutation that corresponds to position 50 of SEQ ID NO: 1, such as E50A, E50S, or E50D, provided that the mutation is not E50K; a mutation that corresponds to position 51 ofSEQ ID NO: 1, such as 151 A, 15 IK, or 15 ID, provided that the mutation is not 15 IS; a mutation that corresponds to position 52 of SEQ ID NO: 1, such as N52A or N52K, provided that the mutation is not N52S or N52D; a mutation that corresponds to position 53 of SEQ ID NO: 1, such as P53S or P53K, provided that the mutation is not P53A or P53D; a mutation that corresponds to position 55 of SEQ ID NO: 1, such as N55D, provided that the mutation is not N55A, N55S, or N55K; a mutation that corresponds to position 56 of SEQ ID NO: 1, such as G56D, provided that the mutation is not G56A, G56S, or G56K; a mutation that corresponds to position 57 of SEQ ID NO: 1, such as R57A, R57K, or R57D, provided that the mutation is not R57S; a mutation that corresponds to position 58 of SEQ ID NO: 1, such as T58S, T58K, or T58D, provided that the mutation is not T58A; a mutation that corresponds to position 59 of SEQ ID NO: 1, such as N59S or N59K, provided that the mutation is not N59A or N59D; a mutation that corresponds to position 97 of SEQ ID NO: 1, such as A97S or A97D, provided that the mutation is not A97K; a mutation that corresponds to position 100 of SEQ ID NO: 1, such as R100A or R100K, provided that the mutation is not R100S or R100D; a mutation that corresponds to position 105 of SEQ ID NO: 1, such as G105A, provided that the mutation is not G105S, G105K, or G105D; a mutation that corresponds to position 107 of SEQ ID NO: 1, such as S107A, provided that the mutation is not S107K or S107D; a mutation that corresponds to position 110 of SEQ ID NO: 1, such as Y110S, Y110K, or Y110D, provided that the mutation is not Y110A; a mutation that corresponds to position 112 of SEQ ID NO: 1, such as DI 12S, provided that the mutation is not DI 12A or DI 12K; a mutation that corresponds to position 113 of SEQ ID NO: 1, such as VI 13A, VI 13S, or VI 13K, provided that the mutation is not VI 13D; or any combination thereof. In some embodiments, the variable light chain comprises a mutation that corresponds to position 24 of SEQ ID NO: 2, such as R24A, R24S R24K, or R24D; a mutation that corresponds to position 26 of SEQ ID NO: 2, such as S26A, S26K, or S26D; a mutation that corresponds to position 28 of SEQ ID NO: 2, such as S28A, S28K, or S28D; a mutation that corresponds to position 33 of SEQ ID NO: 2, such as N33A, N33S, N33K, or N33D; a mutation that corresponds to position 58 of SEQ ID NO: 2, such as N58A, N58S, N58K, or N58D; a mutation that corresponds to position 59 of SEQ ID NO: 2, such as R59A, R59S, R59K, or R59D; a mutation that corresponds to position 102 of SEQ ID NO: 2, such as T102A, T102S, T102K, or T102D; a mutation that corresponds to position 41 of SEQ ID NO: 2, such as Y41F; a mutation that corresponds to position 88 of SEQ ID NO: 2, such as L88V; a mutation that corresponds to position 90 of SEQ ID NO: 2, such as I90V; or any combination thereof; and / or a mutation that corresponds to position 25 of SEQ ID NO: 2,such as S25A, provided that the mutation is not S25K or S25D; a mutation that corresponds to position 27 of SEQ ID NO: 2, such as Q27S or Q27D, provided that the mutation is not Q27A or Q27K; a mutation that corresponds to position 29 of SEQ ID NO: 2, such as I29S, I29K, or I29D, provided that the mutation is not I29A; a mutation that corresponds to position 30 of SEQ ID NO: 2, such as V30S, V30K, or V30D, provided that the mutation is not V30A; a mutation that corresponds to position 32 of SEQ ID NO: 2, such as S32K, or S32D, provided that the mutation is not S32A; a mutation that corresponds to position 34 of SEQ ID NO: 2, such as V34A, V34K, or V34D, provided that the mutation is not V34S; a mutation that corresponds to position 35 of SEQ ID NO: 2, such as N35S, or N35K, provided that the mutation is not N35A or N35D; a mutation that corresponds to position 36 of SEQ ID NO: 2, such as T36S or T36K, provided that the mutation is not T36A or T36D; a mutation that corresponds to position 37 of SEQ ID NO: 2, such as Y37K, provided that the mutation is not Y37A, Y37S, or Y37D; a mutation that corresponds to position 38 of SEQ ID NO: 2, such as L38A, L38K, or L38D, provided that the mutation is not L38S; a mutation that corresponds to position 54 of SEQ ID NO: 2, such as Y54A or Y54S, provided that the mutation is not Y54K or Y54D; a mutation that corresponds to position 55 of SEQ ID NO: 2, such as K55S, provided that the mutation is not K55A or K55D; a mutation that corresponds to position 56 of SEQ ID NO: 2, such as V56A, V56K, or V56D, provided that the mutation is not V56S; a mutation that corresponds to position 57 of SEQ ID NO: 2, such as S57A or S57K, provided that the mutation is not S57D; a mutation that corresponds to position 60 of SEQ ID NO: 2, such as F60A, F60S, or F60K, provided that the mutation is not F60D; a mutation that corresponds to position 61 of SEQ ID NO: 2, such as S61 A or S61K, provided that the mutation is not S61D; a mutation that corresponds to position 94 of SEQ ID NO: 2, such as F94A, provided that the mutation is not F94S, F94K, or F94D; a mutation that corresponds to position 95 of SEQ ID NO: 2, such as Q95A, Q95S or Q95D, provided that the mutation is not Q95K; a mutation that corresponds to position 96 of SEQ ID NO: 2, such as G96S, provided that the mutation is not G96A, G96K, or G96D; a mutation that corresponds to position 97 of SEQ ID NO: 2, such as S97A or S97D, provided that the mutation is not S97K; a mutation that corresponds to position 98 of SEQ ID NO: 2, such as H98A, H98K, or H98D, provided that the mutation is not H98S; a mutation that corresponds to position 99 of SEQ ID NO: 2, such as V99A, V99S, or V99D, provided that the mutation is not V99K; a mutation that corresponds to position 100 of SEQ ID NO: 2, such as P100S, P100K, or P100D, provided that the mutation is not P100A; a mutation that corresponds to position 101 of SEQ ID NO: 2, such as P101K, provided that the mutationis not P101A, P101S, or P101D; or any combination thereof.

[0009] In some embodiments, the variable heavy chain comprises a K23 A mutation. In some embodiments, the variable heavy chain comprises an amino acid of SEQ ID NO: 3.

[0010] In some embodiments, the variable heavy chain comprises an A24S or A24K, mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 6 or 7.

[0011] In some embodiments, the variable heavy chain comprises an S25D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 11.

[0012] In some embodiments, the variable heavy chain comprises a G26A or G26D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 12 or 15.

[0013] In some embodiments, the variable heavy chain comprises a Y27K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 18.

[0014] In some embodiments, the variable heavy chain comprises a T28S or T28D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 21 or 23.

[0015] In some embodiments, the variable heavy chain comprises an F29A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 24.

[0016] In some embodiments, the variable heavy chain comprises a T30A, T30S, T30K, or T30D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 28, 29, 30, or 31.

[0017] In some embodiments, the variable heavy chain comprises an S31A or S3 ID mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 32 or 34.

[0018] In some embodiments, the variable heavy chain comprises a W33K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 41.

[0019] In some embodiments, the variable heavy chain comprises an M34A, M34S, M34K, or M34D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 43, 44, 45, or 46.

[0020] In some embodiments, the variable heavy chain comprises a H35A, H35S, H35K, or H35D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 47, 48, 49, or 50.

[0021] In some embodiments, the variable heavy chain comprises an E50A, E50S, or E50D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 51, 52, or 54.

[0022] In some embodiments, the variable heavy chain comprises an 151 A, 15 IK, or15 ID mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 55, 57, or 58.

[0023] In some embodiments, the variable heavy chain comprises a N52A or N52K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 59 or 61.

[0024] In some embodiments, the variable heavy chain comprises a P53S or P53K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 64 or 65.

[0025] In some embodiments, the variable heavy chain comprises a S54A, S54K, or S54D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 67, 68, or 69.

[0026] In some embodiments, the variable heavy chain comprises a N55D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 73.

[0027] In some embodiments, the variable heavy chain comprises a G56D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 77.

[0028] In some embodiments, the variable heavy chain comprises a R57A, R57K, or R57D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 78, 80, or 81.

[0029] In some embodiments, the variable heavy chain comprises a T58S, T58K, or T58D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 83, 84, or 85.

[0030] In some embodiments, the variable heavy chain comprises a N59S or N59K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 87 or 88.

[0031] In some embodiments, the variable heavy chain comprises an A97S or A97D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 90 or 92.

[0032] In some embodiments, the variable heavy chain comprises a R100A or R100K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 101 or 103.

[0033] In some embodiments, the variable heavy chain comprises a G105A mutation.In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 120.

[0034] In some embodiments, the variable heavy chain comprises a S106A, S106K, or S106D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 124, 125, or 126.

[0035] In some embodiments, the variable heavy chain comprises a S107A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 127.

[0036] In some embodiments, the variable heavy chain comprises a Y110S, Y110K, or Y110D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 138, 139, or 140.

[0037] In some embodiments, the variable heavy chain comprises a Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 141, 142, 143, or 144.

[0038] In some embodiments, the variable heavy chain comprises a DI 12S mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 146.

[0039] In some embodiments, the variable heavy chain comprises a VI 13 A, VI 13 S, or VI 13K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 148, 149, or 150.

[0040] In some embodiments, the variable heavy chain comprises a V12K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 276.

[0041] In some embodiments, the variable heavy chain comprises a L20V mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 277.

[0042] In some embodiments, the variable heavy chain comprises a C22A or C22K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 278 or 279.

[0043] In some embodiments, the variable heavy chain comprises a K38R mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 280.

[0044] In some embodiments, the variable heavy chain comprises a S76T mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 288.

[0045] In some embodiments, the variable light chain comprises an R24A, R24S R24K, or R24D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 152, 153, 154, or 155.

[0046] In some embodiments, the variable light chain comprises an S25A mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 156.

[0047] In some embodiments, the variable light chain comprises an S26A, S26K, or S26D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 159, 160, or 161.

[0048] In some embodiments, the variable light chain comprises a Q27S or Q27D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 163 or 165.

[0049] In some embodiments, the variable light chain comprises an S28A, S28K, or S28D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 166, 167, or 168.

[0050] In some embodiments, the variable light chain comprises an I29S, I29K, or I29D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 170, 171, or 172.

[0051] In some embodiments, the variable light chain comprises a V30S, V30K, or V30D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 174, 175, or 176.

[0052] In some embodiments, the variable light chain comprises a S32K, or S32D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 182 or 183.

[0053] In some embodiments, the variable light chain comprises a N33A, N33S, N33K, or N33D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 184, 185, 186, or 187.

[0054] In some embodiments, the variable light chain comprises a V34A, V34K, or V34D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 188, 190, or 191.

[0055] In some embodiments, the variable light chain comprises a N35S, or N35K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 193 or 194.

[0056] In some embodiments, the variable light chain comprises a T36S or T36K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 197 or 198.

[0057] In some embodiments, the variable light chain comprises a Y37K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 202.

[0058] In some embodiments, the variable light chain comprises a L38A, L38K, or L38D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 204, 206, or 207.

[0059] In some embodiments, the variable light chain comprises a Y54A or Y54S mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 212 or 213.

[0060] In some embodiments, the variable light chain comprises a K55S mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 217.

[0061] In some embodiments, the variable light chain comprises a V56A, V56K, or V56D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 219, 221, or 222.

[0062] In some embodiments, the variable light chain comprises a S57A or S57K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 223 or 224.

[0063] In some embodiments, the variable light chain comprises a N58A, N58S, N58K, or N58D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 226, 227, 228, or 229.

[0064] In some embodiments, the variable light chain comprises a R59A, R59S, R59K, or R59D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 230, 231, 232, or 233.

[0065] In some embodiments, the variable light chain comprises a F60A, F60S, or F60K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 234, 235, or 236.

[0066] In some embodiments, the variable light chain comprises a S61A or S61K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 238 or 239.

[0067] In some embodiments, the variable light chain comprises a F94A mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 241.

[0068] In some embodiments, the variable light chain comprises a Q95A, Q95S or Q95D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 245, 246, or 248.

[0069] In some embodiments, the variable light chain comprises a G96S mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 250.

[0070] In some embodiments, the variable light chain comprises a S97A or S97D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 253 or 255.

[0071] In some embodiments, the variable light chain comprises a H98A, H98K, or H98D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 256, 258, or 259.

[0072] In some embodiments, the variable light chain comprises a V99A, V99S, or V99D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 260, 261, or 263.

[0073] In some embodiments, the variable light chain comprises a P100S, P100K, or P100D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 265, 266, or 267.

[0074] In some embodiments, the variable light chain comprises a P101K mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 270.

[0075] In some embodiments, the variable light chain comprises a T102A, T102S, T102K, or T102D mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 272, 273, 274, or 275

[0076] In some embodiments, the variable light chain comprises a Y41F mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 296.

[0077] In some embodiments, the variable light chain comprises a L88V mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO:302.

[0078] In some embodiments, the variable light chain comprises a I90V mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO:303.

[0079] In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 3. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 6 or 7. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 11. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 12 or 15. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 18. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 21 or 23. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 24. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 28, 29, 30, or 31. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 32 or 34. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 41. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 43, 44, 45, or 46. In someembodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 47, 48, 49, or 50. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 51, 52, or 54. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 55, 57, or 58. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 59 or 61. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 64 or 65. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 67, 68, or 69. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 73. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 77. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 78, 80, or 81. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 83, 84, or 85. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 87 or 88. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 90 or 92. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 101 or 103. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 120. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 124, 125, or 126. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 127. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO:138, 139, or 140. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 141, 142, 143, or 144. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 146. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 148, 149, or 150. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 276. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 277. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 278. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 279. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 280. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 288.

[0080] In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 152, 153, 154, or 155. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 156. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 159, 160, or 161. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 163 or 165. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 166, 167, or 168. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 170, 171, or 172. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 174, 175, or 176. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and thevariable light chain has an amino acid sequence of SEQ ID NO: 182 or 183. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 184, 185, 186, or 187. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 188, 190, or 191. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 193 or 194. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 197 or 198. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 202. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 204, 206, or 207. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 212 or 213. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 217. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 219, 221, or 222. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 223 or 224. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 226, 227, 228, or 229. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 230, 231, 232, or 233. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 234, 235, or 236. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 238 or 239. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 241. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 245, 246, or 248. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ IDNO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 250. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 253 or 255. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 256, 258, or 259. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 260, 261, or 263. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 265, 266, or 267. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 270. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 272, 273, 274, or 275. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 296. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 302. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 304.

[0081] Provided herein are methods of treating or reducing the severity of, thyroid- associated ophthalmopathy (TAO), or a symptom thereof, comprising administering to a subject an antibody as provided herein.

[0082] Provided herein are methods of reducing proptosis in an eye in a subject with thyroid-associated ophthalmopathy (TAO) comprising administering to a subject an antibody as provided herein.

[0083] Provided herein are methods of treating thyroid eye disease in a subject comprising administering to a subject an antibody as provided herein.

[0084] Provided herein are methods of reducing Clinical Activity Score (CAS) of thyroid-associated ophthalmopathy (TAO) in a subject comprising administering to a subject an antibody as provided herein.

[0085] Provided herein are methods of a) reducing proptosis by at least 2 mm and b) reducing the clinical activity score (CAS) in a subject with thyroid-associated ophthalmopathy (TAO) comprising administering to a subject an antibody as provided herein.

[0086] In some embodiments, proptosis is reduced by at least 2 mm. In some embodiments, proptosis is reduced by at least 3 mm. In some embodiments, proptosis is reduced by at least 4 mm. In some embodiments, the clinical activity score (CAS) of the subject is reduced by at least 2 points. In some embodiments, the clinical activity score (CAS) of the subject is reduced to one (1). In some embodiments, the clinical activity score (CAS) of the subject is reduced to zero (0).

[0087] Provided herein are methods of treating or reducing the severity of thyroid- associated ophthalmopathy (TAO) in a subject comprising administering to a subject an antibody as provided herein, wherein treatment with said antibody (i) reduces proptosis by at least 2 mm in an eye; (ii) is not accompanied by a deterioration of 2 mm or more in the other (or fellow eye); and (iii) reduces the CAS in said subject to either one (1) or zero (0).

[0088] Provided herein are methods of improving the quality of life in a subject with thyroid-associated ophthalmopathy (TAO, also called Graves' Ophthalmopathy / Graves' Orbitopathy) comprising administering to a subject an antibody as provided herein. In some embodiments, wherein the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment, or either the Visual Functioning or Appearance subscale thereof. In some embodiments, the treatment results in an improvement of greater than or equal to 8 points on the GO-QoL. In some embodiments, the treatment results in an improvement on the Functioning subscale of the GO-QoL. In some embodiments, the treatment results in an improvement on the Appearance subscale of the GO-QoL.

[0089] Provided herein are methods of treating or reducing the severity of diplopia in a subject with thyroid-associated ophthalmopathy (TAO) comprising administering to a subject an antibody as provided herein. In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is inconstant diplopia. In some embodiments, the diplopia is intermittent diplopia. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of antibody administration. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of antibody administration.

[0090] In some embodiments, said antibody is administered at a dosage of about 1 mg / kg to about 5 mg / kg antibody as a first dose. In some embodiments, said antibody is administered at a dosage of about 5 mg / kg to about 10 mg / kg antibody as a first dose. In some embodiments, said antibody is administered at a dosage of about 5 mg / kg to about 20 mg / kg antibody in subsequent doses. In some embodiments, said antibody is administered in thefollowing amounts: about 10 mg / kg antibody as a first dose; and about 20 mg / kg antibody in subsequent doses. In some embodiments, said subsequent doses are administered every three weeks for at least 21 weeks. In some embodiments, the antibody, or an antigen binding fragment thereof, is a human antibody, a monoclonal antibody, a human monoclonal antibody, a purified antibody, a diabody, a single-chain antibody, a multi-specific antibody, Fab, Fab', F(ab')2, Fv or scFv. In some embodiments, the antibody, or an antigen binding fragment thereof, is administered in a pharmaceutical composition that additionally comprises a pharmaceutically acceptable diluent or excipient or carrier. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO. In some embodiments, the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNF alpha antibodies or a thyroid-stimulating hormone receptor (TSHR) inhibitor. In some embodiments, the antibody or an 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 retro-orbital sinus. In some embodiments, the antibody or an antigen binding fragment thereof is administered via an injection. In some embodiments, the injection is a intravitreal injection, intraorbital injection, retro-orbital injection, suprachoroidal injection, or intracameral injection.

[0091] Provided herein are methods of increasing the internalization of IGF-1R on a cell, the method comprising contacting the cell with an antibody as provided herein. In some embodiments, the contacting comprises administering to a subject an antibody as provided herein. In some embodiments, the subject has or is at risk of thyroid eye disease (TED).

[0092] Provided herein are methods of inhibiting IGF-1 stimulated receptor phosphorylation on a cell, the method comprising contacting the cell with an antibody as provided herein. In some embodiments, the contacting comprises administering to a subject an antibody as provided herein. In some embodiments, the subject has or is at risk of thyroid eye disease (TED). In some embodiments, the antibody has an IC50 of less than, or equal to, about 0.2 nm, 0.15 nm, 0.10 nm, 0.09 nm. In some embodiments, the IC50 is measured in an in vitro assay, such as an assay as provided for herein. In some embodiments, the cell is an A549 cell or a HOCF cell.

[0093] Provided herein are methods of treating thyroid eye disease in a subject, the method comprising administering an antibody as provided herein, wherein the antibody has a serum concentration in the subject of at least, or about, 70 pg / ml, 75 pg / ml, 80 pg / ml, 85pg / ml, 90 pg / ml, 95 pg / ml, 100 pg / ml, or 105 pg / ml at least 1, 2, or 3 week after administration. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered at a dose of about 20 mg / kg. In some embodiments, the antibody is administered at least, or about, once a week, once every two weeks, once every 3 weeks, or once every 4 weeks.

[0094] Provided herein are methods of inhibiting IGF-1 induced receptor autophosphorylation in a cell by at least 95%, 96%, 97%, 98%, or 99% or by 100%, the method comprising contacting the cell with an antibody as provided herein. In some embodiments, the inhibition of the IGF-1 induced receptor autophosphorylation is measured as compared to the induced receptor autophosphorylation in the absence of the antibody. In some embodiments, the contacting comprises administering to a subject the antibody comprising the same. In some embodiments, the subject has or is at risk of thyroid eye disease (TED).

[0095] Provided herein are methods of inhibiting IGF-1 induced receptor autophosphorylation by at least 95%, 96%, 97%, 98%, or 99% or by 100% in a subject in need thereof, the method comprising administering to the subject an antibody as provided herein. In some embodiments, the subject has or is at risk of thyroid eye disease (TED). In some embodiments, the antibody is administered intravenously.DETAILED DESCRIPTION

[0096] Provided herein are antibodies that bind and modulate the activity of IGF-1R. The antibodies can be used, for example, to treat thyroid eye disease.

