Anti-IL-11Rα antibodies for treating thyroid eye disease

Abstract

Methods for treating thyroid eye disease (TED) are provided by administering an antibody or antigen-binding fragment thereof that binds to human interleukin-11 receptor subunit alpha (IL-11Rα).

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 63 / 437,607, filed January 6, 2023; U.S. Provisional Patent Application No. 63 / 444,492, filed February 9, 2023; U.S. Provisional Patent Application No. 63 / 466,112, filed May 12, 2023; U.S. Provisional Patent Application No. 63 / 529,910, filed July 31, 2023; U.S. Provisional Patent Application No. 63 / 529,910, filed September 7, 2023; This application claims priority to U.S. Provisional Patent Application No. 63 / 537,030, filed October 24, 2023, U.S. Provisional Patent Application No. 63 / 592,899, filed November 2, 2023, and U.S. Provisional Patent Application No. 63 / 595,626, filed November 2, 2023, and U.S. Provisional Patent Application No. 63 / 608,744, filed December 11, 2023, the contents of which are incorporated herein by reference in their entireties.

[0002] Interleukin-11 (IL-11), a member of the IL-6 family, plays an important role in chronic inflammation, autoimmunity, cancer, and other diseases, as well as in pathological wound healing.

[0003] Thyroid eye disease (TED), also known as Graves' ophthalmopathy, is an autoimmune inflammatory disorder of the orbital and periorbital tissues characterized by upper eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis, and eyeball enlargement (exophthalmos) (see, e.g., Bahn, The New England Journal of Medicine. 362(8):726-738, 2010). Treatments include topical lubrication to avoid corneal damage caused by exposure, corticosteroids, surgery, and teprotumumab, an antibody that binds to the insulin-like growth factor 1 (IGF-1) receptor. However, there is a need in the art for improved therapies for treating TED. Provided herein are compositions and methods that address this need. Summary of the Invention

[0004] Embodiments of the present disclosure include methods of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or antigen-binding fragment thereof that binds to human interleukin-11 receptor subunit alpha (IL-11Rα) (see, e.g., PCT / US2022 / 075680, which is incorporated by reference in its entirety). In certain embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof antagonizes or inhibits binding and / or signaling activity between IL-11Rα and IL-11. In another aspect, the present disclosure provides antibodies that bind to IL-11Rα and interfere with the binding of IL-11 to IL-11Rα.

[0005] In some embodiments, the patient has one or more clinical signs of TED, in some embodiments, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

[0006] In certain embodiments, the patient has a Clinical Activity Score (CAS) of 3 or greater, or 4 or greater, 5 or greater, or 6 or greater, where the CAS is assigned a score of 1 for each of the following: spontaneous orbital pain, gaze-induced orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and inflammation of the caruncle and semilunar folds. In some embodiments, the patient has a VISA (Vision, Inflammation, Strabismus, Appearance / Exposure) score of 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater. In some embodiments, the patient has abnormal thyroid function, optionally hyperthyroidism. In some embodiments, the patient has autoantibody stimulation of the thyroid-stimulating hormone receptor (TSHR). In some embodiments, the patient has increased levels of thyroid-stimulating immunoglobulin (TSI). In some embodiments, the patient has Graves' disease.

[0007] In some embodiments, the patient has one or more risk factors associated with TED. In some embodiments, the one or more risk factors are selected from female gender, middle age, smoking, and currently receiving or having received radioactive iodine treatment. In some embodiments, the patient has increased levels of IL-11Rα and / or IL-11 in the blood or tissues around the eye, for example, in orbital fibroblasts. In some embodiments, the patient has increased levels of circulating IL-11.

[0008] Particular embodiments include: (a) determining whether the patient has TED; and (b) if the patient has TED, administering the pharmaceutical composition to the patient.

[0009] In some embodiments, (a) optionally comprises measuring one or more clinical signs of TED selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in orbital tissues, and chemosis (swelling of the conjunctiva).

[0010] Particular embodiments include: (a) determining the CAR of a patient; and (b) if the CAS is 3 or greater, or 4 or greater, or 5 or greater, or 6 or greater, administering a pharmaceutical composition to the patient.

[0011] Particular embodiments include: (a) determining a patient's VISA score; and (b) administering a pharmaceutical composition to the patient if the VISA score is 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater.

[0012] Particular embodiments include: (a) determining thyroid function in a patient; and (b) if the patient has a thyroid dysfunction, optionally hyperthyroidism, administering the pharmaceutical composition to the patient.

[0013] Particular embodiments include: (a) determining the level of thyroid-stimulating immunoglobulin (TSI) in a patient; and (b) if the level of TSI in the patient is increased compared to a control or reference standard, administering the pharmaceutical composition to the patient.

[0014] Particular embodiments include: (a) determining the level of IL-11Rα and / or IL-11 in the blood or tissue surrounding the eye of the patient, e.g., in orbital fibroblasts; and (b) administering the pharmaceutical composition to the patient if the levels of IL-11Rα and / or IL-11 in the blood or tissues around the eye (e.g., orbital fibroblasts) of the patient are increased compared to a control or reference standard.

[0015] Particular embodiments include: (a) determining the level of circulating IL-11 in a patient; and (b) if the level of circulating IL-11 is increased compared to a control or reference standard, administering the pharmaceutical composition to the patient.

[0016] In some embodiments, patients, including patients with chronic TED, are treatment-naive with respect to TED treatment.

[0017] In some embodiments, the patient is undergoing or has previously undergone TED treatment and is intolerant, relapsed, and / or refractory to the (prior) TED treatment. In some embodiments, a patient with relapsed TED is identified by an initial response to a previous TED treatment, as measured by a decrease in exophthalmos, followed by regression after a period of time despite continued treatment with the same TED treatment. In some embodiments, the decrease in exophthalmos is greater than about 2 mm. In some embodiments, regression of exophthalmos is an increase in exophthalmos returning to the pre-treatment baseline measurement. In some embodiments, regression of exophthalmos is an increase in exophthalmos from the maximum response to the previous TED treatment. In some embodiments, a patient with relapsed TED is identified by an initial response to a previous TED treatment, as measured by a decrease in CAS score, followed by regression after a period of time despite continued treatment with the same TED treatment. In some embodiments, a refractory patient is identified by a lack of improvement in exophthalmos. In some embodiments, the lack of improvement in exophthalmos is less than about 2 mm. In some embodiments, a refractory patient is identified by little or no change in CAS score. In some embodiments, intolerant, relapsed, and / or refractory patients have active TED. In some instances, the patient has progressive TED. In certain embodiments, patients with intolerant / relapsed / refractory disease states have TED that progresses more aggressively in the patient than it did prior to TED treatment. In some embodiments, progression of TED is indicated by a worsening of one or more clinical signs of TED, an increase in CAS score, and / or a worsening VISA score compared to the clinical signs, CAS score, and / or VISA score prior to TED treatment. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanisms of action may provide clinical benefit in treating progressive disease states, including more aggressive disease states, compared to previous (now refractory) TED treatments.