[0097] As used herein, “thyroid-associated ophthalmopathy” (TAO), “thyroid eye disease” (TED), and “Graves’ Ophthalmopathy” or “Graves' Orbitopathy” (GO) refer to the same disorder or condition and are used interchangeably. They all refer to the inflammatory orbital pathology associated with some autoimmune thyroid disorders, most commonly with Graves’ Disease (GD), but sometimes with other diseases, e.g., Hashimoto’s thyroiditis.

[0098] The terms “proptosis” and “exophthalmos” (also known as exophthalmos, exophthalmia, or exorbitism) refer to the forward projection, displacement, bulging, or protrusion of an organ. As used herein, the terms refer to the forward projection, displacement, bulging, or protrusion of the eye anteriorly out of the orbit. Proptosis and exophthalmos are considered by some of skill in the art to have the same meaning and are often used interchangeably, while others attribute subtle differences to their meanings. Exophthalmos is used by some to refer to severe proptosis; or to refer to endocrine-related proptosis. Yet othersuse the term exophthalmos when describing proptosis associated with the eye, in, for example, subjects with TAO (TED or GO).

[0099] As used herein, the terms “proptosis” and “exophthalmos” are used interchangeably and refer to the forward projection, displacement, bulging, or protrusion of the eye anteriorly out of the orbit. Owing to the rigid bony structure of the orbit with only anterior opening for expansion, any increase in orbital soft tissue contents taking place from the side or from behind will displace the eyeball forward. Proptosis or exophthalmos can be the result of a several disease processes including infections, inflammations, tumors, trauma, metastases, endocrine lesions, vascular diseases & extra orbital lesions. TAO (TED or GO) is currently recognized as the most common cause of proptosis in adults. Exophthalmos can be either bilateral, as is often seen in TAO (TED or GO), or unilateral (as is often seen in an orbital tumor).

[0100] Measurement of the degree of exophthalmos can be performed using, for example, an exophthalmometer, an instrument used for measuring the degree of forward displacement of the eye. The device allows measurement of the forward distance of the lateral orbital rim to the front of the cornea. Computed tomography (CT) scanning and Magnetic resonance imaging (MRI) may also be used in evaluating the degree of exophthalmos or proptosis. CT scanning is an excellent imaging modality for the diagnosis of TAO. In addition to allowing visualization of the enlarged extraocular muscles, CT scans provide the surgeon or clinician with depictions of the bony anatomy of the orbit when an orbital decompression is required. MRI, with its multi-planar and inherent contrast capabilities, provides excellent imaging of the orbital contents without the radiation exposure associated with CT scan studies. MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscle, but CT scans provide better views of the bony architecture of the orbit. Orbital ultrasonography can also be a used for the diagnosis and evaluation of TAO, because it can be performed quickly and with a high degree of confidence. High reflectivity and enlargement of the extraocular muscles are assessed easily, and serial ultrasonographic examinations can also be used to assess progression or stability of the ophthalmopathy. Based on the technologies currently available, or that will become available in the future, one of skills in the art would be capable of determining the best modality for diagnosing and evaluating the extent of proptosis or exophthalmos.

[0101] As used herein, the term “antibody” refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fullyhuman antibodies, chimeric antibodies and camelized single domain antibodies (e.g., cam elid antibodies). “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic antibody.

[0102] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions. Examples of antigen binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; singlechain antibody molecules, e.g., scFv; nanobodies and multispecific antibodies formed from antibody fragments.

[0103] A “Fab fragment” is comprised of one light chain and the CHI and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0104] An “Fc” region contains two heavy chain fragments comprising the CHI and CH2 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0105] In some embodiments, the antibodies, or antigen fragments herein, comprise a Fc region. In some embodiments, the Fc region comprises a mutation that extends the half-life of the antibody when linked to the Fc region. In some embodiments, the Fc region comprises a S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutation, or any combination thereof. In some embodiments, the Fc region comprises a M252Y, S254T, and T256E mutations. A non-limiting example of a Fc region comprising the M252Y, S254T, and T256E mutations (collectively, “YTE Mutations”) can be found in a sequence of SEQ ID NO: 89. In some embodiments, the Fc region comprising the YTE Mutations comprises a sequence of SEQ ID NO: 90, which differs from SEQ ID NO: 89 by the presence of a C-terminal lysine (K) residue. The numbering of the Fc region can be according to the Kabat numbering system for the Fc region.

[0106] In some embodiments, the Fc region comprises a S228P and a L235E mutation. In some embodiments, the antibody comprises a L234F, L235E, and P331S mutation. 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 the M428L and N434S mutations. In someembodiments, the Fc region comprises the 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. The numbering referenced herein refers to the Kabat numbering system for the Fc region.

[0107] In some embodiments, the Fc region comprises the sequence of:APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 199);APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 200);APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTFRWSVLTWHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 201);ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG (SEQ ID NO: 202);ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 203);ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG (SEQ ID NO: 204);ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 205); orASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK (SEQ ID NO: 206).

[0108] A “Fab1fragment” contains one light chain and a portion or fragment of one heavy chain that contains the VH domain and the CHI domain and also the region between the CHI and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab') 2 molecule.

[0109] A “F(ab')2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the CHI and CH2domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab') 2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.

[0110] The “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0111] The term “single-chain Fv” or “scFv” antibody refers to antibody fragments comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see 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. WO 88 / 01649 and U.S. Pat. Nos. 4,946, 778 and 5,260,203.

[0112] A “domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.

[0113] A “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).

[0114] In certain embodiments, 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; WO 94 / 04678; WO 94 / 25591; U.S. Pat. No. 6,005,079). In one embodiment, the present invention provides single domain antibodies comprising two VH domains with modifications such that single domain antibodies are formed.

[0115] As used herein, the term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-VH). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigenbinding sites. Diabodies are described more fully in, e.g., EP 404,097; WO 93 / 11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448. For a review of engineered antibody variants generally see Holliger and Hudson (2005) Nat. Biotechnol. 23 : 1126-1136.

[0116] Typically, a variant antibody or antigen binding fragment of the antibodies provided herein retain at least 10% of its IGF-1R binding activity (when compared to a parental antibody that is modified) when that activity is expressed on a molar basis. In some embodiments, a variant antibody (or antigen fragment thereof), or antigen binding fragment ofan antibody provided herein, retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the IGF-1R binding affinity as the parental antibody. As described herein, it is also intended that an antibody or antigen binding fragment of the invention can include conservative or nonconservative amino acid substitutions, which can also be referred to as “conservative variants” or “function conserved variants” of the antibody, that do not substantially alter its biologic activity.

[0117] Isolated antibody” refers to the purification status of a binding compound and in such context means the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

[0118] The term “monoclonal antibody”, as used herein, refers to 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 typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, that are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present 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. Patent No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in, for example, Clackson et al. (1991) Nature 352:624-628; Marks et al. (1991) J Mol Biol. 222:581-597; and Presta LG (2005) J Allergy Clin Immunol. 116:731.

[0119] As used herein, a “chimeric antibody” is an antibody having the variable domain from a first antibody and constant domain from a second antibody, where the first and second antibodies are from different species, such as described in U.S. Patent 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 (the “parental antibody”) from an experimental animal, such as arodent, and the constant domain sequences are obtained from human antibodies, so that the resulting chimeric antibody will be less likely to elicit an adverse immune response in a human subject than the parental (e.g. rodent) antibody.

[0120] As used herein, the term “humanized antibody” refers to forms of antibodies that contain sequences from both human and non-human (e.g., murine, rat) antibodies. In general, the humanized antibody will comprise 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 comprise at least a portion of a human immunoglobulin constant region (Fc).

[0121] The term “fully human antibody” refers to an antibody that comprises human immunoglobulin protein sequences only. A fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” refers to an antibody that comprises mouse immunoglobulin sequences only. Alternatively, a fully human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell. Similarly, “rat antibody” refers to an antibody that comprises rat immunoglobulin sequences only.

[0122] In general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within 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 including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology, Ch. 7 (Paul, W ., ed., 2nd ed. Raven Press, N.Y. (1989).

[0123] The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are, in general, the same.

[0124] Typically, the variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is, generally, in accordance with the definitions of North et al. , “A new clustering of antibody CDR loop conformations,” J Mol Biol. , 2011, Vol. 406, No. 2, Pages 228-256. The assignment of amino acids to each domain may also be in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al:, National Institutes of Health, Bethesda, Md. ; 5thed.; 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.

[0125] As used herein, the term “hypervariable region” refers to the amino acid residues of an antibody that are responsible for antigen-binding. The hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” as defined in North etal., “A new clustering of antibody CDR loop conformations,” J Mol Biol. , 2011, Vol. 406, No. 2, Pages 228-256 (i.e. residues between certain sequence motifs corresponding to starting and ending positions of a CDRL1, CDRL2, and CDRL3 in the light chain variable domain and the starting and ending positions of a CDRH1, CDRH2, and CDRH3 in the heavy chain variable domain). The hypervariable region may also comprise amino acid residues from a “complementarity determining region” or “CDR” as defined in Kabat etal. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (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) and / or those residues from a “hypervariable loop” as defined in Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917 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). Unless provided otherwise, any CDRs provided for herein are defined by the CDR definitions found in North et al. (2011). Asused herein, the term “framework” or “FR” residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope. CDRs of interest can be derived from donor antibody variable heavy and light chain sequences, andinclude analogs of the naturally occurring CDRs, which analogs also share or retain the same antigen binding specificity and / or neutralizing ability as the donor antibody from which they were derived.

[0126] Additionally, in some embodiments, the antibodies can take the form of a full length antibody, single-domain antibody, a recombinant heavy-chain-only 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; an evibody; a fynomer, an armadillo repeat protein, a Kunitz domain, an avimer, an atrimer, a probody, an immunobody, a triomab, a troybody; a pepbody; a vaccibody, a UniBody; Affimers, a DuoBody, a Fv, a Fab, a Fab', a F(ab')2, a peptide mimetic molecule, or a synthetic molecule, as described in U.S. Patent Nos. or Patent Publication Nos. US 7,417,130, US 2004 / 132094, US 5,831 ,012, US 2004 / 023334, US 7,250,297, US 6,818,418, US 2004 / 209243, US 7,838,629, US 7,186,524, US 6,004,746, US 5,475,096, US 2004 / 146938, US 2004 / 157209, US 6,994,982, US 6,794,144, US 2010 / 239633, US 7,803,907, US 2010 / 119446, and / or US 7,166,697, the contents of each of which are hereby incorporated by reference in their entireties. See also, Storz MAbs. 2011 May-Jun; 3(3): 310- 317, which is hereby incorporated by reference.

[0127] The term “antigen” as used herein means any molecule that has the ability to generate antibodies either directly or indirectly or that binds to antibody. Included within the definition of “antigen” is a protein-encoding nucleic acid. An “antigen” can also refer to the binding partner of an antibody. In some embodiments, the antigen is the IGF-1R protein expressed on the surface of a cell. In some embodiments, the cell is an intact cell. An intact cell is a cell that has not been lysed or broken open with the use of detergents or other reagents. A cell that has been treated with detergents or other reagents that breaks up the cellular membrane or punches holes in a cellular membrane is not an intact cell. For example, methods are provided herein for generating an antibody that binds to a IGF-1R protein, the method comprising culturing a cell comprising a nucleic acid molecule encoding the IGF-1R antibody.

[0128] As used herein, “specific binding” or “immunospecific binding” or “binds immunospecifically” refer to antibody binding to a predetermined antigen (e.g., IGF-1R) or epitope present on the antigen. In some embodiments, the antibody binds with a dissociation constant (KD) of 10'7M or less, and binds to the predetermined antigen with a Kothat is at least two-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein, or another non-specific polypeptide) other than the predetermined antigen. The phrases “an antibody recognizing IGF-1R” and “an antibody specific for IGF-1R” are used interchangeably herein with the term “an antibody which binds immunospecifically to IGF-1R.” Reference in the present disclosure may be made to IGF-1R. The degree of specificity necessary for an anti-IGF-lR antibody may depend on the intended use of the antibody, and at any rate is defined by its suitability for use for an intended purpose. In some embodiments, the antibody, or binding compound derived from the antigen-binding site of an antibody, of the contemplated method binds to its antigen (IGF-1R), with an affinity that is at least two-fold greater, at least ten times greater, at least 20-times greater, or at least 100-times greater than the affinity with any other antigen.

[0129] Methods for determining 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, N.Y., 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc, and Wiley Interscience, N.Y., (1992, 1993), and Muller (1983) Meth EnzymoL 92:589-601, each of which is entirely incorporated herein by reference.

[0130] The term “homolog” means protein sequences having between 40% and 100% sequence homology or identity to a reference sequence. Percent identity between two peptide chains can be determined by pair wise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carslbad, Calif.). In some embodiments, the antibody, or antigenic binding fragment thereof has, at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homology or identity to a sequence described herein. In some embodiments, the antibody has conservative substitutions as compared to a sequence described herein. Exemplary conservative substitutions are illustrated in Table 1 and are encompassed within the scope of the disclosed subject matter. The conservative substitution may reside in the framework regions, or in antigen-binding sites, as long they do not adversely affect the properties of the antibody. Substitutions may be made to improve antibody properties, for example stability or affinity. Conservative substitutions will produce molecules having functional and chemical characteristics similar to those molecules into which such modifications are made. Exemplary amino acid substitutions are shown in Table 1, below.

[0131] Table 1. Exemplary Conservative Amino Acid Substitutions

[0132] In some embodiments, variants of the proteins and peptides provided herein are provided. In some embodiments, a variant comprises a substitution, deletions, or insertion. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions. As described herein, the substitutions can be conservative substitutions. In some embodiments, the substitution is non-conservative. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions. In some embodiments, the variant comprises 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 for herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided for herein.

[0133] The term “in combination with” as used herein means that the described agents can be administered to an animal or subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0134] The techniques to raise antibodies to small peptide sequences that recognize and bind to those sequences in the free or conjugated form or when presented as a native sequence in the context of a large protein are well known in the art. Such antibodies include murine, murine-human and human-human antibodies produced by hybridoma or recombinant techniques known in the art. Antibodies can also be produced in a human, a mouse, sheep, a rat, a rabbit, a shark, a llama, or a chicken. In some embodiments, the antibody is produced in a chicken. The antibodies can also be produced in or other small animals.

[0135] The term “epitope” is meant to refer to that portion of any molecule capable of being recognized by and bound by an antibody at one or more of the antibody’s antigen binding regions. 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 IGF-1R epitopes. In some embodiments, the epitope is only present in a non-denatured protein. In some embodiments, the epitope is only present in a denatured protein.

[0136] In some embodiments, the source for the DNA encoding a non-human antibody include cell lines which produce antibody, such as hybrid cell lines commonly known as hybridomas.

[0137] The hybrid cells are formed by the fusion of a non-human antibody-producing cell, typically a spleen cell of an animal immunized against either natural or recombinant antigen, or a peptide fragment of the antigen protein sequence. Alternatively, the non-human antibodyproducing cell can be a B lymphocyte obtained from the blood, spleen, lymph nodes or other tissue of an animal immunized with the antigen.

[0138] The second fusion partner, which provides the immortalizing function, can be a lymphoblastoid cell or a plasmacytoma or myeloma cell, which is not itself an antibody producing cell, but is malignant. Fusion partner cells include, but are not limited to, the hybridoma SP2 / 0-Agl4, abbreviated as SP2 / 0 (ATCC CRL1581) and the myeloma P3X63Ag8 (ATCC TIB9), or its derivatives. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference.

[0139] The antibodies can be generated according to the examples provided herein. Once the sequences are known, the antibodies can also be generated according to known methods. The antibodies can also be converted to different types, such as being converted to Human IgGs and the like. By converting the antibodies to a human antibody, a human subject should not identify the antibodies as foreign. The conversion of a non-human IgG antibody to a human IgG antibody is well known and can routinely be done once the native sequence is known. As discussed herein, the antibodies can be modified according to known methods. Such methods are described in, for example, Riechmann et al. (1988) “Reshaping human antibodies for therapy,” Nature 332(6162):332-323; Tsurushita et al. (2004) “Humanization of a chicken anti-IL-12 monoclonal antibody,” J Immunol Method. 295(l-2):9-19. The antibody-producing cell contributing the nucleotide sequences encoding the antigen-binding region of the chimeric antibody can also beproduced by transformation of a non-human, such as a primate, or a human cell. For example, a B lymphocyte which produces the antibody can be infected and transformed with a virus such as Epstein-Barr virus to yield an immortal antibody producing cell (Kozbor et al. (1983) Immunol. Today 4:72-79). Alternatively, the B lymphocyte can be transformed by providing a transforming gene or transforming gene product, as is well-known in the art. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference. The cell fusions are accomplished by standard procedures well known to those skilled in the field of immunology. Fusion partner cell lines and methods for fusing and selecting hybridomas and screening for mAbs are well known in the art. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference.

[0140] In some embodiments, the antibody is a mAb which binds to IGF-1R. In some embodiments, the antibody binds to amino acids of an epitope of the IGF-1R.

[0141] In some embodiments, the antibody comprises a sequence as provided for herein.

[0142] The sequences of the antibodies can be modified to yield human IgG antibodies. The conversion of the sequences provided herein can be modified to yield other types of antibodies. The CDRs can also be linked to other antibodies, proteins, or molecules to create antibody fragments that bind to IGF-1R. This can be in the form of an antibody-drug conjugate (“ADC”), a multi-specific molecule, or a chimeric antigen receptor. The CDRs and antibody sequences provided herein also be humanized or made fully human according to known methods. The sequences can also be made into chimeric antibodies as described herein.

[0143] In some embodiments, the antibody comprises an amino acid sequence comprising a sequence provided for herein or a fragment thereof. In some embodiments, the antibody comprises one or more amino acid sequences as provided herein, an antigen binding fragments, thereof, or a human IgG variant thereof. “A human IgG variant thereof’ refers to an antibody that has been modified to be a human IgG when the starting antibody is not a human IgG antibody.

[0144] As described herein, the production of antibodies with a known sequence is routine and can be done by any method. Accordingly, in some embodiments, a nucleic acid encoding an antibody or fragment thereof is provided. In some embodiments, the nucleic acid encodes a sequence provided for herein. The antibodies can also be modified to be chimeric antibodies or human antibodies. The antibodies can also be used in injectable pharmaceutical compositions. As also described herein, the antibodies can be isolated antibodies or engineeredantibodies.

[0145] In some embodiments, “derivatives” of the antibodies, fragments, regions or derivatives thereof, which term includes those proteins encoded by truncated or modified genes to yield molecular species functionally resembling the immunoglobulin fragments are provided. The modifications include, but are not limited to, addition of genetic sequences coding for cytotoxic proteins such as plant and bacterial toxins. The modification can also include a reporter protein, such as a fluorescent or chemiluminescent tag. The fragments and derivatives can be produced in any manner.

[0146] The identification of these antigen binding region and / or epitopes recognized by antibodies described herein provide the information necessary to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility that parallel the embodiments of this application.

[0147] The nucleic acid sequence encoding an antibody described herein can be genomic DNA or cDNA, or RNA (e.g., mRNA) which encodes at least one of the variable regions described herein. A convenient alternative to the use of chromosomal gene fragments as the source of DNA encoding the V region antigen-binding segment is the use of cDNA for the construction of chimeric immunoglobulin genes, e.g., as reported by Liu et al. (1987) Proc. Natl. Acad. Sci., USA 84:3439 and Liu et al. (1987) J. Immunology 139:3521, which references are hereby entirely incorporated herein by reference. The use of cDNA requires that gene expression elements appropriate for the host cell be combined with the gene in order to achieve synthesis of the desired protein. The use of cDNA sequences is advantageous over genomic sequences (which contain introns) because cDNA sequences can be expressed in bacteria or other hosts which lack appropriate RNA splicing systems.

[0148] For example, a cDNA encoding a V region antigen-binding segment able to detect, bind, or neutralize an IGF-1R antigen 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 encode a particular amino acid (Watson, et al., infra). Using the genetic code, one or more different oligonucleotides can be identified, each of which would be capable of encoding the amino acid. The probability that a particular oligonucleotide will, in fact, constitute the actual XXX-encoding sequence can be estimated by considering abnormal base pairing relationships and the frequency with which a particular codon is actually used (to encode a particular amino acid) in eukaryotic or prokaryotic cells expressing an antibody or fragment. Such “codon usage rules” are disclosed by Lathe et al. (1985) J Molec Biol. 183: 1-12.Using the “codon usage rules” of Lathe, a single oligonucleotide, or a set of oligonucleotides, that contains a theoretical “most probable” nucleotide sequence capable of encoding an antibody variable or constant region sequences is identified.

[0149] The variable regions described herein can be combined with any type of constant region including a human constant region or murine constant region. Human genes which encode the constant (C) regions of the antibodies, fragments and regions can be derived from a human fetal liver library by known methods. Human C regions genes can be derived from any human cell including those which express and produce human immunoglobulins. The human CH region can be derived from any of the known classes or isotypes of human H chains, including gamma, p, a, 5 or s, and subtypes thereof, such as Gl, G2, G3 and G4. Since the H chain isotype is responsible for the various effector functions of an antibody, the choice of CH region will be guided by the desired effector functions, such as complement fixation, or activity in antibodydependent cellular cytotoxicity (ADCC). Preferably, the CH region is derived from gamma 1 (IgGl), gamma 3 (IgG3), gamma 4 (IgG4), or p (IgM). The human CL region can be derived from either human L chain isotype, kappa or lambda. In some embodiments, the antibody comprises a Fc domain. In some embodiments, the Fc domain comprises a mutation to extend the half-life of the antibody. In some embodiments, the Fc domain comprises a mutation such as those described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety. In some embodiments, the constant region comprises a mutation at position at amino acid residue position 428 relative to a wild-type human IgG constant domain, numbered according to the EU numbering index of Kabat. Without being bound to any particular theory, an antibody comprising a mutation that corresponds to residue 428 can have an increased halflife as compared to the half-life of an IgG having the wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of the native residue with a threonine, leucine, phenylalanine or serine. In some embodiments, the antibody further comprises one or more amino acid substitutions relative 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 Kabat EU numbering index. The specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.

[0150] 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, N.Y. (1989) and Ausubelet al., eds. Current Protocols in Molecular Biology (1987 1993)). Human C region genes are readily available from known clones containing genes representing the two classes of L chains, the five classes of H chains and subclasses thereof. Chimeric antibody fragments, such as F(ab')2 and Fab, can be prepared by designing a chimeric H chain gene which is appropriately truncated. For example, a chimeric gene encoding an H chain portion of an F(ab')2 fragment would include DNA sequences encoding the CHi domain and hinge region of the H chain, followed by a translational stop codon to yield the truncated molecule.

[0151] In some embodiments, the antibodies, murine, human, humanized, or chimeric antibodies, fragments and regions of the antibodies described herein are produced by cloning DNA segments encoding the H and L chain antigen-binding regions of a IGF-1R antigen specific antibody, and joining these DNA segments to DNA segments encoding CH and CL regions, respectively, to produce murine, human or chimeric immunoglobulin-encoding genes.

[0152] Thus, in some embodiments, a fused chimeric gene is created which comprises a first DNA segment that encodes at least the antigen-binding region of non-human origin, such as a functionally rearranged V region with joining (J) segment, linked to a second DNA segment encoding at least a part of a human C region.

[0153] Therefore, cDNA encoding the antibody V and C regions, the method of producing the antibody according to some of the embodiments described herein involve several steps, as exemplified below: 1. isolation of messenger RNA (mRNA) from the cell line producing an anti- IGF-1R antigen antibody and from optional additional antibodies supplying heavy and light constant regions; cloning and cDNA production therefrom; 2. preparation of a full length cDNA library from purified mRNA from which the appropriate V and / or C region gene segments of the L and H chain genes can be: (i) identified with appropriate probes, (ii) sequenced, and (iii) made compatible with a C or V gene segment from another antibody for a chimeric antibody; 3. Construction of complete H or L chain coding sequences by linkage of the cloned specific V region gene segments to cloned C region gene, as described above; 4. Expression and production of L and H chains in selected hosts, including prokaryotic and eukaryotic cells to provide murine-murine, human-murine, human-human or human murine antibodies.

[0154] Two coding DNA sequences are said to be “operably linked” if the linkage results in a continuously 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 that gene expression element to result in expression of the codingsequence.

[0155] As used herein and unless otherwise indicated, the term “about” is intended to mean ± 5% of the value it modifies. Thus, “about 100” means 95 to 105.

[0156] In some embodiments, the antibodies described herein are used to detect the presence of the antigen. The present antibody can be used in any device or method to detect the presence of the antigen.

[0157] The term “purified” with reference to an antibody refers to an antibody that is substantially free of other material that associates with the molecule in its natural environment. For instance, a purified protein is substantially free of the 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% to 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, the antibody is purified.

[0158] As an alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody to a polypeptide may be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with a polypeptide described herein to thereby isolate immunoglobulin library members that bind to the polypeptide. Techniques and commercially available kits for generating and screening phage display libraries are well known to those skilled in the art. Additionally, examples of methods and reagents particularly amenable 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 for other antibodies that can be used therapeutically, diagnostically, or as research tools.Antibody Conjugates

[0159] The antibodies provided for herein may also be conjugated to a chemical moiety. The chemical moiety may be, inter alia, a polymer, a radionuclide or a cytotoxic factor. In some embodiments, this can be referred to as an antibody drug conjugate. In some embodiments, the chemical moiety is a polymer which increases the half-life of the antibody molecule in the body of a subject. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2kDa, 5 kDa, 10 kDa, 12kDa, 20 kDa, 30kDa or 40kDa), dextran and monomethoxypolyethylene glycol (mPEG). Examples of PEG conjugated single-chain antibodies can be found in Lee et al. (1999) Bioconj Chem. 10:973-981, the contents of whichare hereby incorporated by reference in their entireties. Examples of conjugating antibodies with PEG which is attached to a radiometal chelator (diethylenetriaminpentaacetic acid (DTP A) can be found in Wen et al. (2001) Bioconj Chem. 12:545-553, the contents of which are hereby incorporated by reference in their entireties. Examples of chemical moieties include, but are not limited to, anti-mitotics, such as calicheamicins (e.g., ozogamicin), monomethyl auristatin E, mertansine, and the like. Further examples include, but are not limited to, biologically active anti-microtubule agents, alkylating agents, and DNA minor groove binding agents. Further examples are provided herein and below. The chemical moiety can be linked to the antibody through a linking group (e.g., mal eimide), a cleavable linker, such as a cathepsin cleavable linkers (e.g., valine-citrulline), and in some embodiments, one or more spacers (e.g., paraaminobenzylcarbamate). Without being bound to any particular theory, once the antibody conjugate binds IGF-1R, it can be internalized and the chemical moiety can kill the cell or otherwise inhibit its growth. In some embodiments, the cell is a thyroid cell.

[0160] The antibodies and antibody fragments of the invention may also be conjugated with labels such as "TC,90Y,n iIn,32P,14C,1251,3H,131I,nC,150,13N,18F,35S,51Cr,57To,226Ra,60Co,59Fe,57Se,152Eu,67CU,217Ci,211At,212Pb,47Sc,109Pd,234Th, and40K,157Gd,55Mn,52Tr and56Fe.

[0161] The antibodies and antibody fragments may also be conjugated with fluorescent or chemiluminescent labels, including fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin, phycocyanin, allophycocyanin, o-phthaladehyde, fluorescamine,152Eu, dansyl, umbelliferone, luciferin, luminal labels, isoluminal labels, aromatic acridinium ester labels, imidazole labels, acridimium salt labels, oxalate ester labels, aequorin labels, 2,3-dihydrophthalazinediones, biotin / avidin, spin labels, and stable free radicals.

[0162] The antibody molecules may also be conjugated to a cytotoxic factor such as diptheria 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, mitogellin, restrictocin, phenomycin, and enomycin.

[0163] Any method known in the art for conjugating the antibody molecules of the invention to the various moieties may be employed, including those methods described by Hunter et al. 1962) Nature 144:945; David etal., (1974) Biochemistry 13 : 1014; and Pain etal.,(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.Chimeric Antigen Receptors

[0164] The antibodies provided herein can also be incorporated into a chimeric antigen receptor (“CAR”) that can be used, for example, in a CAR-T cell. In some embodiments, the extracellular domain of the CAR can be an antibody as provided for herein. In some embodiments, the antibody is in a scFv format. CAR-T cells are a type of treatment in which a patient’s T cells are modified so they will attack the cells that are expressing IGF-1R. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cells is added in the laboratory. In some embodiments, the receptor binds to IGF- 1R using the binding regions of the antibodies provided for herein. The CAR-T cells comprising the IGF-1R antibody can then be used to treat a condition, such as those provided for herein.

[0165] In some embodiments, antibodies (e.g. an anti-IGF-lR antibody) are provided herein. In some embodiments, the antibody is a recombinant antibody that binds to a IGF-1R protein. In some embodiments, the IGF-1R protein is a human IGF-1R protein. In some embodiments, the IGF-1R protein that is recognized by the antibodies is in its native conformation (non-denatured) conformation. In some embodiments, the antibody does not specifically binds to a denatured IGF-1R protein. As used herein, the term “recombinant antibody” refers to an antibody that is not naturally occurring. In some embodiments, the term “recombinant antibody” refers to an antibody that is not isolated from a human subject.

[0166] In some embodiments, the antibody can comprise the heavy variable region (VH) or light variable region (VL) sequence, or the combination of VH and VL sequences, or variants, as provided for in Table 2, below:

[0167] Table 2. Variable Heavy Region (VH) and Variable Light Region (VL) Sequences of Antibody Variants.

[0168] As provided for herein, the heavy chain can be linked to a Fc region, including those with mutations that can affect the half-life of the antibody. Non-limiting mutations in the Fc region are provided for herein.

[0169] In some embodiments, the light chain region (LC) and heavy chain region (HC) may be combined with the VH and VL domains provided herein, with or without constant regions. The constant regions can be replaced as provided for herein. The VH and VL regions can be used to form an antibody as provided for herein. The VH and the VL sequences can be in any format, including, but not limited to a scFv format where the VH and VL regions are linked with a peptide linker. Examples of peptide linkers that can be used to link various peptides provided for herein include, but are not limited to: (GGGGS)n(SEQ ID NO: 105); (GGGGA)n(SEQ ID NO: 106), or any combination thereof, wherein each n is independently 1-5. In some embodiments, the variable regions are not linked with a peptide linker. In addition to these specific combinations any of the VH peptides and the VL peptides can be combined with one another.

[0170] In some embodiments, an antibody, or an 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, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 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, 61, 62, 63, 64, 65, 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, 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, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 276, 277, 278, 279, 280, 281, 282, 283,284, 285, 286, 287, 288, 289, 290, 291, and 292.

[0171] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain variable region (VL) sequence selected from the group consisting of SEQ ID NOs: 2, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 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, 206,207, 208, 209, 210, 211, 212, 213, 214, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 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, 173,174, 175, 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, 207, 208, 209, 210, 211,212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230,231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249,250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268,269, 270, 271, 272, 273, 274, 275, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, and 303.

[0172] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that: the variable heavy chain comprises: a tyrosine that corresponds to position 32 of SEQ ID NO: 1; an arginine that corresponds to position 98 of SEQ ID NO: 1; a glycine that corresponds to position 99 of SEQ ID NO: 1; a proline that corresponds to position 101 of SEQ ID NO: 1; an aspartate that corresponds to position 102 of SEQ ID NO: 1; a tyrosine that corresponds to position 103 of SEQ ID NO: 1; a tyrosine that corresponds to position 104 of SEQ ID NO: 1; a lysine that corresponds to position 108 of SEQ ID NO: 1; a tryptophane that corresponds to position 109 of SEQ ID NO: 1;an arginine that corresponds to position 40 of SEQ ID NO: 1; an isoleucine that corresponds to position 48 of SEQ ID NO: 1; a lysine that corresponds to position 67 of SEQ ID NO: 1; an alanine that corresponds to position 68 of SEQ ID NO: 1; a leucine that corresponds to position 70 of SEQ ID NO: 1; a valine that corresponds to position 72 of SEQ ID NO: 1; a lysine that corresponds to position 74 of SEQ ID NO: 1; an alanine that corresponds to position 79 of SEQ ID NO: 1; a glutamine that corresponds to position 82 of SEQ ID NO: 1; a threonine that corresponds to position 87 of SEQ ID NO: 1; a serine that corresponds to position 91 of SEQ ID NO: 1; or any combination thereof.

[0173] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a tyrosine that corresponds to position 32 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises an arginine that corresponds to position 98 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a glycine that corresponds to position 99 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a proline that corresponds to position 101 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 2, provided that the variable heavy chain comprises an aspartate that corresponds to position 102 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a tyrosine that corresponds to position 103 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a tyrosine that corresponds to position 104 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a lysine that corresponds to position 108 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a tryptophane that corresponds to position 109 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises an arginine that corresponds to position 40 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises an isoleucine that corresponds to position 48 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a lysine that corresponds to position 67 of SEQ ID NO: 1. Insome embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises an alanine that corresponds to position 68 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a leucine that corresponds to position 70 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a valine that corresponds to position 72 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a lysine that corresponds to position 74 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises an alanine that corresponds to position 79 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a glutamine that corresponds to position 82 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a threonine that corresponds to position 87 of SEQ ID NO: 1. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a serine that corresponds to position 91 of SEQ ID NO: 1.

[0174] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises: a mutation that corresponds to position 30 of SEQ ID NO: 1, such as, but not limited to, T30A, T30S, T30K, or T30D; a mutation that corresponds to position 34 of SEQ ID NO: 1, such as, but not limited to, M34A, M34S, M34K, or M34D; a mutation that corresponds to position 35 of SEQ ID NO: 1, such as, but not limited to, H35A, H35S, H35K, or H35D; a mutation that corresponds to position 54 of SEQ ID NO: 1, such as, but not limited to, S54A, S54K, or S54D; a mutation that corresponds to position 106 of SEQ ID NO: 1, such as, but not limited to, SI 06 A, S106K, or S106D; a mutation that corresponds to position 111 of SEQ ID NO: 1, such as, but not limited to, Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID; a mutation that corresponds to position 12 of SEQ ID NO: 1, such as, but not limited to, V12K; a mutation that corresponds to position 20 of SEQ ID NO: 1, such as, but not limited to, L20V; a mutation that corresponds to position 22 of SEQ ID NO: 1, such as, but not limited to, C22A or C22K; a mutation that corresponds to position 38 of SEQ ID NO: 1, such as, but not limited to, K38R; a mutation that corresponds to position 76 of SEQ ID NO: 1, such as, but not limited to, S76T. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 30 of SEQ ID NO: 1, such as, but not limited to, T30A, T30S, T30K, or T30D. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 34 of SEQ ID NO: 1, such as, but not limited to, M34A, M34S, M34K, or M34D. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 35 of SEQ ID NO: 1, such as, but not limited to, H35A, H35S, H35K, or H35D. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 54 of SEQ ID NO: 1, such as, but not limited to, S54A, S54K, or S54D. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 106 of SEQ ID NO: 1, such as, but not limited to, SI 06 A, S106K, or S106D. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 111 of SEQ ID NO: 1, such as, but not limited to, Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 12 of SEQ ID NO: 1, such as, but not limited to, VI 2K. In some embodiments, thevariable heavy chain comprises a mutation that corresponds to position 20 of SEQ ID NO: 1, such as, but not limited to, L20V. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 22 of SEQ ID NO: 1, such as, but not limited to, C22A or C22K. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 38 of SEQ ID NO: 1, such as, but not limited to, K38R. In some embodiments, the variable heavy chain comprises a mutation that corresponds to position 76 of SEQ ID NO: 1, such as, but not limited to, S76T.

[0175] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 23 of SEQ ID NO: 1, such as, but not limited to, K23A, provided that the mutation is not K23S or K23D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 24 of SEQ ID NO: 1, such as, but not limited to, A24S or A24K, provided that the mutation is not A24D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 25 of SEQ ID NO: 1, such as, but not limited to, S25D, provided that the mutation is not S25A or S25K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 26 of SEQ ID NO: 1, such as, but not limited to, G26A or G26D, provided that the mutation is not G26S or G26K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 27 of SEQ IDNO: 1, such as, but not limited to, Y27K, provided that the mutation is not Y27A, Y27S, or Y27D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 28 of SEQ ID NO: 1, such as, but not limited to, T28S or T28D, provided that the mutation is not T28A or T28K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 29 of SEQ ID NO: 1, such as, but not limited to, F29A, provided that the mutation is not F29S, F29K, or F29D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 31 of SEQ ID NO: 1, such as, but not limited to, S31 A or S3 ID, provided that the mutation is not S3 IK. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 33 of SEQ ID NO: 1, such as, but not limited to, W33K, provided that the mutation is not W33A, W33S, or W33D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 50 of SEQ ID NO: 1, such as, but not limited to, E50A, E50S, or E50D, provided that the mutation is not E50K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 51 of SEQ ID NO: 1, such as, but not limited to, 151 A, 15 IK, or15 ID, provided that the mutation is not 15 IS. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 52 of SEQ ID NO: 1, such as, but not limited to, N52A or N52K, provided that the mutation is not N52S or N52D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 53 of SEQ ID NO: 1, such as, but not limited to, P53S or P53K, provided that the mutation is not P53A or P53D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 55 of SEQ ID NO: 1, such as, but not limited to, N55D, provided that the mutation is not N55A, N55S, or N55K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 56 of SEQ ID NO: 1, such as, but not limited to, G56D, provided that the mutation is not G56A, G56S, or G56K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 57 of SEQ ID NO: 1, such as, but not limited to, R57A, R57K, or R57D, provided that the mutation is not R57S. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 58 of SEQ ID NO: 1, such as, but not limited to, T58S, T58K, or T58D,provided that the mutation is not T58A. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 59 of SEQ ID NO: 1, such as, but not limited to, N59S or N59K, provided that the mutation is not N59A or N59D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 97 of SEQ ID NO: 1, such as, but not limited to, A97S or A97D, provided that the mutation is not A97K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 100 of SEQ ID NO: 1, such as, but not limited to, R100A or R100K, provided that the mutation is not R100S or R100D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 105 of SEQ ID NO: 1, such as, but not limited to, G105A, provided that the mutation is not G105S, G105K, or G105D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 110 of SEQ ID NO: 1, such as, but not limited to, Y110S, Y110K, or Y110D, provided that the mutation is not Y110A. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 112 of SEQ ID NO: 1, such as, but not limited to, DI 12S, provided that the mutation is not DI 12A or DI 12K.In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable heavy chain comprises a mutation that corresponds to position 113 of SEQ ID NO: 1, such as, but not limited to, V113A, V113S, or VI 13K, provided that the mutation is not VI 13D.

[0176] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that: the variable light chain comprises: a glutamate that corresponds to position 39 of SEQ ID NO: 2; a threonine that corresponds to position 7 of SEQ ID NO: 2; a serine that corresponds to position 14 of SEQ ID NO: 2; an aspartate that corresponds to position 17 of SEQ ID NO: 2; a leucine that corresponds to position 42 of SEQ ID NO: 2; a lysine that corresponds to position 44 of SEQ ID NO: 2; a leucine that corresponds to position 51 of SEQ ID NO: 2; an alanine that corresponds to position 72 of SEQ ID NO: 2; an arginine that corresponds to position 79 of SEQ ID NO: 2; or any combination thereof.

[0177] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a glutamate that corresponds to position 39 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a threonine that corresponds to position 7 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 2, provided that the variable light chain comprises a serine that corresponds to position 14 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises an aspartate that corresponds to position 17 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a leucine that corresponds to position 42 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a lysine that corresponds to position 44 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a leucine that corresponds to position 51 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises an alanine that corresponds to position 72 of SEQ ID NO: 2. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises an arginine that corresponds to position 79 of SEQ ID NO: 2.

[0178] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises: amutation that corresponds to position 24 of SEQ ID NO: 2, such as, but not limited to, R24A, R24S R24K, or R24D; a mutation that corresponds to position 26 of SEQ ID NO: 2, such as, but not limited to, S26A, S26K, or S26D; a mutation that corresponds to position 28 of SEQ ID NO: 2, such as, but not limited to, S28A, S28K, or S28D; a mutation that corresponds to position 33 of SEQ ID NO: 2, such as, but not limited to, N33A, N33S, N33K, or N33D; a mutation that corresponds to position 58 of SEQ ID NO: 2, such as, but not limited to, N58A, N58S, N58K, or N58D; a mutation that corresponds to position 59 of SEQ ID NO: 2, such as, but not limited to, R59A, R59S, R59K, or R59D; a mutation that corresponds to position 102 of SEQ ID NO: 2, such as, but not limited to, T102A, T102S, T102K, or T102D; a mutation that corresponds to position 41 of SEQ ID NO: 2, such as, but not limited to, Y41F; a mutation that corresponds to position 88 of SEQ ID NO: 2, such as, but not limited to, L88V; a mutation that corresponds to position 90 of SEQ ID NO: 2, such as, but not limited to, 190 V. In some embodiments, the variable light chain comprises a mutation that corresponds to position 24 of SEQ ID NO: 2, such as, but not limited to, R24A, R24S R24K, or R24D. In some embodiments, the variable light chain comprises a mutation that corresponds to position 26 of SEQ ID NO: 2, such as, but not limited to, S26A, S26K, or S26D. In some embodiments, the variable light chain comprises a mutation that corresponds to position 28 of SEQ ID NO: 2, such as, but not limited to, S28A, S28K, or S28D. In some embodiments, the variable light chain comprises a mutation that corresponds to position 33 of SEQ ID NO: 2, such as, but not limited to, N33A, N33S, N33K, or N33D. In some embodiments, the variable light chain comprises a mutation that corresponds to position 58 of SEQ ID NO: 2, such as, but not limited to, N58A, N58S, N58K, or N58D. In some embodiments, the variable light chain comprises a mutation that corresponds to position 59 of SEQ ID NO: 2, such as, but not limited to, R59A, R59S, R59K, or R59D. In some embodiments, the variable light chain comprises a mutation that corresponds to position 102 of SEQ ID NO: 2, such as, but not limited to, T102A, T102S, T102K, or T102D In some embodiments, the variable light chain comprises a mutation that corresponds to position 41 of SEQ ID NO: 2, such as, but not limited to, Y41F. In some embodiments, the variable light chain comprises a mutation that corresponds to position 88 of SEQ ID NO: 2, such as, but not limited to, L88V. In some embodiments, the variable light chain comprises a mutation that corresponds to position 90 of SEQ ID NO: 2, such as, but not limited to, 190 V.