[0018] In some embodiments, the (previous) TED treatment is selected from insulin-like growth factor-1 receptor (IGF-1R) inhibitor therapy, FcRn inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy, including combinations thereof (e.g., steroid + ORT therapy). In certain embodiments, the IGF-1R inhibitor therapy is a small molecule. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody. In certain embodiments, the IGF-1R inhibitor antibody is selected from the following therapies: teprotumumab, ganitumumab, dalotuzumab, cixutumumab, and figitumumab. In some embodiments, the FcRn inhibitor therapy is selected from the following therapies: batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab. In certain embodiments, the IL-6 inhibitor therapy is selected from the following therapies: clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab. In some embodiments, the steroid therapy is selected from the following therapies: methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone).In certain embodiments, the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapies. In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0019] In some embodiments, the patient is receiving or has previously received teprotumumab treatment and is intolerant, relapsed, and / or refractory to the (prior) teprotumumab treatment. In some embodiments, a patient with relapsed TED is identified by an initial response to previous teprotumumab treatment, as measured by a decrease in exophthalmos, followed by regression after a period of time despite continued treatment with the same teprotumumab treatment. In some embodiments, the decrease in exophthalmos is greater than about 2 mm. In some embodiments, regression of exophthalmos is an increase in exophthalmos returning to the pre-treatment baseline measurement. In some embodiments, regression of exophthalmos is an increase in exophthalmos from the maximal response to previous teprotumumab treatment. In some embodiments, a patient with relapsed TED is identified by an initial response to previous teprotumumab treatment, as measured by a decrease in CAS score, followed by regression after a period of time despite continued treatment with the same teprotumumab treatment. In some embodiments, a refractory patient is identified by a lack of improvement in exophthalmos. In some embodiments, the lack of improvement in exophthalmos is less than about 2 mm. In some embodiments, refractory patients are identified by little or no change in CAS score. In some embodiments, intolerant, relapsed, and / or refractory patients have active TED. In some cases, the patient has progressive TED. In certain embodiments, patients with intolerant / relapsed / refractory disease states have more aggressively progressing TED than before teprotumumab treatment. In some embodiments, TED progression is indicated by a worsening of one or more clinical signs of TED, an increase in CAS score, and / or a worsening VISA score compared to the clinical signs, CAS score, and / or VISA score before teprotumumab treatment. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanisms of action may provide clinical benefit in treating progressive disease states, including more aggressively progressing disease states, compared to previous (now refractory) teprotumumab treatment.In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered one teprotumumab half-life from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered two teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered three teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered four teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered five teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 6 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 7 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 8 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 9 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 10 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered more than 10 teprotumumab half-lives after the last administration of teprotumumab.

[0020] Certain embodiments include combination therapy, in which the method comprises administering a pharmaceutical composition (comprising an anti-IL-11Rα antibody or antigen-binding fragment thereof) in combination with at least one additional TED treatment.

[0021] In some embodiments, at least one additional TED therapy is administered prior to administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered simultaneously with administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered sequentially with administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered in the same composition as an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered in a separate composition from an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure.

[0022] In some embodiments, the at least one additional TED therapy is selected from IGF-1R inhibitor therapy, FcRn inhibitor therapy, IL-6 inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an antibody therapy. In some embodiments, the IGF-1R inhibitor antibody therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapies. In some embodiments, the FcRn inhibitor therapy is selected from the following therapies: batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab. In some embodiments, the IL-6 inhibitor therapy is selected from the following therapies: clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab. In certain embodiments, the steroid therapy is selected from the following therapies: methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone). In some embodiments, the CD20 inhibitor therapy is selected from the following therapies: ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab.In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0023] In some embodiments, the at least one additional TED therapy is an IGF-1R inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody, such as, for example, teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered simultaneously with the administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered before the administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered sequentially with the administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered in the same composition as the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered in a separate composition from the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 2 times during treatment with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 3 times during treatment with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 4 times during treatment with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 5 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 6 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure.In some embodiments, IGF-1R inhibitor therapy (eg, IGF-1R antibody) is administered from about 1 to about 7 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the disclosure.

[0024] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to fibronectin domain III of human IL-11Rα, or binds to approximately residues 90-197 of SEQ ID NO: 260. In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to the second extracellular domain of IL-11Rα.

[0025] In certain embodiments, an IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope spanning residues 115 to 134 of IL-11Rα. In certain embodiments, exemplary antibodies of the disclosure that exhibit such binding include those comprising the V and V sequences of CDRs 25-27 of SEQ ID NOS: 115-27, respectively. H CDR1, V H CDR2, and V H CDR3 sequences, and V sequences of SEQ ID NOs: 28 to 30, respectively L CDR1, V L CDR2, and V L In certain embodiments, an example of an antibody of the disclosure that exhibits such binding comprises the CDR3 sequence V of SEQ ID NO: 201. H Sequence number 202, and V L Contains arrays.

[0026] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope comprising residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261) or to residues located within said sequence. In some embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope comprising residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261) and additionally comprises crosslinks at positions S138, S147, K151, S162, and T165.

[0027] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof comprises a V complementarity determining region selected from Table A1.H CDR1 sequence, V H CDR2 sequence, and V H A heavy chain variable region (V) containing CDR3 sequences and variants thereof that specifically bind to IL-11Rα. H ), and a V of a complementarity-determining region selected from Table A1 L CDR1 sequence, V L CDR2 sequence, and V L A light chain variable region (V) containing CDR3 sequences and variants thereof that specifically bind to IL-11Rα. L ) is included.