[0179] In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 25 of SEQ ID NO: 2, such as, but not limited to, S25A, provided that the mutation is not S25K or S25D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 27 of SEQ ID NO: 2, such as, but not limited to, Q27S or Q27D, provided that the mutation is not Q27A or Q27K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 29 of SEQ ID NO: 2, such as, but not limited to, I29S, I29K, or I29D, provided that the mutation is not I29A. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 30 of SEQ ID NO: 2, such as, but not limited to, V30S, V30K, or V30D, provided that the mutation is not V30A. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 32 of SEQ ID NO: 2, such as, but not limited to, S32K, or S32D, provided that the mutation is not S32A. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 34 of SEQ ID NO: 2, such as, but not limited to, V34A, V34K, or V34D, provided that the mutation is not V34S. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that thevariable light chain comprises a mutation that corresponds to position 35 of SEQ ID NO: 2, such as, but not limited to, N35S, orN35K, provided that the mutation is notN35A orN35D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 36 of SEQ ID NO: 2, such as, but not limited to, T36S or T36K, provided that the mutation is not T36A or T36D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 37 of SEQ ID NO: 2, such as, but not limited to, Y37K, provided that the mutation is not Y37A, Y37S, or Y37D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 38 of SEQ ID NO: 2, such as, but not limited to, L38A, L38K, or L38D, provided that the mutation is not L38S. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 54 of SEQ ID NO: 2, such as, but not limited to, Y54A or Y54S, provided that the mutation is not Y54K or Y54D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 55 of SEQ ID NO: 2, such as, but not limited to, K55S, provided that the mutation is not K55A or K55D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that correspondsto position 56 of SEQ ID NO: 2, such as, but not limited to, V56A, V56K, or V56D, provided that the mutation is not V56S. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 57 of SEQ ID NO: 2, such as, but not limited to, S57A or S57K, provided that the mutation is not S57D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 60 of SEQ ID NO: 2, such as, but not limited to, F60A, F60S, or F60K, provided that the mutation is not F60D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 61 of SEQ ID NO: 2, such as, but not limited to, S61A or S61K, provided that the mutation is not S61D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 94 of SEQ ID NO: 2, such as, but not limited to, F94A, provided that the mutation is not F94S, F94K, or F94D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 95 of SEQ ID NO: 2, such as, but not limited to, Q95A, Q95S or Q95D, provided that the mutation is not Q95K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 96 of SEQ ID NO: 2, such as, but not limited to, G96S,provided that the mutation is not G96A, G96K, or G96D. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 97 of SEQ ID NO: 2, such as, but not limited to, S97A or S97D, provided that the mutation is not S97K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 98 of SEQ ID NO: 2, such as, but not limited to, H98A, H98K, or H98D, provided that the mutation is not H98S. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 99 of SEQ ID NO: 2, such as, but not limited to, V99A, V99S, or V99D, provided that the mutation is not V99K. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 100 of SEQ ID NO: 2, such as, but not limited to, P100S, P100K, or P100D, provided that the mutation is not P100A. In some embodiments, antibodies are provided comprising a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, provided that the variable light chain comprises a mutation that corresponds to position 101 of SEQ ID NO: 2, such as, but not limited to, P101K, provided that the mutation is not P101A, P101S, or P101D.

[0180] In some embodiments, the antibody comprises a variable heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a variable light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and comprising at least one mutation (substitution), such as, but not limited to, those provided for herein, provided that the variable heavy chain does not comprise amutation at position 32, such as, but not limited to, Y32A, Y32S, Y32K, or Y32D; a mutation at position 98, such as, but not limited to, R98A, R98S, R98K, or R98D; a mutation at position 99, such as, but not limited to, G99A, G99S, G99K, or G99D; a mutation at position 101, such as, but not limited to, P101A, P101S, P101K, or P101D; a mutation at position 102, such as, but not limited to, DI 02 A, D102S, or D102K; a mutation at position 103, such as, but not limited to, Y103A, Y103S, Y103K, or Y103D; a mutation at position 104, such as, but not limited to, Y104A, Y104S, Y104K, or Y104D; a mutation at position 108, such as, but not limited to, KI 08 A, K108S, K108K, or K108D; or a mutation at position 109, such as, but not limited to, W109A, W109S, W109K, or W109D; a mutation at position 40 such as, but not limited to, R40A, a mutation at position 48 such as, but not limited to, I48M, a mutation at position 67 such as, but not limited to, K67R, a mutation at position 68 such as, but not limited to, A68V, a mutation at position 70 such as, but not limited to, L70M, a mutation at position 72 such as, but not limited to, V72R, a mutation at position 74 such as, but not limited to, K74T, a mutation at position 79 such as, but not limited to, A79V, a mutation at position 82 such as, but not limited to, Q82E, a mutation at position 87 such as, but not limited to, T87R, a mutation at position 91 such as, but not limited to, S91T; and / or the variable light chain does not comprise a mutation at position 39, such as, but not limited to, a E39A, E39S, E39K, or E39D; a mutation at position 7, such as, but not limited to, T7S, a mutation at position 14, such as, but not limited to, S14T, a mutation at position 17, such as, but not limited to, D17Q, a mutation at position 42, such as, but not limited to, L42Q, a mutation at position 44, such as, but not limited to, K44R, a mutation at position 51, such as, but not limited to, L51R, a mutation at position 72, such as, but not limited to, A72S, a mutation at position 79, such as, but not limited to, R79K. In some embodiments, the variable heavy chain does not comprise a mutation at position 32, such as, but not limited to, Y32A, Y32S, Y32K, or Y32D. In some embodiments, the variable heavy chain does not comprise a mutation at position 98, such as, but not limited to, R98A, R98S, R98K, or R98D. In some embodiments, the variable heavy chain does not comprise a mutation at position 99, such as, but not limited to, G99A, G99S, G99K, or G99D. In some embodiments, the variable heavy chain does not comprise a mutation at position 101, such as, but not limited to, P101A, P101S, P101K, or P101D. In some embodiments, the variable heavy chain does not comprise a mutation at position 102, such as, but not limited to, D102A, D102S, or D102K. In some embodiments, the variable heavy chain does not comprise a mutation at position 103, such as, but not limited to, Y103A, Y103S, Y103K, or Y103D. In some embodiments, the variable heavy chain does not comprise a mutation at position 104, such as, but not limited to, Y104A, Y104S, Y104K, orY104D. In some embodiments, the variable heavy chain does not comprise a mutation at position 108, such as, but not limited to, K108A, K108S, K108K, or K108D. In some embodiments, the variable heavy chain does not comprise or a mutation at position 109, such as, but not limited to, W109A, W109S, W109K, or W109D. In some embodiments, the variable heavy chain does not comprise a mutation at position 40 such as, but not limited to, R40A. In some embodiments, the variable heavy chain does not comprise a mutation at position 48 such as, but not limited to, I48M. In some embodiments, the variable heavy chain does not comprise a mutation at position 67 such as, but not limited to, K67R. In some embodiments, the variable heavy chain does not comprise a mutation at position 68 such as, but not limited to, A68V. In some embodiments, the variable heavy chain does not comprise a mutation at position 70 such as, but not limited to, L70M. In some embodiments, the variable heavy chain does not comprise a mutation at position 72 such as, but not limited to, V72R. In some embodiments, the variable heavy chain does not comprise a mutation at position 74 such as, but not limited to, K74T. In some embodiments, the variable heavy chain does not comprise a mutation at position 79 such as, but not limited to, A79V. In some embodiments, the variable heavy chain does not comprise a mutation at position 82 such as, but not limited to, Q82E. In some embodiments, the variable heavy chain does not comprise a mutation at position 87 such as, but not limited to, T87R. In some embodiments, the variable heavy chain does not comprise a mutation at position 91 such as, but not limited to, S91T. In some embodiments, the variable light chain does not comprise a mutation at position 39, such as, but not limited to, aE39A, E39S, E39K, orE39D. In some embodiments, the variable light chain does not comprise a mutation at position 7, such as, but not limited to, T7S. In some embodiments, the variable light chain does not comprise a mutation at position 14, such as, but not limited to, S 14T. In some embodiments, the variable light chain does not comprise a mutation at position 17, such as, but not limited to, D17Q. In some embodiments, the variable light chain does not comprise a mutation at position 42, such as, but not limited to, L42Q. In some embodiments, the variable light chain does not comprise a mutation at position 44, such as, but not limited to, K44R. In some embodiments, the variable light chain does not comprise a mutation at position 51, such as, but not limited to, L51R. In some embodiments, the variable light chain does not comprise a mutation at position 72, such as, but not limited to, A72S. In some embodiments, the variable light chain does not comprise a mutation at position 79, such as, but not limited to, R79K.

[0181] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical toSEQ ID NO: 1 and a K23 A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 3.

[0182] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an A24S or A24K mutation. In some embodiments, the variable heavy chain comprises an A24S mutation. In some embodiments, the variable heavy chain comprises an A24K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 6 or 7. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 6. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 7.

[0183] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a S25D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 11.

[0184] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a G26A or G26D mutation. In some embodiments, the variable heavy chain comprises a G26A mutation. In some embodiments, the variable heavy chain comprises a G26D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 12 or 15. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 12. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 15.

[0185] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a Y27K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 18.

[0186] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a T28S or T28D mutation. In some embodiments, the variable heavy chain comprises a T28S mutation. In some embodiments, the variable heavy chain comprises a T28D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 21 or 23. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the variable heavy chain comprises anamino acid sequence of SEQ ID NO: 23.

[0187] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an F29A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 24.

[0188] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a T30A, T30S, T30K, or T30D mutation. In some embodiments, the variable heavy chain comprises a T30A mutation. In some embodiments, the variable heavy chain comprises a T30S mutation. In some embodiments, the variable heavy chain comprises a T30K mutation. In some embodiments, the variable heavy chain comprises a T30D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 28, 29, 30, or 31. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 28. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 29. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 30. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 31.

[0189] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an S31 A or S3 ID mutation. In some embodiments, the variable heavy chain comprises an S31A mutation. In some embodiments, the variable heavy chain comprises an S32D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 32 or 34. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 32. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 34.

[0190] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a W33K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 41.

[0191] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an M34A, M34S, M34K, or M34D mutation. In some embodiments, the variable heavy chain comprises an M34A mutation. In some embodiments, the variable heavychain comprises an M34S mutation. In some embodiments, the variable heavy chain comprises an M34K mutation. In some embodiments, the variable heavy chain comprises an M34D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 43, 44, 45, or 46. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 43. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 44. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 45. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 46.

[0192] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a H35 A, H35S, H35K, orH35D mutation. In some embodiments, the variable heavy chain comprises a H35A mutation. In some embodiments, the variable heavy chain comprises a H35S mutation. In some embodiments, the variable heavy chain comprises a H35K mutation. In some embodiments, the variable heavy chain comprises a H35D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 47, 48, 49, or 50. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 47. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 48. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 49. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 50.

[0193] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an E50A, E50S, or E50D mutation. In some embodiments, the variable heavy chain comprises an E50A mutation. In some embodiments, the variable heavy chain comprises an E50S mutation. In some embodiments, the variable heavy chain comprises an E50D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 51, 52, or 54. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 52. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 54.

[0194] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an 151 A, 15 IK, or 15 ID mutation. In some embodiments, the variable heavychain comprises an 151 A mutation. In some embodiments, the variable heavy chain comprises an 15 IK mutation. In some embodiments, the variable heavy chain comprises an 15 ID mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 55, 57, or 58. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 55. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 57. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 58.

[0195] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an N52A or N52K mutation. In some embodiments, the variable heavy chain comprises an N52A mutation. In some embodiments, the variable heavy chain comprises an N52K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 59 or 61. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 59. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 61.

[0196] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a P53S or P53K mutation. In some embodiments, the variable heavy chain comprises a P53S mutation. In some embodiments, the variable heavy chain comprises a P53K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 64 or 65. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 64. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 65.

[0197] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an S54A, S54K, or S54D mutation. In some embodiments, the variable heavy chain comprises an S54A mutation. In some embodiments, the variable heavy chain comprises an S54K mutation. In some embodiments, the variable heavy chain comprises an S54D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 67, 68, or 69. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 67. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 68. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 69.

[0198] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an N55D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 73.

[0199] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a G56D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 77.

[0200] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an R57A, R57K, or R57D mutation. In some embodiments, the variable heavy chain comprises an R57A mutation. In some embodiments, the variable heavy chain comprises an R57K mutation. In some embodiments, the variable heavy chain comprises an R57D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 78, 80, or 81. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 78. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 80. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 81.

[0201] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a T58S, T58K, or T58D mutation. In some embodiments, the variable heavy chain comprises a T58S mutation. In some embodiments, the variable heavy chain comprises a T58K mutation. In some embodiments, the variable heavy chain comprises a T58D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 83, 84, or 85. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 83. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 84. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 85.

[0202] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an N59S or N59K mutation. In some embodiments, the variable heavy chain comprises an N59S mutation. In some embodiments, the variable heavy chain comprises an N59K mutation. In some embodiments, the variable heavy chain comprises an amino acidsequence of SEQ ID NO: 87 or 88. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 87. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 88.

[0203] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an A97S or A97D mutation. In some embodiments, the variable heavy chain comprises an A97S mutation. In some embodiments, the variable heavy chain comprises an A97D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 90 or 92. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 90. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 92.

[0204] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an R100A or R100K mutation. In some embodiments, the variable heavy chain comprises an R100A mutation. In some embodiments, the variable heavy chain comprises an R100K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 101 or 103. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 101. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 103.

[0205] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a G105A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 120.

[0206] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an SI 06 A, S106K, or S106D mutation. In some embodiments, the variable heavy chain comprises an S106A mutation. In some embodiments, the variable heavy chain comprises an S106K mutation. In some embodiments, the variable heavy chain comprises an S106D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 124, 125, or 126. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 124. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 125. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 126.

[0207] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an S107A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 127.

[0208] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a Y110S, Y110K, or Y110D mutation. In some embodiments, the variable heavy chain comprises a Y110S mutation. In some embodiments, the variable heavy chain comprises a Y110K mutation. In some embodiments, the variable heavy chain comprises a Y110D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 138, 139, or 140. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 138. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 139. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 140.

[0209] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and an F111A, F111S, F111K, or F111D mutation. In some embodiments, the variable heavy chain comprises an F111A mutation. In some embodiments, the variable heavy chain comprises an Fl 11 S mutation. In some embodiments, the variable heavy chain comprises an F111K mutation. In some embodiments, the variable heavy chain comprises an F111D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 141, 142, 143, or 144. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 141. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 142. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 143. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 144.

[0210] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a DI 12S mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 146.

[0211] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a V113A, V113S, or V113K mutation. In some embodiments, the variableheavy chain comprises a V113A mutation. In some embodiments, the variable heavy chain comprises a V113S mutation. In some embodiments, the variable heavy chain comprises a V113K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 148, 149, or 150. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 148. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 149. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 150.

[0212] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a V12K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 276.

[0213] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a L20V mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 277.

[0214] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a C22A mutation. In some embodiments, the variable heavy chain comprises a C22A or C22K mutation. In some embodiments, the variable heavy chain comprises a C22K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 278 or 279. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 278. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 279.

[0215] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a K38R mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 280.

[0216] In some embodiments, the variable heavy chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 and a S76T mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 288.

[0217] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical toSEQ ID NO: 2 and an R24A, R24S R24K, or R24D mutation. In some embodiments, the variable heavy chain comprises an R24A mutation. In some embodiments, the variable heavy chain comprises an R24S mutation. In some embodiments, the variable heavy chain comprises an R24K mutation. In some embodiments, the variable heavy chain comprises an R24D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 152, 153, 154, or 155. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 152. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 153. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 154. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 155.

[0218] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S25A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 156.

[0219] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S26A, S26K, or S26D mutation. In some embodiments, the variable heavy chain comprises an S26A mutation. In some embodiments, the variable heavy chain comprises an S26K mutation. In some embodiments, the variable heavy chain comprises an S26D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 159, 160, or 161. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 159. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 160. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 161.

[0220] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a Q27S or Q27D mutation. In some embodiments, the variable heavy chain comprises a Q27S mutation. In some embodiments, the variable heavy chain comprises a Q27D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 163 or 165. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 163. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 165.

[0221] In some embodiments, the variable light chain comprises an amino acidsequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S28A, S28K, or S28D mutation. In some embodiments, the variable heavy chain comprises an S28A mutation. In some embodiments, the variable heavy chain comprises an S28K mutation. In some embodiments, the variable heavy chain comprises an S28D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 166, 167, or 168. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 166. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 167. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 168.

[0222] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an I29S, I29K, or I29D mutation. In some embodiments, the variable heavy chain comprises an I29S mutation. In some embodiments, the variable heavy chain comprises an I29K mutation. In some embodiments, the variable heavy chain comprises an I29D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 170, 171, or 172. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 170. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 171. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 172.

[0223] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a V30S, V30K, or V30D mutation. In some embodiments, the variable heavy chain comprises a V30S mutation. In some embodiments, the variable heavy chain comprises a V30K mutation. In some embodiments, the variable heavy chain comprises a V30D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 174, 175, or 176. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 174. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 175. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 176.

[0224] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S32K or S32D mutation. In some embodiments, the variable heavy chain comprises an S32K mutation. In some embodiments, the variable heavy chain comprises anS32D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 182 or 183. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 182. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 183.

[0225] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an N33A, N33S, N33K, or N33D mutation. In some embodiments, the variable heavy chain comprises an N33A mutation. In some embodiments, the variable heavy chain comprises an N33S mutation. In some embodiments, the variable heavy chain comprises an N33K mutation. In some embodiments, the variable heavy chain comprises an N33D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 184, 185, 186, or 187. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 184. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 185. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 186. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 187.

[0226] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a V34A, V34K, or V34D mutation. In some embodiments, the variable heavy chain comprises a V34A mutation. In some embodiments, the variable heavy chain comprises a V34K mutation. In some embodiments, the variable heavy chain comprises a V34D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 188, 190, or 191. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 188. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 190. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 191.

[0227] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a N35S or N35K mutation. In some embodiments, the variable heavy chain comprises a N35S mutation. In some embodiments, the variable heavy chain comprises a N35K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 193 or 194. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 193. In some embodiments, the variable heavy chain comprisesI l lan amino acid sequence of SEQ ID NO: 194.

[0228] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a T36S or T36K mutation. In some embodiments, the variable heavy chain comprises a T36S mutation. In some embodiments, the variable heavy chain comprises a T36K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 197 or 198. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 197. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 198.

[0229] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a Y37K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 202.

[0230] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an L38A, L38K, or L38D mutation. In some embodiments, the variable heavy chain comprises an L38A mutation. In some embodiments, the variable heavy chain comprises an L38K mutation. In some embodiments, the variable heavy chain comprises an L38D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 204, 206, or 207. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 204. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 206. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 207.

[0231] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a Y54A or Y54S mutation. In some embodiments, the variable heavy chain comprises a Y54A mutation. In some embodiments, the variable heavy chain comprises a Y54S mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 212 or 213. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 212. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 213.

[0232] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical toSEQ ID NO: 2 and a K55S mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 217.

[0233] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a V56A, V56K, or V56D mutation. In some embodiments, the variable heavy chain comprises a V56A mutation. In some embodiments, the variable heavy chain comprises a V56K mutation. In some embodiments, the variable heavy chain comprises a V56D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 219, 221, or 222. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 219. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 221. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 222.

[0234] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S57A or S57K mutation. In some embodiments, the variable heavy chain comprises an S57A mutation. In some embodiments, the variable heavy chain comprises an S57K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 223 or 224. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 223. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 224.

[0235] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an N58A, N58S, N58K, or N58D mutation. In some embodiments, the variable heavy chain comprises an N58A mutation. In some embodiments, the variable heavy chain comprises an N58S mutation. In some embodiments, the variable heavy chain comprises an N58K mutation. In some embodiments, the variable heavy chain comprises an N58D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 226, 227, 228, or 229. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 226. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 227. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 228. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 229.

[0236] In some embodiments, the variable light chain comprises an amino acidsequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an R59A, R59S, R59K, or R59D mutation. In some embodiments, the variable heavy chain comprises an R59A mutation. In some embodiments, the variable heavy chain comprises an R59S mutation. In some embodiments, the variable heavy chain comprises an R59K mutation. In some embodiments, the variable heavy chain comprises an R59D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 230, 231, 232, or 233. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 230. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 231. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 232. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 233.

[0237] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an F60A, F60S, or F60K mutation. In some embodiments, the variable heavy chain comprises an F60A mutation. In some embodiments, the variable heavy chain comprises an F60S mutation. In some embodiments, the variable heavy chain comprises an F60K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 234, 235, or 236. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 234. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 235. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 236.

[0238] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S61 A or S61K mutation. In some embodiments, the variable heavy chain comprises an S61A mutation. In some embodiments, the variable heavy chain comprises an S61K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 238 or 239. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 238. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 239.