[0028] In certain embodiments, V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 1 to 3, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 4 to 6, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 7 to 9, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 10 to 12, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 13 to 15, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 16 to 18, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 19 to 21, respectively, and V L CDR1 sequence, V LCDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 22 to 24, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 25 to 27, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 28 to 30, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 31 to 33, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 34 to 36, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 34 to 39, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 40 to 42, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 43 to 45, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 46 to 48, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 49 to 51, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 52 to 54, respectively; V HCDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 55 to 57, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 58 to 60, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 61 to 63, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 64 to 66, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 67 to 69, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 70 to 72, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 73 to 75, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 76 to 78, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 79 to 81, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 82 to 84, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 85 to 87, respectively, and VL CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 88 to 90, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 91 to 93, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 94 to 96, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 97 to 99, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 100 to 102, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 103 to 105, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 106-108, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 109 to 111, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 112-114, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 115 to 117, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V Lthe CDR3 sequences comprise SEQ ID NOs: 118-120, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 121 to 123, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 124 to 126, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 127 to 129, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 130 to 132, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 133 to 135, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 136 to 138, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 139 to 141, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 142 to 144, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 145 to 147, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 148 to 150, respectively; V HCDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 151 to 153, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 154 to 156, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 157 to 159, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 160 to 162, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 163 to 165, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 166-168, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 169 to 171, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 172 to 174, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 175 to 177, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 178-180, respectively; V H CDR1 sequence, V H CDR2 sequence, and V HThe CDR3 sequences include SEQ ID NOs: 181 to 183, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 187 to 189, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L The CDR3 sequences include SEQ ID NOs: 190 to 192, respectively.

[0029] In certain embodiments, V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, and optionally, V H has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in the framework regions. L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, and optionally, V L has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in the framework regions.

[0030] In certain embodiments, V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196; VH comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and V Lcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; V Hcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and V Lcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248; V Hcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and V L comprises a sequence that is at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:256.

[0031] In some embodiments, the antibody, or antigen-binding fragment thereof, has one or more of the following characteristics: has a binding affinity for human IL-11Rα of less than about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 30 pM, and optionally has increased binding affinity for human IL-11Rα compared to the TS7 and 8E2 antibodies; antagonize the binding and / or signaling activity between IL-11Rα and IL-11, and optionally have increased potency as an IL-11 signaling antagonist compared to the TS7 and 8E2 antibodies. optionally, reducing IL-11Rα / gp130 dimerization or complex formation in a cell-based assay; and / or Optionally, compared to the TS7 antibody and the 8E2 antibody, V L There is reduced N-linked glycosylation in CDR3.

[0032] In some embodiments, the IL-11Rα antibody or antigen-binding fragment thereof comprises an IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or a hybrid and / or variant thereof. In specific embodiments, the antibody or antigen-binding fragment thereof comprises an IgG Fc domain with high effector function in humans, optionally an IgG1 or IgG3 Fc domain. In some embodiments, the antibody or antigen-binding fragment thereof comprises an IgG Fc domain with reduced effector function in humans, optionally an IgG2 or IgG4 Fc domain. In specific embodiments, the antibody or antigen-binding fragment thereof optionally comprises a human IgG1 or IgG4 Fc domain selected from Table F1.

[0033] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof is a monoclonal antibody. In certain embodiments, the antibody or antigen-binding fragment thereof is a humanized antibody, and the antibody or antigen-binding fragment thereof is a humanized monoclonal antibody comprising a human IgG4 Fc domain with an S228P mutation (EU numbering).

[0034] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof is selected from an Fv fragment, a single-chain Fv (scFv) polypeptide, an adnectin, anticalin, an aptamer, an avimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.

[0035] In certain embodiments, the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the antibody or antigen-binding fragment, and is substantially free of aggregates and endotoxins. L The CDR3 sequences have reduced or undetectable heterogeneity of N-linked glycosylation (optionally compared to the TS7 and 8E2 antibodies). In certain embodiments, the composition is optionally a sterile injectable solution suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.

[0036] In certain embodiments, administering the pharmaceutical composition to a patient ameliorates one or more clinical signs of TED, hi some embodiments, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

[0037] In certain embodiments, administering the pharmaceutical composition to a patient improves the patient's Clinical Activity Score (CAS), optionally by at least 1, 2, 3, 4, or 5 points, optionally to a CAS of 3 or less, 2 or less, or 1 or less. In certain embodiments, administering the pharmaceutical composition to a patient improves the patient's VISA score, optionally by at least 1, 2, 3, 4, or 5 points, optionally to a VISA of 4 or less, 3 or less, 2 or less, or 1 or less. In certain embodiments, administering the pharmaceutical composition to a patient reduces the level of IL-11Rα or IL-11 in the blood or tissues around the patient's eye. [Brief explanation of the drawings]

[0038] [Figure 1A]Figure 1A shows cell surface expression of CD90 on fibroblasts from orbital tissue of TED patients compared to healthy (non-TED) patients. Figure 1A shows CD90 expression. Healthy control (dashed line); TED (black line); unstained / secondary Ab alone (light gray line). [Figure 1B] Figure 1B shows cell surface expression of CD45 on fibroblasts from orbital tissue of TED patients compared with healthy (non-TED) patients. Figure 1B shows CD45 expression. Healthy control (dashed line); TED (black line); unstained / secondary Ab alone (light gray line). [Figure 1C] Figure 1C shows cell surface expression of IL-11Rα on fibroblasts from orbital tissue of a TED patient compared to a healthy (non-TED) patient. Figure 1C shows IL-11Rα expression using the mAb5 antibody. Healthy control (dashed line); TED (black line); unstained / secondary Ab alone (light gray line). [Figure 2] Figure 2 shows hyaluronan release by orbital fibroblasts preincubated with medium alone (no antibody control) or mAb5 (10 μg / mL) for 1 hour and then stimulated with human recombinant IL-11 (1.1, 3.3, or 10 ng / mL) for an additional 96 hours. Data are presented as fold change relative to vehicle control for n=4 independent experiments using n=3 TED donors with two biological replicates per treatment. ** indicates p<0.01 compared to mAb5-treated cells using one-way ANOVA with Dunnett's post hoc multiple comparison test. [Figure 3] Figure 3 shows cell proliferation by orbital fibroblasts preincubated with medium alone (no antibody control) or mAb5 (10 μg / mL) for 1 hour and then stimulated with human recombinant IL-11 (1.1, 3.3, or 10 ng / mL) for an additional 96 hours. Data are presented as fold change relative to vehicle control for n = 4 independent experiments using n = 3 TED donors with two biological replicates per treatment. ** indicates p < 0.0001 compared to mAb5-treated cells using one-way ANOVA with Dunnett's post hoc multiple comparison test. [Figure 4A]Figure 4A shows the dose-dependent effect of IL-11 with mAb5 (10 ng / mL, hatched line) and without mAb5 (solid line) on hyaluronan release from orbital fibroblasts from patient sample #2 (Figure 4A, no prior TED treatment). [Figure 4B] Figure 4B shows the dose-dependent effect of IL-11 with mAb5 (10 ng / mL, hatched lines) and without mAb5 (solid lines) on hyaluronan release from orbital fibroblasts from patient sample #1 (Figure 4B, previously treated with teprotumumab) and patient sample #3 (Figure 4C, previously treated with corticosteroids). [Figure 4C] Figure 4C shows the dose-dependent effect of IL-11 with mAb5 (10 ng / mL, hatched line) and without mAb5 (solid line) on hyaluronan release from orbital fibroblasts of patient sample #3 (Figure 4C, previously treated with corticosteroids). [Figure 5A] Figure 5A shows the effect of mAb5 at 3, 10, 30, and 100 μg / mL on IL-11 (10 ng / mL)-induced HA release from orbital fibroblasts from patient samples #2, #4, and #5 (Figure 5A, no prior TED treatment). [Figure 5B] Figure 5B shows the effect of mAb5 at 3, 10, 30, and 100 μg / mL on IL-11 (10 ng / mL)-induced HA release from orbital fibroblasts from patient sample #1 (Figure 5B, previously treated with teprotumumab). [Figure 5C] FIG. 5C shows the effect of mAb5 at 3, 10, 30, and 100 μg / mL on IL-11 (10 ng / mL)-induced HA release from orbital fibroblasts of patient sample #3 (FIG. 5C, previously treated with corticosteroids). [Figure 6A] Figure 6A shows the comparative inhibitory effects of mAb5, teprotumumab, and an isotype control (all at 10 μg / mL) on HA release from orbital fibroblasts of TED patients induced by 10 ng / mL IL-11. Figure 6B shows the effect on naive patient samples (no prior TED treatment, n=4). [Figure 6B]Figure 6B shows the comparative inhibitory effects of mAb5, teprotumumab, and an isotype control (all at 10 μg / mL) on HA release from orbital fibroblasts of a TED patient induced by 10 ng / mL IL-11. Figure 6B shows the effect on a patient sample previously treated with teprotumumab (n=1). [Figure 6C] Figure 6C shows the comparative inhibitory effects of mAb5, teprotumumab, and an isotype control (all at 10 μg / mL) on HA release from orbital fibroblasts of TED patients induced by 10 ng / mL IL-11. Figure 6C shows the effect on patient samples previously treated with corticosteroids (n=2). [Figure 7A] Figure 7A shows the comparative effect of mAb 5 teprotumumab (and an isotype control antibody, all at 10 μg / mL) on the expansion of orbital fibroblasts from TED patients induced by 10 ng / mL IL-11. Figure 7B shows the effect on naive patient samples (no prior TED treatment, n=4). [Figure 7B] Figure 7B shows the comparative effect of mAb 5 teprotumumab (and an isotype control antibody, all at 10 μg / mL) on the expansion of orbital fibroblasts from TED patients induced by 10 ng / mL IL-11. Figure 7B shows the effect on a patient sample previously treated with teprotumumab (n=1). [Figure 7C] Figure 7C shows the comparative effect of mAb 5 teprotumumab (and an isotype control antibody, all at 10 μg / mL) on the expansion of orbital fibroblasts from TED patients induced by 10 ng / mL IL-11. Figure 7C shows the effect on patient samples previously treated with corticosteroids (n=2). [Figure 8A] FIG. 8A shows that mAb5 has a binding affinity of approximately 37 pm for human IL-11Rα (FIG. 8A). [Figure 8B] FIG. 8B shows that the 340 antibody has a significantly weaker (about 35-fold weaker) binding affinity for human IL-11Rα at about 1.3 nM (FIG. 8B). [Figure 9A]FIG. 9A shows that mAb5 (FIG. 9A) has strong functional potency as measured by pSTAT3 inhibition. [Figure 9B] FIG. 9B shows that mAb29 (FIG. 9B) has strong functional potency as measured by pSTAT3 inhibition. [Figure 9C] In contrast, the 340 antibody (FIG. 9C) showed no functional activity in this assay. [Figure 10] Figure 10 shows the effect of the combination of mAb5 and teprotumumab on HA release in orbital fibroblasts after stimulation with IL-11 and IGF-1. Data are from n≧8 donors from two separate experiments. ####p<0.0001 compared to vehicle, ***p<0.001 compared to IGF-1 and IL-11, ****p<0.0001, and Φp<0.05 compared to the combination of teprotumumab and mAb5 by one-way ANOVA with Dunnett's post-hoc test. IGF-1 (100 ng / mL), IL-11 (10 ng / mL), mAb5 (10 μg / mL), and teprotumumab (10 μg / mL). [Figure 11A] FIG. 11A shows the dose-response curve of mAb5 as measured by its effect on pSTAT3 (FIG. 11A) in orbital fibroblasts from TED patients. [Figure 11B] FIG. 11B shows the dose-response curve for mAb5 as measured by its effect on HA release (FIG. 11B) in orbital fibroblasts from TED patients. [Figure 12A] Figure 12A shows the release of type I procollagen (ng / mL) by orbital fibroblasts from n=6 TED donors stimulated with TGFβ (5 ng / mL) for 96 hours. ###p<0.001 compared to vehicle, **p<0.01 compared to TGFβ by one-way ANOVA with Dunnett's post hoc multiple comparison test. [Figure 12B]Figure 12B shows inhibition of TGFβ-stimulated type I procollagen release (ng / mL) by orbital fibroblasts from n=6 TED donors preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour and then stimulated with human recombinant TGFβ (5 ng / mL) for an additional 96 hours. ###p<0.001 compared to vehicle and **p<0.01 compared to TGFβ by one-way ANOVA with Dunnett's post hoc multiple comparisons test. [Figure 13-1] Figure 13 shows the ability of mAb5 to reduce multiple cytokines in orbital fibroblasts after stimulation with IL-11 and IGF-1. Cytokine release by human orbital fibroblasts preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour before stimulation with either human recombinant cytokine, followed by an additional 96-hour stimulation with a combination of IL-11 and IGF-1 (100 ng / mL). Cell supernatants were measured by multiplex analysis at Eve Technologies (Calgary, Canada), and data are shown as individual replicates from n=6 TED patients for each treatment. [Figure 13-2] Figure 13 shows the ability of mAb5 to reduce multiple cytokines in orbital fibroblasts after stimulation with IL-11 and IGF-1. Cytokine release by human orbital fibroblasts preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour before stimulation with either human recombinant cytokine, followed by an additional 96-hour stimulation with a combination of IL-11 and IGF-1 (100 ng / mL). Cell supernatants were measured by multiplex analysis at Eve Technologies (Calgary, Canada), and data are shown as individual replicates from n=6 TED patients for each treatment. [Figure 14A]Figure 14A shows the ability of mAb5 to inhibit IL-6 and MCP-1 / CCL2 release more effectively than teprotumumab. IL-6 (Figure 14A) release by human orbital fibroblasts preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour, followed by stimulation with a combination of human recombinant IL-11 (10 ng / mL, Figure 14A) for an additional 96 hours. Data represent the mean ± SEM of n=6 TED patients, compared by one-way ANOVA with Dunnett's post-hoc comparison test. Compared to vehicle control, ###, p<0.001; ####p<0.0001. Compared to isotype control alone, ****p<0.05; **p<0.01; ****p<0.0001 by one-way ANOVA with Dunnett's post-hoc multiple comparison test. [Figure 14B] Figure 14B shows the ability of mAb5 to inhibit IL-6 and MCP-1 / CCL2 release more effectively than teprotumumab. IL-6 (Figure 14B) release by human orbital fibroblasts preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour, followed by stimulation with a combination of IL-11 and IGF-1 (100 ng / mL, Figure 14B) for an additional 96 hours. Data represent the mean ± SEM of n=6 TED patients, compared by one-way ANOVA with Dunnett's post-hoc comparison test. Compared to vehicle control, ###, p<0.001; ####p<0.0001. Compared to isotype control alone, ****p<0.05; **p<0.01; ****p<0.0001 by one-way ANOVA with Dunnett's post-hoc multiple comparison test. [Figure 14C]Figure 14C shows the ability of mAb5 to inhibit IL-6 and MCP-1 / CCL2 release more effectively than teprotumumab. Release of MCP-1 (Figure 14C) by human orbital fibroblasts preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour, followed by stimulation with a combination of human recombinant IL-11 (10 ng / mL, Figure 14C) for an additional 96 hours. Data represent the mean ± SEM of n=6 TED patients, compared by one-way ANOVA with Dunnett's post-hoc comparison test. Compared to vehicle control, ###, p<0.001; ####p<0.0001. Compared to isotype control alone, ****p<0.05; **p<0.01; ****p<0.0001 by one-way ANOVA with Dunnett's post-hoc multiple comparison test. [Figure 14D] Figure 14D shows the ability of mAb5 to inhibit IL-6 and MCP-1 / CCL2 release more effectively than teprotumumab. Release of MCP-1 (Figure 14D) by human orbital fibroblasts preincubated with mAb5 (3 μg / mL) or teprotumumab (10 μg / mL) for 1 hour followed by stimulation with a combination of IL-11 and IGF-1 (100 ng / mL, Figure 14D) for an additional 96 hours. Data represent the mean ± SEM of n=6 TED patients compared by one-way ANOVA with Dunnett's post-hoc comparison test. Compared to vehicle control, ###, p<0.001; ####p<0.0001. Compared to isotype control alone, ****p<0.05; **p<0.01; ****p<0.0001 by one-way ANOVA with Dunnett's post-hoc multiple comparison test. [Figure 15] Figure 15 shows a panel of commercially available antibodies against IL-11 and IL-11Rα compared to mAb5 for their ability to inhibit HA production from TED donor orbital fibroblasts stimulated with IL-11 and IL-1. Antibodies against IL-11 are shown in dark gray bars, and antibodies against IL-11Rα are shown in black bars. [Figure 16]Figure 16 shows the partial sequence of IL-11Rα, with the epitope of mAb5 indicated. Epitope mapping of mAb5 was performed using two mass spectrometry methods. The epitope identified by HDX-MS spans residues 115-134 of mature IL-11Rα and is shown in bold text. Crosslinks identified by XL-MS are shown at positions S138, S147, K151, S162, and T165, indicating that these residues are at or near the mAb5 epitope. [Figure 17A] Figure 17A shows that anti-IL-11Rα mAb5 is effective in inhibiting IL-11 and hyper-IL-11 signaling. Inhibition of STAT3 phosphorylation was tested using a luciferase reporter assay. Figure 17A shows inhibition of IL-11 signaling induced by the addition of IL-11. The solid line and circle symbols represent data using mAb5, and the dashed line and triangle symbols represent data using anti-IL-11 mAb. Symbols and lines are shown for each antibody in Figure 17A. mAb5 effectively inhibited signaling in both assays, whereas anti-IL-11 mAb was effective in inhibiting IL-11-induced signaling but not hyper-IL-11 (a complex of soluble receptor IL-11). [Figure 17B] Figure 17B shows that anti-IL-11Rα mAb5 is effective in inhibiting IL-11 and hyper-IL-11 signaling. Inhibition of STAT3 phosphorylation was tested using a luciferase reporter assay. Figure 17B shows the inhibition of hyper-IL-11-induced STAT3 phosphorylation. mAb5 effectively inhibits signaling in both assays, whereas anti-IL-11 mAb is effective in inhibiting IL-11-induced signaling, but hyper-IL-11 (a complex of soluble receptor IL-11) is not. [Figure 18]Figure 18 shows the ability of mAb5 to reduce HA production by TED orbital fibroblasts stimulated by M22. HA release by human orbital fibroblasts preincubated with mAb5 (1 or 10 μg / mL) or teprotumumab (10 μg / mL) for 1 hour and then stimulated with the TSHR agonist antibody M22. Three donors were used, and data are expressed as mean HA levels (ng / mL). Stimulation by M22 is indicated by dotted and dashed lines. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present disclosure relates to a method of treating thyroid eye disease (TED) in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or antigen-binding fragment thereof that binds to human interleukin-11 receptor subunit alpha (IL-11Rα). In some embodiments, the antibody or antigen-binding fragment thereof binds to fibronectin domain III of human IL-11Rα or binds to the second extracellular domain of IL-11Rα and antagonizes the binding and / or signaling activity between IL-11Rα and IL-11. Examples of antibodies and antigen-binding fragments thereof are described herein.