[0239] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an F94A mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 241.

[0240] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a Q95A, Q95S or Q95D mutation. In some embodiments, the variable heavy chain comprises a Q95 A mutation. In some embodiments, the variable heavy chain comprises a Q95S mutation. In some embodiments, the variable heavy chain comprises a Q95D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 245, 246, or 248. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 245. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 246. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 248.

[0241] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a G96S mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 250.

[0242] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an S97A or S97D mutation. In some embodiments, the variable heavy chain comprises an S97A mutation. In some embodiments, the variable heavy chain comprises an S97D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 253 or 255. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 253. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 255.

[0243] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and an H98A, H98K, or H98D mutation. In some embodiments, the variable heavy chain comprises an H98A mutation. In some embodiments, the variable heavy chain comprises an H98K mutation. In some embodiments, the variable heavy chain comprises an H98D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 256, 258, or 259. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 256. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 258. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 259.

[0244] In some embodiments, the variable light chain comprises an amino acidsequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a V99A, V99S, or V99D mutation. In some embodiments, the variable heavy chain comprises a V99A mutation. In some embodiments, the variable heavy chain comprises a V99S mutation. In some embodiments, the variable heavy chain comprises a V99D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 260, 261, or 263. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 260. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 261. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 263.

[0245] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a P100S, P100K, or P100D mutation. In some embodiments, the variable heavy chain comprises a P100S. In some embodiments, the variable heavy chain comprises a P100K. In some embodiments, the variable heavy chain comprises a P100D. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 265, 266, or 267. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 265. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 266. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 267.

[0246] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a P101K mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 270.

[0247] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a T102A, T102S, T102K, or T102D mutation. In some embodiments, the variable heavy chain comprises a T102A mutation. In some embodiments, the variable heavy chain comprises a T102S mutation. In some embodiments, the variable heavy chain comprises a T102K mutation. In some embodiments, the variable heavy chain comprises a T102D mutation. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 272, 273, 274, or 275. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 272. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 273. In some embodiments, the variable heavy chaincomprises an amino acid sequence of SEQ ID NO: 274. In some embodiments, the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 275.

[0248] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a Y41F mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 296.

[0249] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a L88V mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 302.

[0250] In some embodiments, the variable light chain comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a I90V mutation. In some embodiments, the variable light chain comprises an amino acid sequence of SEQ ID NO: 303.

[0251] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 3.

[0252] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 6 or 7. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 7.

[0253] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 11.

[0254] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 12 or 15. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chainhaving the amino acid sequence of SEQ ID NO: 15.

[0255] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 18.

[0256] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 21 or 23. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 23.

[0257] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 24.

[0258] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 28, 29, 30, or 31. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 28. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 31.

[0259] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 32 or 34. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 34.

[0260] In some embodiments, the antibody comprises a variable light chain having theamino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 41.

[0261] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 43, 44, 45, or 46. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 46.

[0262] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 47, 48, 49, or 50. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 50.

[0263] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 51, 52, or 54. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 54.

[0264] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 55, 57, or 58. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 58.

[0265] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 59 or 61. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 61.

[0266] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 64 or 65. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 65.

[0267] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 67, 68, or 69. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 69.

[0268] In some embodiments, the antibody comprises a variable light chain having theamino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 73.

[0269] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 77.

[0270] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 78, 80, or 81. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 78. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 80. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 81.

[0271] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 83, 84, or 85. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 83. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 84. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 85.

[0272] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 87 or 88. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 87. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 88.

[0273] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 90 or 92. In some embodiments, the antibody comprises a variablelight chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 90. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 92.

[0274] In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 101 or 103. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 101. In some embodiments, the antibody comprises a variable light chain having the amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 103.

[0275] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having the amino acid sequence of SEQ ID NO: 120.

[0276] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 124, 125, or 126. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 124. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 125. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 126.

[0277] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 127.

[0278] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 138, 139, or 140. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 138. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 139. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 140.

[0279] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 141, 142, 143, or 144. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 141. In some embodiments, the variable heavy chain hasan amino acid sequence of SEQ ID NO: 142. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 143. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 144.

[0280] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 146.

[0281] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 148, 149, or 150. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 148. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 149. In some embodiments, the variable heavy chain has an amino acid sequence of SEQ ID NO: 150.

[0282] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 276.

[0283] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 277.

[0284] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 278.

[0285] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 279.

[0286] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 280.

[0287] In some embodiments, the antibody comprises a variable light chain having an amino acid sequence of SEQ ID NO: 2 and a variable heavy chain having an amino acid sequence of SEQ ID NO: 288.

[0288] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 152, 153, 154, or 155. In some embodiments, the variable light chain has anamino acid sequence of SEQ ID NO: 152. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 153. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 154. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 155.

[0289] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 156.

[0290] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 159, 160, or 161. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 159. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 160. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 161.

[0291] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 163 or 165. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 163. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 165.

[0292] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 166, 167, or 168. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 166. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 167. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 168.

[0293] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 170, 171, or 172. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 170. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 171. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 172.

[0294] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 174, 175, or 176. In some embodiments, the variable light chain has an aminoacid sequence of SEQ ID NO: 174. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 175. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 176.

[0295] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 182 or 183. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 182. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 183.

[0296] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 184, 185, 186, or 187. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 184. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 185. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 186. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 187.

[0297] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 188, 190, or 191. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 188. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 190. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 191.

[0298] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 193 or 194. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 193. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 194.

[0299] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 197 or 198. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 197. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 198.

[0300] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequenceof SEQ ID NO: 202.

[0301] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 204, 206, or 207. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 204. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 206. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 207.

[0302] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 212 or 213. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 212. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 213.

[0303] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 217.

[0304] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 219, 221, or 222. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 219. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 221. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 222.

[0305] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 223 or 224. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 223. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 224.

[0306] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 226, 227, 228, or 229. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 226. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 227. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 228. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 229.

[0307] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 230, 231, 232, and 233. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 230. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 231. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 232. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 233.

[0308] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 234, 235, or 236. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 234. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 235. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 236.

[0309] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 238 or 239. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 238. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 239.

[0310] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 241.

[0311] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 245, 246, or 248. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 245. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 246. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 248.

[0312] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 250.

[0313] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 253 or 255. In some embodiments, the variable light chain has an amino acidsequence of SEQ ID NO: 253. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 255.

[0314] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 256, 258, 259. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 256. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 258. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 259.

[0315] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 260, 261, or 263. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 260. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 261. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 263.

[0316] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 265, 266, or 267. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 265. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 266. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 267.

[0317] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 270.

[0318] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 272, 273, 274, or 275. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 272. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 273. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 274. In some embodiments, the variable light chain has an amino acid sequence of SEQ ID NO: 275.

[0319] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 296.

[0320] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 302.

[0321] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 303.

[0322] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 49 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

[0323] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 52 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

[0324] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 87 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

[0325] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 92 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

[0326] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 142 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

[0327] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 156.

[0328] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 219.

[0329] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 221.

[0330] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 235.

[0331] In some embodiments, the antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 267.

[0332] In addition to these specific combinations, any of the variable heavy chains and variable light chains can be combined with one another.

[0333] Additionally, as provided for herein, the antibodies can be multi-specific antibodies, in that the antibodies have multiple binding regions that target different proteins or the same protein at different epitopes. In some embodiments, the antibody is a bi-specific antibody.

[0334] As provided for herein, the different peptides (VH or VL) described herein can be linked with a peptide linker or not linked with a peptide linker and instead for a contiguous sequence. In some embodiments, the peptide linker comprises a sequence of: (GGGGS)n(SEQ ID NO: 304); (GGGGA)n(SEQ ID NO: 305), or any combination thereof, wherein each n is independently 1-5. The linked peptide format can be represented by a formula of VH-Z-VL or VL-Z-VH, wherein Z is the peptide linker. In some embodiments, Z is (GGGGS)n(SEQ ID NO: 304); (GGGGA)n (SEQ ID NO: 305), or any combination thereof, wherein each n is independently 1-5. These antibodies can be referred to as being in a scFv format.Methods of Treatment

[0335] Provided herein are methods of treatment.

[0336] In some embodiments, a method of treating or reducing the severity of, thyroid- associated ophthalmopathy (TAO), or a symptom thereof is provided. In some embodiments, the method of treating or reducing the severity of, thyroid-associated ophthalmopathy (TAO), or a symptom thereof comprises administering to a subject any antibody disclosed herein. In some embodiments, a method of reducing proptosis in an eye in a subject with thyroid-associated ophthalmopathy (TAO) is provided. In some embodiments, the method of reducing proptosis in an eye in a subject with thyroid-associated ophthalmopathy (TAO) comprises administering to a subject any antibody disclosed herein.

[0337] In some embodiments, a method of treating thyroid eye disease (TED) in a subject is provided, comprising administering to a subject any antibody disclosed herein. In some embodiments, the subject has active thyroid eye disease or chronic thyroid eye disease. Active thyroid eye disease refers to a subject diagnosed with thyroid eye disease within one to two years of administration of the therapeutic and a CAS > than 1. Chronic thyroid eye disease generallyrefers to an initial diagnosis of thyroid eye disease 2-10 years prior to administration of therapeutic and with a Clinical Activity Score (CAS) of <1 in both eyes for at least one year prior to screening or all of the following one year prior to screening, and having no progression in proptosis, no progression in diplopia and no new inflammatory TED or TAO symptoms.

[0338] In some embodiments, a method of reducing Clinical Activity Score (CAS) of thyroid-associated ophthalmopathy (TAO) in a subject is provided, comprising administering to a subject any antibody disclosed herein.

[0339] In some embodiments, a method of a) reducing proptosis by at least 2 mm and b) reducing the clinical activity score (CAS) in a subject with thyroid-associated ophthalmopathy (TAO) is provided, comprising administering to a subject any antibody disclosed herein. In some embodiments, proptosis is reduced by at least 2 mm. In some embodiments, proptosis is reduced by at least 3 mm. In some embodiments, proptosis is reduced by at least 4 mm. In some embodiments, the clinical activity score (CAS) of the subject is reduced by at least 2 points. In some embodiments, the clinical activity score (CAS) of the subject is reduced to one (1). In some embodiments, the clinical activity score (CAS) of the subject is reduced to zero (0).

[0340] In some embodiments, a method of treating or reducing the severity of thyroid- associated ophthalmopathy (TAO) in a subject is provided, comprising administering to a subject any antibody disclosed herein, wherein treatment with said antibody (i) reduces proptosis by at least 2 mm in an eye; (ii) is not accompanied by a deterioration of 2 mm or more in the other (or fellow eye); and (iii) reduces the CAS in said subject to either one (1) or zero (0).

[0341] In some embodiments, a method of improving the quality of life in a subj ect with thyroid-associated ophthalmopathy (TAO, also called Graves’ Ophthalmopathy / Graves’ Orbitopathy) is provided, comprising administering to a subject any antibody disclosed herein. In some embodiments, the quality of life is measured by the Graves’ Ophthalmopathy Quality of Life (GO-QoL) assessment, or either the Visual Functioning or Appearance subscale thereof. In some embodiments, the treatment results in an improvement of greater than or equal to 8 points on the GO-QoL. In some embodiments, the treatment results in an improvement on the Functioning subscale of the GO-QoL. In some embodiments, the treatment results in an improvement on the Appearance subscale of the GO-QoL.

[0342] In some embodiments, a method of treating or reducing the severity of diplopia in a subject with thyroid-associated ophthalmopathy (TAO) is provided, comprising administering to a subject any antibody disclosed herein. In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is inconstant diplopia. In someembodiments, the diplopia is intermittent diplopia. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of antibody administration. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of antibody administration.

[0343] In some embodiments, the antibody is administered at a dosage of about 1 mg / kg to about 20 mg / kg antibody as a first dose and then the same dose in subsequent doses. In some embodiments, the dose is administered at a dose of 1, 3, 5, 10, 15, or 20 mg / kg every 3, 4, 5, 6, 7, 8, or 12 weeks. In some embodiments, the antibody is administered every 3 weeks. In some embodiments, the antibody is administered for a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses. In some embodiments, a total of 5 doses are administered. In some embodiments, a total of 8 doses are administered. In some embodiments, the subsequent doses, after the initial dose, are administered every three weeks for at least 12, 15, 18, or 21 weeks. In some embodiments, the antibody, or an antigen binding fragment thereof, is a human antibody, a monoclonal antibody, a human monoclonal antibody, a purified antibody, a diabody, a single-chain antibody, a multi-specific antibody, Fab, Fab', F(ab')2, Fv, or scFv.

[0344] In some embodiments, a method is provided wherein the antibody, or an antigen binding fragment thereof, is administered in a pharmaceutical composition that additionally comprises a pharmaceutically acceptable diluent or excipient or carrier.

[0345] In some embodiments, a method is provided wherein the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO. In some embodiments, a method is provided wherein the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFa antibodies or a thyroid- stimulating hormone receptor (TSHR) inhibitor.

[0346] In some embodiments, a method is provided wherein the antibody or an 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 retro-orbital sinus. In some embodiments, a method is provided wherein the antibody or an antigen binding fragment thereof is administered via an injection. In some embodiments, a method of injection is provided wherein the injection is a intravitreal injection, intraorbital injection, retro-orbital injection, suprachoroidal injection, or intracam eral injection.

[0347] In some embodiments, a method of increasing the internalization of IGF-1R on a cell is provided, the method comprising contacting the cell with an antibody as provided herein.In some embodiments, the method of contacting comprises administering to a subject an antibody as provided herein. In some embodiments, a method is provided wherein the subject has or is at risk of thyroid eye disease (TED).

[0348] In some embodiments, a method of inhibiting IGF-1 stimulated receptor phosphorylation on a cell is provided, the method comprising contacting the cell with an antibody as provided herein. In some embodiments, a method is provided wherein the contacting comprises administering to a subject an antibody as provided herein. In some embodiments, a method is provided wherein the subject has or is at risk of thyroid eye disease (TED). In some embodiments, a method is provided wherein the antibody has an IC50 of less than, or equal to, about 0.2 nm, 0.15 nm, 0.10 nm, or 0.09 nm. In some embodiments, a method is provided wherein the IC50 is measured in an in vitro assay, such as, but not limited to, an assay as provided for herein. In some embodiments, a method is provided wherein the cell is an A549 cell or an HOCF cell.

[0349] In some embodiments, a method of treating thyroid eye disease in a subject is provided, the method comprising administering an antibody as provided for herein, wherein the antibody has a serum concentration in the subject of at least, or about, 70 pg / ml, 75 pg / ml, 80 ug / ml, 85 ug / ml, 90 pg / ml, 95 g / ml, 100 g / ml, or 105 pg / ml at least 1, 2, or 3 weeks after administration. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered subcutaneously.

[0350] In some embodiments, methods of inhibiting IGF-1 induced receptor autophosphorylation in a cell by at least 95%, 96%, 97%, 98%, or 99%, or by 100% are provided, the method comprising contacting the cell with an antibody as provided herein. In some embodiments, a method is provided wherein the inhibition of the IGF-1 induced receptor autophosphorylation is measured as compared to the induced receptor autophosphorylation in the absence of the antibody. In some embodiments, a method is provided wherein the contacting comprises administering to a subject the antibody comprising the same. In some embodiments, a method is provided wherein the subject has or is at risk of thyroid eye disease (TED). In some embodiments, a method of inhibiting IGF-1 induced receptor autophosphorylation by at least 95%, 96%, 97%, 98%, or 99%, or by 100% in a subject in need thereof is provided, the methods comprising administering to the subject an antibody as provided for herein. In some embodiments, the subject has or is at risk of thyroid eye disease (TED).Pharmaceutical Compositions

[0351] Provided herein are pharmaceutical or sterile compositions comprising an antibody as provided for herein. The pharmaceutical or sterile compositions of the anti-IGF-lR antibodies, or antigen binding fragment thereof, can be admixed with a pharmaceutically acceptable carrier or excipients to produce the pharmaceutical composition. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0352] Formulations of therapeutic and diagnostic agents may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (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: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY). In some embodiments, the antibodies are diluted to an appropriate concentration in a sodium acetate solution of pH 5-6, and NaCl or sucrose is added for tonicity. Additional agents, such as polysorbate 20 or polysorbate 80, may be added to enhance stability.

[0353] Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with another agent, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index (LD50 / ED50). In particular aspects, antibodies exhibiting high therapeutic indices are desirable. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration.

[0354] In some embodiments, an antibody, or antigen binding fragment thereof, or a pharmaceutical composition thereof, as provided herein is administered to a subject in accordance with the Physicians’ Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0355] The mode of administration can vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.

[0356] In some embodiments, pharmaceutical compositions comprising the antibody, or antigen binding fragment thereof, can be administered by an invasive route, such as by injection. In some embodiments, the pharmaceutical composition is administered intravenously, subcutaneously, intramuscularly, intraarterially, intra-articularly (e.g., in arthritis joints), or by inhalation, aerosol delivery. Administration by non-invasive routes (e.g., orally, such as in a pill, capsule, or tablet) is also within the scope of the present embodiments. In some embodiments, the pharmaceutical composition can be administered subcutaneously. In some embodiments, the pharmaceutical composition can be administered intravenously.

[0357] In some embodiments, the antibody or antigen binding fragment thereof, or pharmaceutical composition 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 retro-orbital sinus. In some embodiments, administration to the eye, the anterior chamber of the eye, the vitreous chamber of the eye, the suprachoroidal space, or the retro-orbital sinus is via an injection. In some embodiments, the injection is an intravitreal injection, intraorbital injection, retro-orbital injection, suprachoroidal injection, or intracam eral 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 retro-orbital injection. In some embodiments, the injection is a suprachoroidal injection. In some embodiments, the injection is an intracameral injection.

[0358] In some embodiments, the anti-IGF-lR 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 used to treat thyroid eye disease. For example, in some embodiments, the anti-IGF-lR 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 used to treat thyroid eye disease or a condition related to the same. Examples of such treatments and therapeutics include, but are not limited to anti-thyroid 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, insulinglulisine, insulin lispro, insulin isophane, insulin degludec, insulin detemir, insulin glargine, acerbose, miglitol, acebutolol, atenolol, betaxolol, bisoprolol, cartelol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol, sotalol, timolol, tomolol ophthalmic solution, sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0359] Compositions can be administered with medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.

[0360] The pharmaceutical compositions may also be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Patent 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.

[0361] The pharmaceutical compositions may also be administered by infusion. Examples of well-known implants and modules form administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0362] Alternately, one may administer the antibody in a local rather than systemic manner, for example, via injection of the antibody directly into an arthritic joint or pathogen- induced lesion characterized by immunopathology, often in a depot or sustained release formulation. Furthermore, one may administer the antibody in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody, targeting, for example, arthritic joint or pathogen-induced lesion characterized by immunopathology. The liposomes will be targeted to and taken up selectively by the afflicted tissue.

[0363] The administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix. Preferably, the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects.Accordingly, the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance in selecting appropriate doses of therapeutic antibodies is available (see, 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. (NED) New Engl. J. Med. 348:24-32; Lipsky et al. (2000) Yew Engl. J. Med. 343: 1594-1602).

[0364] Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced. In general, it is desirable that a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized and fully human antibodies may be desirable.

[0365] The antibodies, or antigen binding fragments thereof, provided for herein can be administered by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, monthly, bimonthly, quarterly, semiannually, annually etc. Doses may be provided, e.g., intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation. In some embodiments, the antibody is administered every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. In some embodiments, the antibody is administered every four weeks. In some embodiments, the antibody is administered every five weeks. In some embodiments, the antibody is administered every seven weeks. In some embodiments, the antibody is administered every six weeks. In some embodiments, the antibody is administered every eight weeks. In some embodiments, the antibody is administered for at least 21-52 weeks or longer. 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 32weeks. 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 (e.g., infusion or subcutaneous injection) once. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) twice. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) three times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) four times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) five times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) six times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) seven times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) eight times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) nine times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 10 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 11 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 12 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 13 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 14 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 15 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 16 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 17 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 18 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 19 times. In some embodiments, the antibody is administered (e.g., infusion or subcutaneous injection) 20 times. When the antibody is administered more than once it can be administered according to a schedule, such as the schedules provided for herein.

[0366] A total weekly dose can be as provided for herein. In some embodiments, the total weekly dose is at least 0.05 pg / kg body weight, more generally at least 0.2 pg / kg, 0.5 pg / kg, 1 pg / kg, 10 pg / kg, 100 pg / 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 Immunol. Immunother. 52: 133-144). Doses may also be provided to achieve a pre-determined target concentration of the antibody in the subject’s serum, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300 pg / ml or more.

[0367] In some embodiments, the antibody has a serum concentration in the subject of at least, or about, 10 pg / ml or 20 pg / ml or 50 pg / ml, 70 pg / ml, 75 pg / ml, 80 pg / ml, 85 pg / ml, 90 pg / ml, 95 pg / ml, 100 pg / ml, or 105 pg / ml at least 1, 2, or 3 weeks after administration.

[0368] In some embodiments, a dose of 3, 5, 10, or 20 mg / kg IV is administered. In some embodiments, a dosing is used to provide a Cmin of 133 pg / mL after about 5 weeks. In some embodiments, the dose of the antibody that is administered that provides a Cmin of 102 pg / mL after 6 weeks. In some embodiments, the dose of the antibody is as provided for herein, such as 3, 5, 10, or 20 mg / kg as a loading dose with subsequent doses being the same or lower. In some embodiments, the antibody is administered as provided for herein at a dose to achieve a Cmin of at least, or about, 100 pg / mL.

[0369] As used herein, “inhibit” or “treat” or “treatment” includes a postponement of development of the symptoms associated with a disorder and / or a reduction in the severity of the symptoms of such disorder. The terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms. Thus, the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom.

[0370] As used herein, the terms “therapeutically effective amount”, “therapeutically effective dose” and “effective amount” refer to an amount of the antibody, or antigen binding fragment thereof, that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition. A therapeutically effective dose further refers to that amount of the binding compound sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. 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 combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. An effective amount of a therapeutic will result in an improvement of adiagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%. An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity. In some embodiments, an amount is a therapeutically effective amount if it is an amount that can be used to treat or ameliorate a condition as provided for herein.

[0371] The term “subject” as used throughout includes any organism, such as an animal, including a mammal (e.g., rat, mouse, dog, cat, rabbit) and, for example, a human. A subject can also be referred to as a patient. In some embodiments, the subject is a subject in need thereof. A subject that is “in need thereof’ refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition. The conditions can be, for example, any of the conditions described herein.

[0372] Whereas, an isolated antibody binds an epitope on a IGF-1R protein, or other protein described herein, and displays in vitro and / or in vivo IGF-1R inhibiting or therapeutic activities, the antibodies or antigen binding fragments thereof, capable of inhibiting IGF-1R function, are suitable both as therapeutic agents for treating IGF-1R -associated conditions in humans and animals. These conditions include thyroid eye disease. According, methods of treating such conditions are also provided, wherein the method comprises administering an antibody, or antigen binding fragment thereof, to the subject with such a condition.

[0373] In some embodiments, the methods comprise administering a therapeutically or prophylactically effective amount of one or more monoclonal antibodies or antigen binding fragments of the antibodies described herein to a susceptible subject or to one exhibiting a condition in which IGF-1R is known or suspected to have caused the pathology observed. Any active form of the antibody can be administered, including, but not limited to scFV, Fab and F(ab')2 fragments and other forms of antibodies provided for herein.

[0374] As used herein, a IGF-1R associated pathology refers to conditions that are caused by the modulation of IGF-1R. These conditions include, but are not limited to, thyroid eye disease and other conditions provided for herein.

[0375] In some embodiments, the antibodies used are compatible with the recipient species such that the immune response to the mAbs does not result in an unacceptably short circulating half-life or induce an immune response to the mAbs in the subject.

[0376] Treatment of individuals may comprise the administration of a therapeutically effective amount of the antibodies described herein. The antibodies can be provided in a kit, suchas those provided herein. The antibodies can be used or administered alone or in admixture with another therapeutic, analgesic, or diagnostic agent, such as provided for herein. In providing a patient with an antibody, or fragment thereof, capable of binding to IGF-1R, or an antibody capable of protecting against IGF-1R, pathology in a recipient patient, the dosage of administered agent will vary depending upon such factors as the patient’s age, weight, height, sex, general medical condition, previous medical history, etc.

[0377] An antibody, capable treating a condition associated with IGF-1R activity or use to treat a IGF-1R related pathology, is intended to be provided to subjects in an amount sufficient to affect a reduction, resolution, or amelioration in the IGF-1R related symptom or pathology. Such a pathology includes thyroid eye disease and the like

[0378] Accordingly, in some embodiments, methods of treating a subject with a IGF- 1R mediated disorder are provided. In some embodiments, the method comprises administering a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, as provided herein. In some embodiments, the disorder is thyroid eye disease. As provided for herein, the antibodies, or antigen binding fragments thereof, can be administered with other therapeutics. These can be administered simultaneously or sequentially.

[0379] In some embodiments, the antibodies, or antigen binding fragments thereof, may be used to treat thyroid eye disease. In some embodiments, the antibodies, or antigen binding fragments thereof, may be used to treat or reduce the severity of, thyroid-associated ophthalmopathy (TAO), or a symptom thereof.

[0380] In some embodiments, methods or uses are provided to reduce proptosis in an eye in a subject with thyroid-associated ophthalmopathy (TAO).

[0381] In some embodiments, the subject is a subject how has previously been treated with a different antibody than those provided herein.

[0382] In some embodiments, methods or uses are provided to Clinical Activity Score (CAS) in subject who has or is suspected of having thyroid-associated ophthalmopathy (TAO).

[0383] In some embodiments, methods or uses are provided to reduce proptosis by at least 2 mm and b) reducing the clinical activity score (CAS) in a subject with thyroid-associated ophthalmopathy (TAO).

[0384] As used herein, the term Clinical Activity Score (CAS) refers to the protocol described and scored according to Table 3. According to this protocol, one point is given for the presence of each of the parameters assessed in Table 3, below. The sum of all points defines clinical activity and provides the CAS, where 0 or 1 constitutes inactive disease and 7 severeactive ophthalmopathy.

[0385] Table 3. Parameters for Calculating Clinical Activity Score

[0386] As provided in Table 3, the CAS consists of seven components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, side-to-side, and downward gazes), conjunctival redness, redness of the eyelids, chemosis, swelling of the caruncle / plica, and swelling of the eyelids. Each component is scored as present (1 point) or absent (0 points). The score at each efficacy assessment is the sum of all items present; giving a range of 0-7, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy. A change of > 2 points is considered clinically meaningful.

[0387] Item 1, spontaneous orbital pain could be a painful, or oppressive feeling on, or behind, the globe. This pain may be caused by the rise in intraorbital pressure, when the orbital tissues volume increases through excess synthesis of extracellular matrix, fluid accumulation, and cellular infiltration and expansion. Item 2, gaze evoked orbital pain, could be pain in the eyes when looking, or attempting to look, up, down or sideways, z.e., pain with upward, downward, or lateral eye movement, or when attempting eye movement. This kind of pain could arise from the stretching of the inflamed muscle(s), especially on attempted upgaze. The “stretching pain” cannot be provoked by digital pressing on the eyeball, as would be expected if it were a manifestation of the raised intraorbital pressure. Both kinds of pain can be reduced after anti-inflammatory treatment. These kinds of pain are therefore considered to be directly related to autoimmune inflammation in the orbit and thus useful in assessing TAO activity.

[0388] Swelling in TAO is seen as chemosis (edema of the conjunctiva), item 6 in Table3, and swelling of the caruncle and / or plica semilunaris. Both are signs of TAO activity. Swollen eyelids can be caused by edema, fat prolapse through the orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicative of active TAO include redness and / or pain of the conjunctiva, eyelid, caruncle, and / or plica semilunaris.

[0389] In some embodiments, the subject who is treated has the proptosis is reduced by at least 2 mm. In some embodiments, the subject who is treated has the proptosis is reduced by at least 3 mm. In some embodiments, the subject who is treated has the proptosis is reduced by at least 4 mm.

[0390] In some embodiments, in the subjects who are treated the clinical activity score (CAS) of the subject is reduced by at least 2 points. In some embodiments, the clinical activity score (CAS) of the subject is reduced to one (1). In some embodiments, the clinical activity score (CAS) of the subject is reduced to zero (0).

[0391] In some embodiments, methods off treating or reducing the severity of thyroid- associated ophthalmopathy (TAO) in a subject are provided, wherein the treatment with said antibody (i) reduces proptosis by at least 2 mm in an eye; (ii) is not accompanied by a deterioration of 2 mm or more in the other (or fellow eye); and (iii) reduces the CAS in said subject to either one (1) or zero (0).

[0392] In some embodiments, methods of improving the quality of life in a subject with thyroid-associated ophthalmopathy (TAO, also called Graves’ Ophthalmopathy / Graves’ Orbitopathy) are provided. In some embodiments, the quality of life is measured by the Graves’ Ophthalmopathy Quality of Life (GO-QoL) assessment, or either the Visual Functioning or Appearance subscale thereof. In some embodiments, the treatment results in an improvement of greater than or equal to 8 points on the GO-QoL. In some embodiments, the treatment results in an improvement on the Functioning subscale of the GO-QoL. In some embodiments, the treatment results in an improvement on the Appearance subscale of the GO-QoL.

[0393] In some embodiments, methods of treating or reducing the severity of diplopia in a subject with thyroid-associated ophthalmopathy (TAO) are provided. In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is inconstant diplopia. In some embodiments, the diplopia is intermittent diplopia. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of antibody administration. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of antibody administration.

[0394] The severity of the disease can be measured in the following non-limiting embodiments. For example, for lid aperture, the distance between the lid margins is measured (in mm) with the patient looking in the primary position, sitting relaxed, and with distant fixation. For swelling of the eyelids, the measure / evaluation is either “absent / equivocal,” “moderate,” or“severe.” Redness of the eyelids is either absent or present. Redness of the conjunctivae is either absent or present. In some embodiments, conjunctival edema is either absent or present. In some embodiments, inflammation of the caruncle or plica is either absent or present. Exophthalmos is measured in millimeter using the same Hertel exophthalmometer and same intercanthal distance for an individual patient. Subjective diplopia is scored from 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., diplopia in primary position of gaze, when tired or when first awakening; 2 = inconstant, i.e., diplopia at extremes of gaze; 3 = constant, i.e., continuous diplopia in primary or reading position). For eye muscle involvement, the ductions are measured in degrees. Corneal involvement is either absent / punctate or keratopathy / ulcer. For optic nerve involvement, i.e., best-corrected visual acuity, color vision, optic disc, relative afferent pupillary defect, the condition is either absent or present. In addition, visual fields are checked if optic nerve compression is suspected. In some embodiments, the patient can be classified according to the following severity classification. For example, Sight-Threatening Thyroid Eye Disease: Patients with dysthyroid optic neuropathy (DON) and / or corneal breakdown. This category warrants immediate intervention. Moderate-to- Severe Thyroid Eye Disease: Patients without sightthreatening disease whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate-to- severe thyroid eye disease usually have any one or more of the following: lid retraction greater than or equal to 2 mm, moderate or severe soft tissue involvement, exophthalmos greater than or equal to 3 mm above normal for race and gender, inconstant or constant diplopia. Mild Thyroid Eye Disease: Patients whose features of thyroid eye disease have only a minor impact on daily life insufficient to justify immunosuppressive or surgical treatment. They usually have only one or more of the following: minor lid retraction (< 2 mm), mild soft tissue involvement, exophthalmos < 3 mm above normal for race and gender, transient or no diplopia, and corneal exposure responsive to lubricants.

[0395] In some embodiments, a patient can be characterized by Graves’ Ophthalmopathy Quality of Life (GO-QoL) score. In addition to proptosis (or exophthalmos) and CAS, quality of life is also evaluated with the use of the GO quality of life (GO-QoL) questionnaire. This questionnaire is designed to determine the improved quality of life after treatment with a method disclosed herein. In some embodiments, questionnaire may determine the decreased or lack of side effects after being treated with an antibody, or an antigen binding fragment thereof, according to a method disclosed herein as compared to treatment with glucocorticoids. The GO-QoL is a 16-item self-administered questionnaire divided into 2 subsetsand used to assess the perceived effects of TED by the subjects on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. Quality of life is evaluated with the use of the GO QoL questionnaire. The GO-QoL questionnaire (C. B. Terwee et al, 1998) is completed on Day 1 and 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 selfadministered questionnaire divided into two self-assessment subscales; one covering impact of visual function on daily activities, the other assesses the impact of self-perceived appearance. The visual function subscale covers activities such as driving, walking outdoors, reading, watching television. The appearance subscale asks the subject questions such as whether ophthalmopathy has altered the subject’s appearance, caused other people to have a negative reaction to the subject, caused social isolation, and caused the subject to try to mask his or her appearance. Each subscale has 8 questions which are answered with: yes— very much so; yes— a little; or no— not at all. Each question is scored 0-2, respectively, and the total raw score is then mathematically transformed to a 0-100 scale, where 0 represents the most negative impact on quality of life, and 100 represents no impact. A change of > or greater than equal to 8 points on the 0-100 scale has been shown to be clinically meaningful. The combined score takes raw scores from both subscales and again transforms them to a single 0-100 scale. The questionnaire has two self-assessment subscales. Each subscale has 8 questions which are answered with: (i) yes- -very much so; (ii) yes— a little; or (iii) no— not at all. Each question is scored 0-2, respectively, and the total raw score is then mathematically transformed to a 0-100 scale, where 0 represents the most negative impact on quality of life, and 100 represents no impact. A change of > 8 points on the 0-100 scale is considered to be clinically meaningful. The combined score takes raw scores from both subscales and again transforms them to a single 0-100 scale.

[0396] Patients can also be assessed by the presence of absence of Gorman Grading of Diplopia. The Gorman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or awakening (intermittent), diplopia at extremes of gaze (inconstant), and continuous diplopia in the primary or reading position (constant). Patients are scored according to which grade of diplopia they are experiencing. An improvement of greater than equal or to 1 grade is considered clinically meaningful.

[0397] In some embodiments, the methods comprise 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 as a first dose. In some embodiments, the antibody is administered at a dosage of about 5 mg / kg to about 10 mg / kg as a first dose. In some embodiments, the antibodyis administered at a dosage of about 10 mg / kg to about 20 mg / kg as a first dose. In some embodiments, the antibody is administered at a dosage of about 1 mg / kg to about 20 mg / kg in subsequent doses. In some embodiments, the antibody is administered in the following amounts: about 10 mg / kg antibody as a first dose; and about 10 mg / kg antibody in subsequent doses. In some embodiments, the antibody is administered in the following amounts: about 3 mg / kg antibody as a first dose; and about 3 mg / kg antibody in subsequent doses. In some embodiments, the antibody is administered in the following amounts: about 5 mg / kg antibody as a first dose; and about 5 mg / kg antibody in subsequent doses. In some embodiments, the antibody is administered in the following amounts: about 20 mg / kg antibody as a first dose; and about 20 mg / kg antibody in subsequent doses. In some embodiments, the antibody is administered in the following amounts: about 20 mg / kg antibody as a first dose; and about 10 mg / kg antibody in subsequent doses. In some embodiments, the subsequent doses are administered every three weeks for at least 12, 15, 18, or 21 weeks.

[0398] 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 pharmaceutically active compounds for the treatment of TAO. In some embodiments, the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFa antibodies or a thyroid-stimulating hormone receptor (TSHR) inhibitor.

[0399] In some embodiments, the methods provided herein comprise administering to a subject an antibody, or an antigen binding fragment thereof, that specifically binds to and inhibits IGF-1R. In some embodiments, the antibody is as provided herein.

[0400] Kits are also provided which are useful for carrying out embodiments described herein. The present kits comprise a first container containing or packaged in association with the above-described antibodies. The kit may also comprise another container containing or packaged in association solutions necessary or convenient for carrying out the embodiments. The containers can be made of glass, plastic or foil and can be a vial, bottle, pouch, tube, bag, etc. The kit may also contain written information, such as procedures for carrying out the embodiments or analytical information, such as the amount of reagent contained in the first container means. The container may be in another container apparatus, e.g., a box or a bag, along with the written information.

[0401] Yet another aspect provided for herein is a kit for detecting IGF-1R protein in abiological sample. The kit includes a container holding one or more antibodies which binds an epitope of IGF-1R protein and instructions for using the antibody for the purpose of binding to 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 presence or absence of IGF-1R protein in the sample. Examples of containers include multi -well plates which allow simultaneous detection of IGF-1R protein in multiple samples.

[0402] In some embodiments, antibodies that bind to a IGF-1R protein are provided. In some embodiments, the antibody is isolated. In some embodiments, the antibody binds specifically. In some embodiments, the antibody binds to a IGF-1R protein that is properly folded. In some embodiments, the antibody is specific for a specific IGF-1R conformational state (open or closed). In some embodiments, the antibody binds to a IGF-1R protein in a cell membrane. In some embodiments, the antibody binds to a IGF-1R protein that is in a cell membrane in an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of a 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 at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The percent inhibition can be based upon the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits the glucose transport facilitated by IGF-1R. In some embodiments, the antibody inhibits the internalization of the IGF-1R protein.

[0403] In some embodiments, the antibody comprises a sequence as provided for herein or antigen binding fragment thereof. In some embodiments, the antibody comprises a heavy chain CDR or an antigen binding fragment thereof described herein. The heavy chain may be one or more of the heavy chains described herein. In some embodiments, the antibody comprises a light chain, or an antigen binding fragment thereof as described herein

[0404] In some embodiments, methods of treating, inhibiting or ameliorating a IGF-1R associated pathology are provided. In some embodiments, the methods comprise administering an antibody described herein or a pharmaceutical composition described herein to a subject to treat, inhibit or ameliorate a IGF-1R associated pathology. In some embodiments, the pathology is as described herein.

[0405] In some embodiments, methods of detecting the presence or absence of a IGF- 1R in a sample are provided, the method comprising contacting a sample with one or moreantibodies described herein detecting the binding to a IGF-1R antigen by the antibody. In some embodiments, the detection of the binding indicates the presence IGF-1R antigen; or the absence of the detection of the binding to the IGF-1R antigen indicates the absence of the IGF-1R antigen. The detecting can be done with any known method, such as using a biosensor, ELISA, sandwich assay, and the like. However, in some embodiments, the method comprises detecting the presence of the protein in non-denaturing conditions. The non-denaturing conditions can be used so that the protein of interest is detected in its native, or properly folded form.

[0406] In some embodiments, methods of identifying a test antibody that binds to an epitope on IGF-1R protein, are provided, the method comprising contacting a test antibody with the epitope on IGF-1R protein and determining whether the test antibody binds to the epitope. In some embodiments, the determining comprises determining whether the test antibody binds to the protein and is competitively inhibited by an antibody comprising a sequence as provided herein. In some embodiments, the determining comprises mutating one or more residues of epitope or protein and determining binding of the test antibody to the mutated epitope, wherein if the mutation reduces binding of the test antibody as compared to the non-mutated epitope, the test antibody is deemed to bind to that epitope.

[0407] In some embodiments, methods of monitoring internalization of IGF-1R from the surface of a cell are provided. In some embodiments, the method comprising contacting the cell with an anti- IGF-1R antibody as provided herein and detecting the presence of IGF-1R in the cell or on the surface of the cell. The differences in cell surface expression can be measured and the internalization can be monitored and measured. This can be used, for example, to measure the effect of another molecule, such as a test agent, to modulate internalization of IGF - 1R protein. Thus, the antibodies provided for herein can be used to identify test agents that modulate (increase or decrease) the internalization of IGF-1R protein. Test molecules that increase the internalization, which would be measured as a decrease in binding of an anti- IGF- 1R antibody to IGF-1R protein on the cell surface, can be identified according to the methods provided herein. Test molecules that decrease the internalization, which would be measured as an increase in binding of an anti- IGF-1R antibody to IGF-1R protein on the cell surface, can be identified according to the methods provided herein. The surface expression can be measured by fluorescence, which can be done through a secondary antibody that recognized the IGF-1R antibodies or by labelling the anti- IGF-1R antibodies provided for herein.

[0408] In some embodiments, methods of inhibiting IGF-1 stimulated receptor phosphorylation on a cell are provided. In some embodiments, the methods comprise contactingthe cell with an antibody as provided for herein, or a pharmaceutical composition comprising the same. In some embodiments, the contacting comprises administering to a subject the antibody or a pharmaceutical composition comprising the same. In some embodiments, the cell is a cell in the eye. In some embodiments, the subject has or is at risk of thyroid eye disease (TED). In some embodiments, the antibody has an IC50 of less than, or equal to, about 0.2 nm, 0.15 nm, 0.10 nm, 0.09 nm. In some embodiments, the IC50 is measured in an in vitro assay, such as an assay as provided for herein, such as illustrated in the Examples. In some embodiments, the IC50 is measured in an cell that is an A549 cell or a HOCF cell.

[0409] In some embodiments, methods of treating thyroid eye disease in a subject are provided, the method comprising administering an antibody as provided for herein, or a pharmaceutical composition comprising the same to the subject, wherein the antibody has a serum concentration in the subject of at least, or about, 70 pg / ml, 75 pg / ml, 80 pg / ml, 85 pg / ml, 90 pg / ml, 95 pg / ml, 100 pg / ml, or 105 pg / ml at least 1, 2, or 3 weeks after administration. In some embodiments, the serum concentration is measured after one, two or three doses of the antibody, or the pharmaceutical composition comprising the same, are administered to the subject.