[0040] The practice of the present disclosure will employ, unless specifically indicated to the contrary, conventional methods of virology, immunology, microbiology, molecular biology, and recombinant DNA technology within the skill of the art, many of which are described below for illustrative purposes. Such techniques are fully explained in the literature. See, for example, Current Protocols in Molecular Biology or Current Protocols in Immunology, John Wiley & Sons, New York, NY (2009); Ausubel et al., Short Protocols in Molecular Biology, 3 rded., Wiley & Sons, 1995; Sambrook and Russell, Molecular Cloning: A Laboratory Manual (3rd Edition, 2001); Maniatis et al. Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A Practical Approach, vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., 1985); Transcription and Translation (B. Hames & S. Higgins, eds., 1984); Animal Cell Culture (R. Freshney, ed., 1986); Perbal, A Practical Guide to Molecular Cloning (1984), and other similar references.

[0041] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise.

[0042] By "about" is meant an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to the reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0043] The term "antigen" refers to a molecule or portion of a molecule that can be bound by a selective binding agent, such as an antibody, and can be used in an animal to generate antibodies capable of binding to an epitope of that antigen. An antigen may have one or more epitopes. As used herein, the term "antigen" includes a substance that, under appropriate conditions, is capable of inducing an immune response against the substance and reacting with the products of the immune response. For example, an antigen can be recognized by antibodies (humoral immune response) or sensitized T lymphocytes (T helper or cell-mediated immune response), or both. Antigens can be soluble substances, such as toxins and foreign proteins, or microparticles, such as bacteria and tissue cells; however, only portions of a protein or polysaccharide molecule, known as an antigenic determinant (epitope), combine with antibodies or specific receptors on lymphocytes. More broadly, the term "antigen" includes any substance to which an antibody binds or for which an antibody is desired, regardless of whether the substance is immunogenic. For such antigens, antibodies can be identified by recombinant methods, independent of any immune response.

[0044] "Antagonist" refers to an agent (e.g., an antibody) that interferes with or otherwise reduces the physiological action of another agent or molecule. In some instances, antagonists specifically bind to other agents or molecules. Included are full and partial antagonists.

[0045] "Agonist" refers to an agent (e.g., an antibody) that increases or enhances the physiological effect of another agent or molecule. In some instances, agonists specifically bind to other agents or molecules. Included are full and partial agonists.

[0046] As used herein, the term "amino acid" is intended to refer to both natural and unnatural amino acids, as well as amino acid analogs and mimetics. Natural amino acids include the 20 (L) amino acids utilized during protein biosynthesis, as well as others, such as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, homocysteine, citrulline, and ornithine. Unnatural amino acids include, for example, (D)-amino acids, norleucine, norvaline, p-fluorophenylalanine, ethionine, and the like, which are known to those skilled in the art. Amino acid analogs include modified forms of natural and unnatural amino acids. Such modifications can include, for example, the substitution or exchange of chemical groups and moieties on the amino acid or by derivatization of the amino acid. Amino acid mimetics include, for example, organic structures that exhibit functionally similar properties, such as the charge and charge-spacing characteristics of the reference amino acid. For example, an organic structure that mimics arginine (Arg or R) will have a positively charged portion positioned in a similar molecular space and with the same degree of flexibility as the e-amino group of the side chain of the natural Arg amino acid. Mimetics also include structures that are constrained to maintain optimal spacing and charge interactions of amino acids or amino acid functional groups. Those skilled in the art will know or be able to determine which structures constitute functionally equivalent amino acid analogs and amino acid mimetics.

[0047] As used herein, the term "antibody" includes not only intact polyclonal or monoclonal antibodies, but also fragments thereof (e.g., dAb, Fab, Fab', F(ab'), Fv, etc.), single chain (scFv), synthetic variants thereof, naturally occurring variants, fusion proteins comprising an antibody portion with an antigen-binding fragment of the required specificity, humanized antibodies, chimeric antibodies, and any other modified configuration of an immunoglobulin molecule that contains an antigen-binding site or fragment (epitope-recognition site) of the required specificity. Specific features and characteristics of antibodies (and antigen-binding fragments thereof) are described in more detail herein.

[0048] The antibody or antigen-binding fragment can be of essentially any type. As is well known in the art, an antibody is an immunoglobulin molecule capable of specifically binding to a target, such as an immune checkpoint molecule, through at least one epitope recognition site located in the variable region of the immunoglobulin molecule.

[0049] As used herein, the term "antigen-binding fragment" refers to a polypeptide fragment that contains at least one CDR of an immunoglobulin heavy chain and / or light chain that binds to an antigen of interest. In this regard, an antigen-binding fragment of an antibody described herein is a V CDR from an antibody that binds to a target molecule. H and V L In certain embodiments, the antigen-binding fragments of the present disclosure may comprise one, two, three, four, five, or all six CDRs of the V of an antibody disclosed herein. H Array and V L The sequence includes all six CDRs.

[0050] The binding properties of antibodies and antigen-binding fragments thereof can be quantified using methods well known in the art (see Davies et al., Annual Rev. Biochem. 59:439-473, 1990). In some embodiments, the antibody or antigen-binding fragment thereof binds to a target molecule, e.g., an IL-11Rα polypeptide or epitope or complex thereof, with a binding affinity of about ≦10 -7 M ~ about 10 -8 M. In some embodiments, the equilibrium dissociation constant is about ≦10 -9 M~approx.≦10 -10In certain exemplary embodiments, the antibody or antigen-binding fragment thereof has an affinity (K) for the target molecule (to which it specifically binds) of less than about, at least about, or about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 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, 40, or 50 nM. D or EC 50 )

[0051] A molecule, such as a polypeptide or antibody, is said to exhibit "specific binding" or "preferential binding" if it reacts or associates with a particular cell, substance, or particular epitope more frequently, more rapidly, with greater duration, and / or with greater affinity than it does with alternative cells, substances, or epitopes. An antibody "specifically binds" or "preferentially binds" to a target molecule or epitope if it binds, for example, by a statistically significant amount, with greater affinity, avidity, more readily, and / or with longer duration than it binds to other substances or epitopes. Typically, one member of a pair of molecules exhibiting specific binding has a region or cavity on its surface that specifically binds to, and is therefore complementary to, a particular spatial and / or polar structure of the other member of the pair of molecules. In this way, the members of the pair have the property of specifically binding to each other. For example, an antibody that specifically or preferentially binds to a specific epitope is one that binds to that specific epitope with greater affinity, avidity, more readily, and / or with longer duration than it binds to other epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. This term is also applicable, for example, when an antibody is specific for a particular epitope carried by multiple antigens, in which case a specific binding member carrying an antigen-binding fragment or domain can bind to various antigens that carry the epitope; for example, it may be cross-reactive with multiple different forms of a target antigen from multiple species that share a common epitope.

[0052] Immunological binding generally refers to the type of non-covalent interaction that occurs between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific, for example, by way of illustration and not limitation, as a result of electrostatic, ionic, hydrophilic and / or hydrophobic attractions or repulsions, steric forces, hydrogen bonding, van der Waals forces, and other interactions. The strength, or affinity, of an immunological binding interaction is determined by the dissociation constant (K D ) and smaller K D represents a greater affinity. The immunological binding properties of a selected polypeptide can be quantified using methods well known in the art. One such method involves measuring the rates of antigen-binding site / antigen complex formation and dissociation, where these rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that affect the rates equally in both directions. In this way, both the "on-rate constant" (Kon) and the "dissociation rate constant" (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. The ratio of Koff / Kon allows for the removal of all parameters not related to affinity, and thus the dissociation constant K D As used herein, the term "affinity" includes the equilibrium constant for the reversible binding of two drugs, K D or EC 50 The affinity of a binding protein to a ligand, such as the affinity of an antibody for an epitope, can be, for example, about 100 nanomolar (nM) to about 0.1 nM, about 100 nM to about 1 picomolar (pM), or about 100 nM to about 1 femtomolar (fM). As used herein, the term "avidity" refers to the resistance of a complex of two or more agents to dissociation after dilution. In some embodiments, affinity is measured using the half-maximal effective concentration (EC 50 ) and refers to the concentration of an agent, such as an antibody disclosed herein, or an anti-IL-11Rα antibody, that induces a response halfway between baseline and maximum after a particular exposure time. 50 is commonly used as a measure of antibody potency.

[0053] Antibodies can be prepared by any of a variety of techniques known to those of skill in the art. See, e.g., Harlow and Lane, *Antibodies: A Laboratory Manual*, Cold Spring Harbor Laboratory, 1988. Monoclonal antibodies specific for a polypeptide of interest can be prepared, for example, using the techniques of Kohler and Milstein, *Eur. J. Immunol.* 6:511-519*, and modifications thereto. Also included are methods for expressing human antibodies using transgenic animals, such as mice. See, e.g., Neuberger et al., *Nature Biotechnology* 14:826, 1996; Lonberg et al., *Handbook of Experimental Pharmacology* 113:49-101, 1994; and Lonberg et al., *Internal Review of Immunology* 13:65-93, 1995. A particular example includes the VELOCIMMUNE® platform by REGENEREX® (see, eg, US Pat. No. 6,596,541).

[0054] Antibodies can also be generated or identified using phage display libraries or yeast display libraries (see, e.g., U.S. Patent No. 7,244,592; Chao et al., Nature Protocols. 1:755-768, 2006). Non-limiting examples of available libraries include cloned or synthetic libraries, such as the human combinatorial antibody library (HuCAL), in which the structural diversity of the human antibody repertoire is represented by seven heavy chain and seven light chain variable region genes. Combinations of these genes generate 49 frameworks in the master library. By stacking highly variable gene cassettes (CDRs = complementarity-determining regions) on these frameworks, a vast human antibody repertoire can be reproduced. Also included are human libraries designed using human donor-supplied fragments encoding the light chain variable region, synthetic DNA encoding the heavy chain CDR-3, heavy chain CDR-1 diversity, and synthetic DNA encoding the heavy chain CDR-2 diversity. Other libraries suitable for use will be apparent to those skilled in the art.

[0055] In certain embodiments, the antibodies and antigen-binding fragments thereof described herein comprise a set of heavy and light chain CDRs, each inserted between a set of heavy and light chain framework regions (FRs), which provide support for the CDRs and define the spatial relationship of the CDRs to each other. As used herein, the term "CDR set" refers to the three hypervariable regions of a heavy or light chain V region. Proceeding from the N-terminus of the heavy or light chain, these regions are designated "CDR1," "CDR2," and "CDR3," respectively. An antigen-binding site therefore comprises six CDRs, including a set of CDRs from each of the heavy and light chain V regions. A polypeptide comprising a single CDR (e.g., CDR1, CDR2, or CDR3) is referred to herein as a "molecular recognition unit." Crystallographic analysis of numerous antigen-antibody complexes has demonstrated that the amino acid residues of the CDRs form extensive contacts with the bound antigen, with the most extensive antigen contacts being with the heavy chain CDR3. Thus, the molecular recognition unit is primarily responsible for the specificity of the antigen-binding site.

[0056] As used herein, the term "FR set" refers to four adjacent amino acid sequences that frame the CDRs of a CDR set of a heavy or light chain V region. Some FR residues may contact the bound antigen; however, FRs are primarily involved in folding the V region into the antigen-binding site, particularly the FR residues directly adjacent to the CDRs. Within FRs, certain amino acid residues and certain structural features are highly conserved. In this regard, most V region sequences contain an internal disulfide loop of approximately 90 amino acid residues. When the V region folds into the binding site, the CDRs are presented as protruding loop motifs that form the antigen-binding surface. Regardless of the exact CDR amino acid sequence, it is generally recognized that conserved structural regions of FRs that affect the folded shape of the CDR loops exist in certain "canonical" structures. Furthermore, certain FR residues are known to participate in non-covalent interdomain contacts that stabilize the interaction of antibody heavy and light chains.

[0057] The structure and location of immunoglobulin variable domains can be determined by reference to Kabat, EA et al., Sequences of Proteins of Immunological Interest. 4th Edition. U.S. Department of Health and Human Services, 1987, and updates thereof.

[0058] Also included are monoclonal antibodies, which refer to homogeneous antibody populations composed of amino acids (natural and non-natural) involved in selective binding of an epitope. The term "monoclonal antibody" encompasses not only intact and full-length monoclonal antibodies, but also fragments thereof (e.g., Fab, Fab', F(ab')2, Fv, etc.), single chain (scFv), variants thereof, fusion proteins containing the antigen-binding portion, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of an immunoglobulin molecule containing an antigen-binding fragment (epitope recognition site) of the required specificity and ability to bind to the epitope. It is not intended to be limited with regard to the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals). The term includes whole immunoglobulins, as well as fragments such as those described above under the definition of "antibody."

[0059] The proteolytic enzyme papain preferentially cleaves IgG molecules to produce several fragments, two of which (F(ab) fragments) each comprise a covalently linked heterodimer containing an intact antigen-binding site. The enzyme pepsin can cleave IgG molecules to provide several fragments, including the F(ab')2 fragment, which contains both antigen-binding sites. Fv fragments for use according to certain embodiments can be produced by preferential proteolytic cleavage of IgM, and in rare cases, IgG or IgA immunoglobulin molecules. Fv fragments, however, are more commonly derived using recombinant techniques known in the art. Fv fragments comprise a noncovalent VH::VL heterodimer containing an antigen-binding site that retains much of the antigen recognition and binding capabilities of a native antibody molecule (Inbar et al., PNAS USA. 69:2659-2662, 1972; Hochman et al., Biochem. 15:2706-2710, 1976; and Ehrlich et al., Biochem. 19:4091-4096, 1980). In some embodiments, the Fv is stabilized by other means, such as the incorporation of at least one disulfide bond (Worn & Pluckthun, J. Mol. Biol. 305, 989-1010, 2001).

[0060] In certain embodiments, single-chain Fv (scFv) antibodies are contemplated. For example, kappabodies (Ill et al., Prot. Eng. 10:949-57, 1997); minibodies (Martin et al., EMBO J 13:5305-9, 1994); diabodies (Holliger et al., PNAS 90:6444-8, 1993); or Janusins ​​(Traunecker et al., EMBO J 10:3655-59, 1991; and Traunecker et al., Int. J. Cancer Suppl. 7:51-52, 1992) can be prepared using standard molecular biology techniques following the teachings of the present application for selecting antibodies with the desired specificity.