[0410] In some embodiments, methods of inhibiting IGF-1 induced receptor autophosphorylation by at least 95%, 96%, 97%, 98%, or 99% or by 100% in a subject in need thereof are provided. In some embodiments,, the methods comprise administering to the subject an antibody as provided for herein, or a pharmaceutical composition comprising the same. In some embodiments, the IGF-1 induced receptor autophosphorylation is inhibited in the eye or orbital region of the subject. In some embodiments, the IGF-1 induced receptor autophosphorylation is inhibited thereby treating a subject for thyroid eye disease or improving a symptom as described herein.Enumerated Embodiments

[0411] In some embodiments, embodiments provided herein also include, but are not limited to:

[0412] 1. An antibody comprising a variable heavy chain that is at least 90% identical to SEQ ID NO: 1 and a variable light chain that is at least 90% identical to SEQ ID NO: 2, wherein: the variable heavy chain comprises: a tyrosine that corresponds to position 32 of SEQ ID NO: 1; an arginine that corresponds to position 98 of SEQ ID NO: 1; a glycine that corresponds to position 99 of SEQID NO: 1; a proline that corresponds to position 101 of SEQ ID NO: 1; an aspartate that corresponds to position 102 of SEQ ID NO: 1; a tyrosine that corresponds to position 103 of SEQ ID NO: 1; a tyrosine that corresponds to position 104 of SEQ ID NO: 1; a lysine that corresponds to position 108 of SEQ ID NO: 1; a tryptophane that corresponds to position 109 of SEQ ID NO: 1; or any combination thereof; an arginine that corresponds to position 40 of SEQ ID NO: 1; an isoleucine that corresponds to position 48 of SEQ ID NO: 1; a lysine that corresponds to position 67 of SEQ ID NO: 1; an alanine that corresponds to position 68 of SEQ ID NO: 1; a leucine that corresponds to position 70 of SEQ ID NO: 1; a valine that corresponds to position 72 of SEQ ID NO: 1; a lysine that corresponds to position 74 of SEQ ID NO: 1; an alanine that corresponds to position 79 of SEQ ID NO: 1; a glutamine that corresponds to position 82 of SEQ ID NO: 1; a threonine that corresponds to position 87 of SEQ ID NO: 1; a serine that corresponds to position 91 of SEQ ID NO: 1; and / or a mutation that corresponds to position 30 of SEQ ID NO: 1, such as T30A, T30S, T30K, or T30D; a mutation that corresponds to position 34 of SEQ ID NO: 1, such as M34A, M34S, M34K, or M34D; a mutation that corresponds to position 35 of SEQ ID NO: 1, such as H35A, H35S, H35K, or H35D; a mutation that corresponds to position 54 of SEQ ID NO: 1, such as S54A, S54K, or S54D; a mutation that corresponds to position 106 of SEQ ID NO: 1, such as SI 06 A, S106K, or S106D; a mutation that corresponds to position 111 of SEQ ID NO: 1, such as Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID; or any combination thereof; and / or a mutation that corresponds to position 23 of SEQ ID NO: 1, such as K23A, provided that the mutation is not K23S or K23D; a mutation that corresponds to position 24 of SEQ ID NO: 1, such as A24S or A24K, provided that the mutation is not A24D; a mutation that corresponds to position 25 of SEQ ID NO: 1, such as S25D, provided that th...

Claims

WHAT IS CLAIMED IS:

1. An antibody comprising a variable heavy chain that is at least 90% identical to SEQ ID NO: 1 and a variable light chain that is at least 90% identical to SEQ ID NO: 2, wherein: the variable heavy chain comprises: a tyrosine that corresponds to position 32 of SEQ ID NO: 1; an arginine that corresponds to position 98 of SEQ ID NO: 1; a glycine that corresponds to position 99 of SEQ ID NO: 1; a proline that corresponds to position 101 of SEQ ID NO: 1; an aspartate that corresponds to position 102 of SEQ ID NO: 1; a tyrosine that corresponds to position 103 of SEQ ID NO: 1; a tyrosine that corresponds to position 104 of SEQ ID NO: 1; a lysine that corresponds to position 108 of SEQ ID NO: 1; a tryptophane that corresponds to position 109 of SEQ ID NO: 1; or any combination thereof; an arginine that corresponds to position 40 of SEQ ID NO: 1; an isoleucine that corresponds to position 48 of SEQ ID NO: 1; a lysine that corresponds to position 67 of SEQ ID NO: 1; an alanine that corresponds to position 68 of SEQ ID NO: 1; a leucine that corresponds to position 70 of SEQ ID NO: 1; a valine that corresponds to position 72 of SEQ ID NO: 1; a lysine that corresponds to position 74 of SEQ ID NO: 1; an alanine that corresponds to position 79 of SEQ ID NO: 1; a glutamine that corresponds to position 82 of SEQ ID NO: 1; a threonine that corresponds to position 87 of SEQ ID NO: 1; a serine that corresponds to position 91 of SEQ ID NO: 1; and / or a mutation that corresponds to position 30 of SEQ ID NO: 1, such as T30A, T30S, T30K, or T30D; a mutation that corresponds to position 34 of SEQ ID NO: 1, such as M34A, M34S, M34K, or M34D; a mutation that corresponds to position 35 of SEQ ID NO: 1, such as H35A, H35S, H35K, or H35D; a mutation that corresponds to position 54 of SEQ ID NO: 1, such as S54A, S54K, or S54D; a mutation that corresponds to position 106 of SEQ ID NO: 1, such as SI 06 A, S106K, or S106D; a mutation that corresponds to position 111 of SEQ ID NO: 1, such as F111A, Fl 1 IS, F111K, or F111D; or any combination thereof; a mutation that corresponds to position 12 of SEQ ID NO: 1, such as V12K; a mutation that corresponds to position 20 of SEQ ID NO: 1, such as L20V; a mutation that corresponds to position 22 of SEQ ID NO: 1, such as C22A or C22K; a mutation that corresponds to position 38 of SEQ ID NO: 1, such as K38R; a mutation that corresponds to position 76 of SEQ ID NO: 1, such as S76T; and / or a mutation that corresponds to position 23 of SEQ ID NO: 1, such as K23A, provided that the mutation is not K23S or K23D; a mutation that corresponds to positionmutation that corresponds to position 25 of SEQ ID NO: 1, such as S25D, provided that the mutation is not S25A or S25K; a mutation that corresponds to position 26 of SEQ ID NO: 1, such as G26A or G26D, provided that the mutation is not G26S or G26K; a mutation that corresponds to position 27 of SEQ ID NO: 1, such as Y27K, provided that the mutation is not Y27A, Y27S, or Y27D; a mutation that corresponds to position 28 of SEQ ID NO: 1, such as T28S or T28D, provided that the mutation is not T28A or T28K; a mutation that corresponds to position 29 of SEQ ID NO: 1, such as F29A, provided that the mutation is not F29S, F29K, or F29D; a mutation that corresponds to position 31 of SEQ ID NO: 1, such as S31 A or S3 ID, provided that the mutation is not S3 IK; a mutation that corresponds to position 33 of SEQ ID NO: 1, such as W33K, provided that the mutation is not W33A, W33S, or W33D; a mutation that corresponds to position 50 of SEQ ID NO: 1, such as E50A, E50S, or E50D, provided that the mutation is not E50K; a mutation that corresponds to position 51 of SEQ ID NO: 1, such as 151 A, 15 IK, or 15 ID, provided that the mutation is not 15 IS; a mutation that corresponds to position 52 of SEQ ID NO: 1, such as N52A or N52K, provided that the mutation is not N52S or N52D; a mutation that corresponds to position 53 of SEQ ID NO: 1, such as P53S or P53K, provided that the mutation is not P53 A or P53D; a mutation that corresponds to position 55 of SEQ ID NO: 1, such as N55D, provided that the mutation is not N55A, N55S, or N55K; a mutation that corresponds to position 56 of SEQ ID NO: 1, such as G56D, provided that the mutation is not G56A, G56S, or G56K; a mutation that corresponds to position 57 of SEQ ID NO: 1, such as R57A, R57K, or R57D, provided that the mutation is not R57S; a mutation that corresponds to position 58 of SEQ ID NO: 1, such as T58S, T58K, or T58D, provided that the mutation is not T58A; a mutation that corresponds to position 59 of SEQ ID NO: 1, such as N59S or N59K, provided that the mutation is not N59A or N59D; a mutation that corresponds to position 97 of SEQ ID NO: 1, such as A97S or A97D, provided that the mutation is not A97K; a mutation that corresponds to position 100 of SEQ ID NO: 1, such as R100A or R100K, provided that the mutation is not R100S or R100D; a mutation that corresponds to position 105 of SEQ ID NO: 1, such as G105A, provided that the mutation is not G105S, G105K, or G105D; a mutation that corresponds to position 107 of SEQ ID NO: 1, such as SI 07 A, provided that the mutation is not S107K or S107D; a mutation that corresponds to position 110 of SEQ ID NO: 1, such as Y110S, Y110K, or Y110D, provided that the mutation is notY110A; a mutation that corresponds to position 112 of SEQ ID NO: 1, such as DI 12S, provided that the mutation is not D112A or D112K; a mutation that corresponds to position 113 of SEQ ID NO: 1, such as V113A, V113S, or V113K, provided that the mutation is not VI 13D; or any combination thereof; and / or the variable light chain comprises: a glutamate that corresponds to position 39 of SEQ ID NO: 2; a threonine that corresponds to position 7 of SEQ ID NO: 2; a serine that corresponds to position 14 of SEQ ID NO: 2; an aspartate that corresponds to position 17 of SEQ ID NO: 2; a leucine that corresponds to position 42 of SEQ ID NO: 2; a lysine that corresponds to position 44 of SEQ ID NO: 2; a leucine that corresponds to position 51 of SEQ ID NO: 2; an alanine that corresponds to position 72 of SEQ ID NO: 2; an arginine that corresponds to position 79 of SEQ ID NO: 2; or any combination thereof; and / or a mutation that corresponds to position 24 of SEQ ID NO: 2, such as R24A, R24S R24K, or R24D; a mutation that corresponds to position 26 of SEQ ID NO: 2, such as S26A, S26K, or S26D; a mutation that corresponds to position 28 of SEQ ID NO: 2, such as S28A, S28K, or S28D; a mutation that corresponds to position 33 of SEQ ID NO: 2, such as N33A, N33S, N33K, or N33D; a mutation that corresponds to position 58 of SEQ ID NO: 2, such as N58A, N58S, N58K, or N58D; a mutation that corresponds to position 59 of SEQ ID NO: 2, such as R59A, R59S, R59K, or R59D; a mutation that corresponds to position 102 of SEQ ID NO: 2, such as T102A, T102S, T102K, or T102D; or any combination thereof; a mutation that corresponds to position 41 of SEQ ID NO: 2, such as Y41F; a mutation that corresponds to position 88 of SEQ ID NO: 2, such as L88V; a mutation that corresponds to position 90 of SEQ ID NO: 2, such as I90V; and / or a mutation that corresponds to position 25 of SEQ ID NO: 2, such as S25A, provided that the mutation is not S25K or S25D; a mutation that corresponds to position 27 of SEQ ID NO: 2, such as Q27S or Q27D, provided that the mutation is not Q27A or Q27K; a mutation that corresponds to position 29 of SEQ ID NO: 2, such as I29S, I29K, or I29D, provided that the mutation is not I29A; a mutation that corresponds to position 30 of SEQ ID NO: 2, such as V30S, V30K, or V30D, provided that the mutation is not V30A; a mutation that corresponds to position 32 of SEQ ID NO: 2, such as S32K, or S32D, provided that the mutation is not S32A; a mutation that corresponds to position 34 of SEQ ID NO: 2, such as V34A, V34K, or V34D, provided that the mutation is not V34S; a mutation that corresponds to position 35 of SEQ ID NO: 2, such as N35S, orN35K, provided that the mutation is not N35A or N35D; a mutation that corresponds to position 36 of SEQ ID NO: 2, such as T36S or T36K, provided that the mutation is not T36A or T36D; a mutation that corresponds to position 37 of SEQ ID NO: 2, such as Y37K, provided that the mutation is not Y37A, Y37S, or Y37D; a mutation that corresponds to position 38 of SEQ ID NO: 2, such as L38A, L38K, or L38D, provided that the mutation is not L38S; a mutation that corresponds to position 54 of SEQ ID NO: 2, such as Y54A or Y54S, provided that the mutation is not Y54K or Y54D; a mutation that corresponds to position 55 of SEQ ID NO: 2, such as K55S, provided that the mutation is not K55A or K55D; a mutation that corresponds to position 56 of SEQ ID NO: 2, such as V56A, V56K, or V56D, provided that the mutation is not V56S; a mutation that corresponds to position 57 of SEQ ID NO: 2, such as S57A or S57K, provided that the mutation is not S57D; a mutation that corresponds to position 60 of SEQ ID NO: 2, such as F60A, F60S, or F60K, provided that the mutation is not F60D; a mutation that corresponds to position 61 of SEQ ID NO: 2, such as S61A or S61K, provided that the mutation is not S61D; a mutation that corresponds to position 94 of SEQ ID NO: 2, such as F94A, provided that the mutation is not F94S, F94K, or F94D; a mutation that corresponds to position 95 of SEQ ID NO: 2, such as Q95A, Q95S or Q95D, provided that the mutation is not Q95K; a mutation that corresponds to position 96 of SEQ ID NO: 2, such as G96S, provided that the mutation is not G96A, G96K, or G96D; a mutation that corresponds to position 97 of SEQ ID NO: 2, such as S97A or S97D, provided that the mutation is not S97K; a mutation that corresponds to position 98 of SEQ ID NO: 2, such as H98A, H98K, or H98D, provided that the mutation is not H98S; a mutation that corresponds to position 99 of SEQ ID NO: 2, such as V99A, V99S, or V99D, provided that the mutation is not V99K; a mutation that corresponds to position 100 of SEQ ID NO: 2, such as P100S, P100K, or P100D, provided that the mutation is notPlOOA; a mutation that corresponds to position 101 of SEQ ID NO: 2, such as PlOlK, provided that the mutation is not P101A, P101S, or P101D; or any combination thereof.

2. The antibody of claim 1, wherein the antibody comprises a variable heavy chain that is at least 90% identical to SEQ ID NO: 1 and a variable light chain that is at least 90% identical to SEQ ID NO: 2, wherein the SEQ ID NO: 1 does not comprise a mutation at position 32, such as Y32A, Y32S, Y32K, or Y32D, a mutation at position 98, such as R98A, R98S, R98K, or R98D, a mutation at position 99, such as G99A, G99S, G99K, or G99D, a mutation at position101, such as P101A, P101S, P101K, or P101D, a mutation at position 102, such as D102A, D102S, or D102K, a mutation at position 103, such as Y103A, Y103S, Y103K, or Y103D, a mutation at position 104, such as Y104A, Y104S, Y104K, or Y104D, a mutation at position 108, such as KI 08 A, K108S, K108K, or K108D, or a mutation at position 109, such as W109A, W109S, W109K, or W109D; a mutation at position 40 such as R40A, a mutation at position 48 such as I48M, a mutation at position 67 such as K67R, a mutation at position 68 such as A68V, a mutation at position 70 such as L70M, a mutation at position 72 such as V72R, a mutation at position 74 such as K74T, a mutation at position 79 such as A79V, a mutation at position 82 such as Q82E, a mutation at position 87 such as T87R, a mutation at position 91 such as S91T, and SEQ ID NO: 2 does not comprise a mutation at position 39, such as a E39A, E39S, E39K, or E39D, a mutation at position 7, such as T7S, a mutation at position 14, such as S14T, a mutation at position 17, such as D17Q, a mutation at position 42, such as L42Q, a mutation at position 44, such as K44R, a mutation at position 51, such as L51R, a mutation at position 72, such as A72S, a mutation at position 79, such as R79K; and wherein: the variable heavy chain comprises: a mutation that corresponds to position 30 of SEQ ID NO: 1, such as T30A, T30S, T30K, or T30D; a mutation that corresponds to position 34 of SEQ ID NO: 1, such as M34A, M34S, M34K, or M34D; a mutation that corresponds to position 35 of SEQ ID NO: 1, such as H35A, H35S, H35K, or H35D; a mutation that corresponds to position 54 of SEQ ID NO: 1, such as S54A, S54K, or S54D; a mutation that corresponds to position 106 of SEQ ID NO: 1, such as SI 06 A, S106K, or S106D; a mutation that corresponds to position 111 of SEQ ID NO: 1, such as Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID; a mutation that corresponds to position 12 of SEQ ID NO: 1, such as V12K; a mutation that corresponds to position 20 of SEQ ID NO: 1, such as L20V; a mutation that corresponds to position 22 of SEQ ID NO: 1, such as C22A or C22K; a mutation that corresponds to position 38 of SEQ ID NO: 1, such as K38R; a mutation that corresponds to position 76 of SEQ ID NO: 1, such as S76T; or any combination thereof; and / or a mutation that corresponds to position 23 of SEQ ID NO: 1, such as K23A, provided that the mutation is not K23S or K23D; a mutation that corresponds to position 24 of SEQ ID NO: 1, such as A24S or A24K, provided that the mutation is not A24D; a mutation that corresponds to position 25 of SEQ ID NO: 1, such as S25D, provided that the mutation is not S25A or S25K; a mutation that corresponds to position 26 of SEQ ID NO: 1, such as G26A or G26D, provided that the mutation is not G26S or G26K; amutation that corresponds to position 27 of SEQ ID NO: 1, such as Y27K, provided that the mutation is not Y27A, Y27S, or Y27D; a mutation that corresponds to position 28 of SEQ ID NO: 1, such as T28S or T28D, provided that the mutation is not T28A or T28K; a mutation that corresponds to position 29 of SEQ ID NO: 1, such as F29A, provided that the mutation is not F29S, F29K, or F29D; a mutation that corresponds to position 31 of SEQ ID NO: 1, such as S31 A or S3 ID, provided that the mutation is not S3 IK; a mutation that corresponds to position 33 of SEQ ID NO: 1, such as W33K, provided that the mutation is not W33A, W33S, or W33D; a mutation that corresponds to position 50 of SEQ ID NO: 1, such as E50A, E50S, or E50D, provided that the mutation is not E50K; a mutation that corresponds to position 51 of SEQ ID NO: 1, such as 151 A, 15 IK, or 15 ID, provided that the mutation is not 15 IS; a mutation that corresponds to position 52 of SEQ ID NO: 1, such as N52A or N52K, provided that the mutation is not N52S or N52D; a mutation that corresponds to position 53 of SEQ ID NO: 1, such as P53S or P53K, provided that the mutation is not P53 A or P53D; a mutation that corresponds to position 55 of SEQ ID NO: 1, such as N55D, provided that the mutation is not N55A, N55S, or N55K; a mutation that corresponds to position 56 of SEQ ID NO: 1, such as G56D, provided that the mutation is not G56A, G56S, or G56K; a mutation that corresponds to position 57 of SEQ ID NO: 1, such as R57A, R57K, or R57D, provided that the mutation is not R57S; a mutation that corresponds to position 58 of SEQ ID NO: 1, such as T58S, T58K, or T58D, provided that the mutation is not T58A; a mutation that corresponds to position 59 of SEQ ID NO: 1, such as N59S or N59K, provided that the mutation is not N59A or N59D; a mutation that corresponds to position 97 of SEQ ID NO: 1, such as A97S or A97D, provided that the mutation is not A97K; a mutation that corresponds to position 100 of SEQ ID NO: 1, such as R100A or R100K, provided that the mutation is not R100S or R100D; a mutation that corresponds to position 105 of SEQ ID NO: 1, such as G105A, provided that the mutation is not G105S, G105K, or G105D; a mutation that corresponds to position 107 of SEQ ID NO: 1, such as SI 07 A, provided that the mutation is not S107K or S107D; a mutation that corresponds to position 110 of SEQ ID NO: 1, such as Y110S, Y110K, or Y110D, provided that the mutation is not Y110A; a mutation that corresponds to position 112 of SEQ ID NO: 1, such as DI 12S, provided that the mutation is not D112A or D112K; a mutation that corresponds to position 113 of SEQ ID NO: 1, such as V113A, V113S, or V113K, provided that the mutation is not VI 13D; or any combination thereof; and / orthe variable light chain comprises: a mutation that corresponds to position 24 of SEQ ID NO: 2, such as R24A, R24S R24K, or R24D; a mutation that corresponds to position 26 of SEQ ID NO: 2, such as S26A, S26K, or S26D; a mutation that corresponds to position 28 of SEQ ID NO: 2, such as S28A, S28K, or S28D; a mutation that corresponds to position 33 of SEQ ID NO: 2, such as N33A, N33S, N33K, or N33D; a mutation that corresponds to position 58 of SEQ ID NO: 2, such as N58A, N58S, N58K, or N58D; a mutation that corresponds to position 59 of SEQ ID NO: 2, such as R59A, R59S, R59K, or R59D; a mutation that corresponds to position 102 of SEQ ID NO: 2, such as T102A, T102S, T102K, or T102D; a mutation that corresponds to position 41 of SEQ ID NO: 2, such as Y41F; a mutation that corresponds to position 88 of SEQ ID NO: 2, such as L88V; a mutation that corresponds to position 90 of SEQ ID NO: 2, such as I90V; or any combination thereof; and / or a mutation that corresponds to position 25 of SEQ ID NO: 2, such as S25A, provided that the mutation is not S25K or S25D; a mutation that corresponds to position 27 of SEQ ID NO: 2, such as Q27S or Q27D, provided that the mutation is not Q27A or Q27K; a mutation that corresponds to position 29 of SEQ ID NO: 2, such as I29S, I29K, or I29D, provided that the mutation is not I29A; a mutation that corresponds to position 30 of SEQ ID NO: 2, such as V30S, V30K, or V30D, provided that the mutation is not V30A; a mutation that corresponds to position 32 of SEQ ID NO: 2, such as S32K, or S32D, provided that the mutation is not S32A; a mutation that corresponds to position 34 of SEQ ID NO: 2, such as V34A, V34K, or V34D, provided that the mutation is not V34S; a mutation that corresponds to position 35 of SEQ ID NO: 2, such as N35S, or N35K, provided that the mutation is not N35A or N35D; a mutation that corresponds to position 36 of SEQ ID NO: 2, such as T36S or T36K, provided that the mutation is not T36A or T36D; a mutation that corresponds to position 37 of SEQ ID NO: 2, such as Y37K, provided that the mutation is not Y37A, Y37S, or Y37D; a mutation that corresponds to position 38 of SEQ ID NO: 2, such as L38A, L38K, or L38D, provided that the mutation is not L38S; a mutation that corresponds to position 54 of SEQ ID NO: 2, such as Y54A or Y54S, provided that the mutation is not Y54K or Y54D; a mutation that corresponds to position 55 of SEQ ID NO: 2, such as K55S, provided that the mutation is not K55A or K55D; a mutation that corresponds to position 56 of SEQ ID NO: 2, such as V56A, V56K, or V56D, provided that the mutation is not V56S; a mutation that corresponds to position 57 of SEQ ID NO: 2, such as S57A or S57K,provided that the mutation is not S57D; a mutation that corresponds to position 60 of SEQ ID NO: 2, such as F60A, F60S, or F60K, provided that the mutation is not F60D; a mutation that corresponds to position 61 of SEQ ID NO: 2, such as S61A or S61K, provided that the mutation is not S61D; a mutation that corresponds to position 94 of SEQ ID NO: 2, such as F94A, provided that the mutation is not F94S, F94K, or F94D; a mutation that corresponds to position 95 of SEQ ID NO: 2, such as Q95A, Q95S or Q95D, provided that the mutation is not Q95K; a mutation that corresponds to position 96 of SEQ ID NO: 2, such as G96S, provided that the mutation is not G96A, G96K, or G96D; a mutation that corresponds to position 97 of SEQ ID NO: 2, such as S97A or S97D, provided that the mutation is not S97K; a mutation that corresponds to position 98 of SEQ ID NO: 2, such as H98A, H98K, or H98D, provided that the mutation is not H98S; a mutation that corresponds to position 99 of SEQ ID NO: 2, such as V99A, V99S, or V99D, provided that the mutation is not V99K; a mutation that corresponds to position 100 of SEQ ID NO: 2, such as P100S, P100K, or P100D, provided that the mutation is notPlOOA; a mutation that corresponds to position 101 of SEQ ID NO: 2, such as PlOlK, provided that the mutation is not P101A, P101S, or P101D; or any combination thereof.

3. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a K23 A mutation.

4. The antibody of claim 3, wherein the variable heavy chain comprises an amino acid of SEQ ID NO: 3.

5. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an A24S or A24K, mutation.

6. The antibody of claim 5, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 6 or 7.

7. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an S25D mutation.

8. The antibody of claim 7, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 11.

9. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a G26A or G26D mutation.

10. The antibody of claim 9, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 12 or 15.

11. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a Y27K mutation.

12. The antibody of claim 11, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 18.

13. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a T28S or T28D mutation.

14. The antibody of claim 13, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 21 or 23.

15. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an F29A mutation.

16. The antibody of claim 15, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 24.

17. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a T30A, T30S, T30K, or T30D mutation.

18. The antibody of claim 17, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 28, 29, 30, or 31.

19. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an S31A or S3 ID mutation.

20. The antibody of claim 19, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 32 or 34.

21. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a W33K mutation.

22. The antibody of claim 21, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 41.

23. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an M34A, M34S, M34K, or M34D mutation.

24. The antibody of claim 23, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 43, 44, 45, or 46.

25. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a H35A, H35S, H35K, or H35D mutation.

26. The antibody of claim 25, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 47, 48, 49, or 50.

27. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an E50A, E50S, or E50D mutation.

28. The antibody of claim 27, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 51, 52, or 54.

29. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an 151 A, 15 IK, or 15 ID mutation.

30. The antibody of claim 29, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 55, 57, or 58.

31. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an N52A or N52K mutation.

32. The antibody of claim 31, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 59 or 61.

33. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a P53S or P53K mutation.

34. The antibody of claim 33, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 64 or 65.

35. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an S54A, S54K, or S54D mutation.

36. The antibody of claim 35, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 67, 68, or 69.

37. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an N55D mutation.

38. The antibody of claim 37, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 73.

39. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a G56D mutation.

40. The antibody of claim 39, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 77.

41. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an R57A, R57K, or R57D mutation.

42. The antibody of claim 41, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 78, 80, or 81.

43. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a T58S, T58K, or T58D mutation.

44. The antibody of claim 43, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 83, 84, or 85.

45. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an N59S or N59K mutation.

46. The antibody of claim 45, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 87 or 88.

47. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an A97S or A97D mutation.

48. The antibody of claim 47, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 90 or 92.

49. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an R100A or R100K mutation.

50. The antibody of claim 49, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 101 or 103.

51. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a G105A mutation.

52. The antibody of claim 51, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 120.

53. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an S106A, S106K, or S106D mutation.

54. The antibody of claim 53, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 124, 125, or 126.

55. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an S107A mutation.

56. The antibody of claim 55, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 127.

57. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a Y110S, Y110K, or Y110D mutation.

58. The antibody of claim 57, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 138, 139, or 140.

59. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises an Fl 11A, Fl 1 IS, Fl 1 IK, or Fl 1 ID mutation.

60. The antibody of claim 59, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 141, 142, 143, or 144.

61. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a DI 12S mutation.

62. The antibody of claim 61, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 146.

63. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a VI 13 A, VI 13S, or VI 13K mutation.

64. The antibody of claim 63, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 148, 149, or 150.

65. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a V12K mutation.

66. The antibody of claim 65, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 276.

67. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a L20V mutation.

68. The antibody of claim 67, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 277.

69. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a C22A or C22K mutation.

70. The antibody of claim 69, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 278 or 279.

71. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a K38R mutation.

72. The antibody of claim 71, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 280.

73. The antibody of any one of the preceding claims, wherein the variable heavy chain comprises a S76T mutation.

74. The antibody of claim 73, wherein the variable heavy chain comprises an amino acid sequence of SEQ ID NO: 288.

75. The antibody of any one of the preceding claims, wherein the variable light chain comprises an R24A, R24S R24K, or R24D mutation.

76. The antibody of claim 75, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 152, 153, 154, or 155.

77. The antibody of any one of the preceding claims, wherein the variable light chain comprises an S25A mutation.

78. The antibody of claim 77, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 156.

79. The antibody of any one of the preceding claims, wherein the variable light chain comprises an S26A, S26K, or S26D mutation.

80. The antibody of claim 79, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 159, 160, or 161.

81. The antibody of any one of the preceding claims, wherein the variable light chain comprises a Q27S or Q27D mutation.

82. The antibody of claim 81, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 163 or 165.

83. The antibody of any one of the preceding claims, wherein the variable light chain comprises an S28A, S28K, or S28D mutation.

84. The antibody of claim 83, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 166, 167, or 168.

85. The antibody of any one of the preceding claims, wherein the variable light chain comprises a I29S, I29K, or I29D mutation.

86. The antibody of claim 85, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 170, 171, or 172.

87. The antibody of any one of the preceding claims, wherein the variable light chain comprises a V30S, V30K, or V30D mutation.

88. The antibody of claim 87, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 174, 175, or 176.

89. The antibody of any one of the preceding claims, wherein the variable light chain comprises a S32K, or S32D mutation.

90. The antibody of claim 89, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 182 or 183.

91. The antibody of any one of the preceding claims, wherein the variable light chain comprises a N33A, N33S, N33K, or N33D mutation.

92. The antibody of claim 91, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 184, 185, 186, or 187.

93. The antibody of any one of the preceding claims, wherein the variable light chain comprises a V34A, V34K, or V34D mutation.

94. The antibody of claim 93, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 188, 190, or 191.

95. The antibody of any one of the preceding claims, wherein the variable light chain comprises a N35S, or N35K mutation.

96. The antibody of claim 95, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 193 or 194.

97. The antibody of any one of the preceding claims, wherein the variable light chain comprises a T36S or T36K mutation.

98. The antibody of claim 97, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 197 or 198.

99. The antibody of any one of the preceding claims, wherein the variable light chain comprises a Y37K mutation.

100. The antibody of claim 99, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 202.

101. The antibody of any one of the preceding claims, wherein the variable light chain comprises a L38A, L38K, or L38D mutation.

102. The antibody of claim 101, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 204, 206, or 207.

103. The antibody of any one of the preceding claims, wherein the variable light chain comprises a Y54A or Y54S mutation.

104. The antibody of claim 103, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 212 or 213.

105. The antibody of any one of the preceding claims, wherein the variable light chain comprises a K55S mutation.

106. The antibody of claim 105, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 217.

107. The antibody of any one of the preceding claims, wherein the variable light chain comprises a V56A, V56K, or V56D mutation.

108. The antibody of claim 107, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 219, 221, or 222.

109. The antibody of any one of the preceding claims, wherein the variable light chain comprises a S57A or S57K mutation.

110. The antibody of claim 109, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 223 or 224.

111. The antibody of any one of the preceding claims, wherein the variable light chain comprises a N58A, N58S, N58K, or N58D mutation.

112. The antibody of claim 111, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 226, 227, 228, or 229.

113. The antibody of any one of the preceding claims, wherein the variable light chain comprises a R59A, R59S, R59K, or R59D mutation.

114. The antibody of claim 113, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 230, 231, 232, or 233.

115. The antibody of any one of the preceding claims, wherein the variable light chain comprises a F60A, F60S, or F60K mutation.

116. The antibody of claim 115, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 234, 235, or 236.

117. The antibody of any one of the preceding claims, wherein the variable light chain comprises a S61A or S61K mutation.

118. The antibody of claim 117, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 238 or 239.

119. The antibody of any one of the preceding claims, wherein the variable light chain comprises a F94A mutation.

120. The antibody of claim 119, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 241.

121. The antibody of any one of the preceding claims, wherein the variable light chain comprises a Q95A, Q95S or Q95D mutation.

122. The antibody of claim 121, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 245, 246, or 248.

123. The antibody of any one of the preceding claims, wherein the variable light chain comprises a G96S mutation.

124. The antibody of claim 123, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 250.

125. The antibody of any one of the preceding claims, wherein the variable light chain comprises a S97A or S97D mutation.

126. The antibody of claim 125, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 253 or 255.

127. The antibody of any one of the preceding claims, wherein the variable light chain comprises a H98A, H98K, or H98D mutation.

128. The antibody of claim 127, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 256, 258, or 259.

129. The antibody of any one of the preceding claims, wherein the variable light chain comprises a V99A, V99S, or V99D mutation.

130. The antibody of claim 129, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 260, 261, or 263.

131. The antibody of any one of the preceding claims, wherein the variable light chain comprises a PlOOS, P100K, or PlOOD mutation.

132. The antibody of claim 131, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 265, 266, or 267.

133. The antibody of any one of the preceding claims, wherein the variable light chain comprises a P101K mutation.

134. The antibody of claim 133, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 270.

135. The antibody of any one of the preceding claims, wherein the variable light chain comprises a T102A, T102S, T102K, or T102D mutation.

136. The antibody of claim 135, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 272, 273, 274, or 275.

137. The antibody of any one of the preceding claims, wherein the variable light chain comprises a Y41F mutation.

138. The antibody of claim 137, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 296.

139. The antibody of any one of the preceding claims, wherein the variable light chain comprises a L88V mutation.

140. The antibody of claim 139, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 302.

141. The antibody of any one of the preceding claims, wherein the variable light chain comprises a I90V mutation.

142. The antibody of claim 141, wherein the variable light chain comprises an amino acid sequence of SEQ ID NO: 303.

143. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 3.

144. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 6 or 7.

145. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 11.

146. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 12 or 15.

147. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 18.

148. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 21 or 23.

149. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 24.

150. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 28,29, 30, or 31.

151. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 32 or 34.

152. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 41.

153. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 43, 44, 45, or 46.

154. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 47, 48, 49, or 50.

155. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 51, 52, or 54.

156. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 55, 57, or 58.

157. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 59 or 61.

158. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 64 or 65.

159. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 67, 68, or 69.

160. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 73.

161. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 77.

162. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 78, 80, or 81.

163. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 83, 84, or 85.

164. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 87 or 88.

165. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 90 or 92.

166. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 101 or 103.

167. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 120.

168. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 124, 125, or 126.

169. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 127.

170. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequenceof SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 138, 139, or 140.

171. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 141, 142, 143, or 144.

172. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 146.

173. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 148, 149, or 150.

174. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 276.

175. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 277.

176. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 278.

177. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 279.

178. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 280.

179. The antibody of claim 1 or 2, wherein the variable light chain has an amino acid sequence of SEQ ID NO: 2 and the variable heavy chain has an amino acid sequence of SEQ ID NO: 288180. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 152, 153, 154, or 155.

181. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ IDNO: 156.

182. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 159, 160, or 161.

183. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 163 or 165.

184. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 166, 167, or 168.

185. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 170, 171, or 172.

186. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 174, 175, or 176.

187. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 182 or 183.

188. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 184, 185, 186, or 187.

189. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 188, 190, or 191.

190. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 193 or 194.

191. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 197 or 198.

192. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 202.

193. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 204, 206, or 207.

194. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 212 or 213.

195. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 217.

196. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 219, 221, or 222.

197. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 223 or 224.

198. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 226, 227, 228, or 229.

199. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 230, 231, 232, or 233.

200. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acidsequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 234, 235, or 236.

201. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 238 or 239.

202. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 241.

203. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 245, 246, or 248.

204. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 250.

205. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 253 or 255.

206. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 256, 258, or 259.

207. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 260, 261, or 263.

208. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 265, 266, or 267.

209. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ IDNO: 270.

210. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 272, 273, 274, or 275.

211. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 296.

212. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 302.

213. The antibody of claim 1 or 2, wherein the variable heavy chain has an amino acid sequence of SEQ ID NO: 1 and the variable light chain has an amino acid sequence of SEQ ID NO: 304.

214. A method of treating or reducing the severity of, thyroid-associated ophthalmopathy (TAO), or a symptom thereof, comprising administering to a subject an antibody of any one of claims 1-213.

215. A method of reducing proptosis in an eye in a subject with thyroid-associated ophthalmopathy (TAO) comprising administering to a subject an antibody of any one of claims 1-213.

216. A method of treating thyroid eye disease in a subject comprising administering to a subject an antibody of any one of claims 1-213.

217. A method of reducing Clinical Activity Score (CAS) of thyroid-associated ophthalmopathy (TAO) in a subject comprising administering to a subject an antibody of any one of claims 1-213.

218. A method of a) reducing proptosis by at least 2 mm and b) reducing the clinical activity score (CAS) in a subject with thyroid-associated ophthalmopathy (TAO) comprising administering to a subject an antibody of any one of claims 1-213.

219. The method of any of claims 214-218, wherein proptosis is reduced by at least 2 mm.

220. The method of any of claims 214-218, wherein proptosis is reduced by at least 3 mm.

221. The method of any of claims 214-218, wherein proptosis is reduced by at least 4 mm.

222. The method of any of claims 214-218, wherein the clinical activity score (CAS) of the subject is reduced by at least 2 points.

223. The method of any of claims 214-218, wherein the clinical activity score (CAS) of the subject is reduced to one (1).

224. The method of any of claims 214-218, wherein the clinical activity score (CAS) of the subject is reduced to zero (0).

225. A method of treating or reducing the severity of thyroid-associated ophthalmopathy (TAO) in a subject comprising administering to a subject an antibody of any one of claims 1- 213, wherein treatment with said antibody (i) reduces proptosis by at least 2 mm in an eye; (ii) is not accompanied by a deterioration of 2 mm or more in the other (or fellow eye); and (iii) reduces the CAS in said subject to either one (1) or zero (0).

226. A method of improving the quality of life in a subject with thyroid-associated ophthalmopathy (TAO, also called Graves' Ophthalmopathy / Graves' Orbitopathy) comprising administering to a subject an antibody of any one of claims 1-213.

227. The method of claim 226, wherein the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment, or either the Visual Functioning or Appearance subscale thereof.

228. The method of claim 227, wherein the treatment results in an improvement of greater than or equal to 8 points on the GO-QoL.

229. The method of claim 227, wherein the treatment results in an improvement on the Functioning subscale of the GO-QoL.

230. The method of claim 227, wherein the treatment results in an improvement on the Appearance subscale of the GO-QoL.

231. A method of treating or reducing the severity of diplopia in a subject with thyroid- associated ophthalmopathy (TAO) comprising administering to a subject an antibody of any one of claims 1-213.

232. The method of claim 231, wherein the diplopia is constant diplopia.

233. The method of claim 231, wherein the diplopia is inconstant diplopia.

234. The method of claim 231, wherein the diplopia is intermittent diplopia.

235. The method of claim 231 , wherein the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of antibody administration.

236. The method of claim 231, wherein the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of antibody administration.

237. The method of any one of claims 214-236, wherein said antibody is administered at a dosage of about 1 mg / kg to about 5 mg / kg antibody as a first dose.

238. The method of any one of claims 214-236, wherein said antibody is administered at a dosage of about 5 mg / kg to about 10 mg / kg antibody as a first dose.

239. The method of any one of claims 214-236, wherein said antibody is administered at a dosage of about 5 mg / kg to about 20 mg / kg antibody in subsequent doses.

240. The method of any one of claims 214-236, wherein said antibody is administered in the following amounts: about 10 mg / kg antibody as a first dose; and about 20 mg / kg antibody in subsequent doses.

241. The method of claim 240, wherein said subsequent doses are administered every three weeks for at least 21 weeks.

242. The method of any one of claims 214-241, wherein the antibody, or an antigen binding fragment thereof, is a human antibody, a monoclonal antibody, a human monoclonal antibody, a purified antibody, a diabody, a single-chain antibody, a multi-specific antibody, Fab, Fab', F(ab')2, Fv or scFv.

243. The method of any one of claims 214-242, wherein the antibody, or an antigen binding fragment thereof, is administered in a pharmaceutical composition that additionally comprises a pharmaceutically acceptable diluent or excipient or carrier.

244. The method of claim 243, wherein the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO.

245. The method of claim 243 or 244, wherein the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti- IL-6 antibodies; or selenium, infliximab or other anti-TNFalpha antibodies or a thyroid- stimulating hormone receptor (TSHR) inhibitor.

246. The method of any one of the claims 214-245, wherein the antibody or an 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 retro-orbital sinus.

247. The method of claim 246, wherein the antibody or an antigen binding fragment thereof is administered via an injection.

248. The method of claim 247, wherein the injection is a intravitreal injection, intraorbital injection, retro-orbital injection, suprachoroidal injection, or intracam eral injection.

249. A method of increasing the internalization of IGF-1R on a cell, the method comprising contacting the cell with an antibody of any one of claims 1-213.

250. The method of claim 249, wherein the contacting comprises administering to a subject an antibody of any one of claims 1-213.

251. The method of claim 250, wherein the subject has or is at risk of thyroid eye disease (TED).

252. A method of inhibiting IGF-1 stimulated receptor phosphorylation on a cell, the method comprising contacting the cell with an antibody of any one of claims 1-213.

253. The method of claim 252, wherein the contacting comprises administering to a subject an antibody of any one of claims 1-213.

254. The method of claim 253, wherein the subject has or is at risk of thyroid eye disease (TED).

255. The method of any one of claims 252-254, wherein the antibody has an IC50 of less than, or equal to, about 0.2 nm, 0.15 nm, 0.10 nm, 0.09 nm.

256. The method of claim 255, wherein the IC50 is measured in an in vitro assay, such as an assay as provided for herein.

257. The method of any one of claims 252-256, wherein the cell is an A549 cell or a HOCF cell.

258. A method of treating thyroid eye disease in a subject, the method comprising administering an antibody of any one of claims 1-188, wherein the antibody has a serum concentration in the subject of at least, or about, 70 pg / ml, 75 pg / ml, 80 pg / ml, 85 pg / ml, 90 pg / ml, 95 pg / ml, 100 pg / ml, or 105 pg / ml at least 1, 2, or 3 week after administration.

259. The method of claim 258, wherein the antibody is administered intravenously.

260. The method of any one of claims 258-259, wherein the antibody is administered at a dose of about 20 mg / kg.

261. The method of any one of claims 258-260, wherein the antibody is administered at least, or about, once a week, once every two weeks, once every 3 weeks, or once every 4 weeks.

262. A method of inhibiting IGF-1 induced receptor autophosphorylation in a cell by at least 95%, 96%, 97%, 98%, or 99% or by 100%, the method comprising contacting the cell with an antibody of any one of claims 1-213.

263. The method of claim 262, wherein the inhibition of the IGF-1 induced receptor autophosphorylation is measured as compared to the induced receptor autophosphorylation in the absence of the antibody.

264. The method of claims 262 or 263, wherein the contacting comprises administering to a subject the antibody comprising the same.

265. The method of claim 264, wherein the subject has or is at risk of thyroid eye disease (TED).

266. A method of inhibiting IGF-1 induced receptor autophosphorylation by at least 95%, 96%, 97%, 98%, or 99% or by 100% in a subject in need thereof, the method comprising administering to the subject an antibody of any one of claims 1-213.

267. The method of claim 266, wherein the subject has or is at risk of thyroid eye disease (TED).

268. The method of any one of claims 266 or 267, wherein the antibody is administered intravenously.

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