[0061] Single-chain Fv (scFv) polypeptides are covalently linked VH::VL heterodimers expressed from gene fusions containing VH and VL-encoding genes connected by a peptide-encoding linker. Huston et al. (PNAS USA. 85(16):5879-5883, 1988). Numerous methods have been described for identifying chemical structures for converting naturally aggregated but chemically separated light and heavy polypeptide chains from antibody V regions into scFv molecules that fold into a three-dimensional structure substantially similar to that of an antigen-binding site. See, for example, U.S. Patent Nos. 5,091,513 and 5,132,405 to Huston et al. and U.S. Patent No. 4,946,778 to Ladner et al.

[0062] In certain embodiments, the antibodies or antigen-binding fragments described herein are in the form of "diabodies." Diabodies are multimers of polypeptides, each of which contains a first domain comprising an immunoglobulin light chain binding region and a second domain comprising an immunoglobulin heavy chain binding region, the two domains being linked (e.g., by a peptide linker) but unable to associate with each other to form an antigen-binding site; the antigen-binding site is formed by the association of a first domain of one polypeptide in the multimer with a second domain of another polypeptide in the multimer (WO 94 / 13804). A dAb fragment of an antibody consists of a VH domain (Ward et al., Nature 341:544-546, 1989). Diabodies and other multivalent or multispecific fragments can be constructed, for example, by gene fusion (see WO 94 / 13804; and Holliger et al., PNAS USA. 90:6444-6448, 1993).

[0063] Also included are minibodies comprising scFvs linked to CH3 domains (see Hu et al., Cancer Res. 56:3055-3061, 1996). See also Ward et al., Nature. 341:544-546, 1989; Bird et al., Science. 242:423-426, 1988; Huston et al., PNAS USA. 85:5879-5883, 1988); PCT / US92 / 09965; WO94 / 13804; and Reiter et al., Nature Biotech. 14:1239-1245, 1996.

[0064] Where bispecific antibodies are used, they may be conventional bispecific antibodies, which can be produced in a variety of ways (Holliger and Winter, Current Opinion Biotechnol. 4:446-449, 1993), for example, prepared chemically or from hybridomas, or may be any of the bispecific antibody fragments mentioned above.

[0065] Bispecific diabodies, in contrast to bispecific whole antibodies, can also be particularly useful because they can be easily constructed and expressed in E. coli. Diabodies (and many other polypeptides, such as antibody fragments) of suitable binding specificities can be easily selected using phage display (WO94 / 13804) from libraries. A library can be created in which one arm of the diabody is held constant, for example, with specificity directed against antigen X, and then the other arm is varied to select antibodies of suitable specificity. Bispecific whole antibodies can be generated by a number of methods, including knob-into-hole engineering (Brinkman & Kontermann, mAbs 9:182-212, 2017) (Ridgeway et al., Protein Eng. 9:616-621, 1996).

[0066] In certain embodiments, the antibodies or antigen-binding fragments described herein are in the form of a UniBody®. A UniBody® is an IgG4 antibody with the hinge region removed (see GenMab Utrecht, The Netherlands; see also US20090226421). This antibody technology creates a stable, smaller antibody format with an expected longer therapeutic window than current small antibody formats. IgG4 antibodies are considered inert and thus do not interact with the immune system. Fully human IgG4 antibodies can be engineered by removing the hinge region of the antibody to obtain half-molecule fragments with different stability characteristics compared to the corresponding intact IgG4 (GenMab, Utrecht). Halving the IgG4 molecule leaves only one region on the UniBody® that can bind to the cognate antigen (e.g., disease target); therefore, the UniBody® binds monovalently to only one site on the target cell.

[0067] In certain embodiments, the antibodies and antigen-binding fragments described herein are in the form of Nanobodies. Nanobodies are encoded by a single gene and are efficiently produced in almost all prokaryotic and eukaryotic hosts, such as Escherichia coli (see U.S. Pat. No. 6,765,087), molds (e.g., Aspergillus or Trichoderma), and yeasts (e.g., Saccharomyces, Kluyveromyces, Hansenula, or Pichia (see U.S. Pat. No. 6,838,254). The production process is scalable, and multi-kilogram quantities of Nanobodies have been produced. Nanobodies can be formulated as a ready-to-use solution with a long shelf life. The Nanoclone method (see WO 06 / 079372) is a proprietary method for generating Nanobodies against desired targets based on automated high-throughput selection of B cells.

[0068] In some embodiments, the antibodies or antigen-binding fragments described herein are in the form of aptamers (see, e.g., Ellington et al., Nature. 346, 818-22, 1990; and Tuerk et al., Science. 249, 505-10, 1990, which are incorporated by reference). Examples of aptamers include nucleic acid aptamers (e.g., DNA aptamers, RNA aptamers) and peptide aptamers. Nucleic acid aptamers generally refer to nucleic acid species that are engineered through repeated rounds of in vitro selection or equivalent methods, such as SELEX (systematic evolution of ligands by exponential enrichment), to bind to various molecular targets, such as small molecules, proteins, nucleic acids, and even cells, tissues, and organisms. See, e.g., U.S. Patent Nos. 6,376,190 and 6,387,620, which are incorporated by reference.

[0069] Peptide aptamers typically contain a variable peptide loop attached at both ends to a protein scaffold, typically a dual structural constraint that increases the binding affinity of the peptide aptamer to levels comparable to those of antibodies (e.g., in the nanomolar range). In certain embodiments, the variable loop length may be comprised of approximately 10 to 20 amino acids (including all integers therebetween), and the scaffold may comprise any protein with good solubility and compaction properties. Certain exemplary embodiments utilize the bacterial protein thioredoxin-A as the scaffold protein, with the variable loop inserted into the reducing active site (the -Cys-Gly-Pro-Cys-loop in the wild-type protein), and two cysteine ​​side chains capable of forming disulfide bridges. Methods for identifying peptide aptamers are described, for example, in U.S. Patent Application Publication No. 2003 / 0108532, which is incorporated by reference. Peptide aptamer selection can be performed using different systems known in the art, including the yeast two-hybrid system.

[0070] In some embodiments, the antibodies or antigen-binding fragments described herein are in the form of avimers. Avimers refer to multimeric binding proteins or peptides engineered using in vitro exon shuffling and phage display. Multiple binding domains are linked, resulting in greater affinity and specificity compared to single-epitope immunoglobulin domains. See, for example, Silverman et al., Nature Biotechnology. 23:1556-1561, 2005; U.S. Patent No. 7,166,697; and U.S. Patent Application Nos. 2004 / 0175756, 2005 / 0048512, 2005 / 0053973, 2005 / 0089932, and 2005 / 0221384, which are incorporated by reference. (a) In some embodiments, the antibodies or antigen-binding fragments described herein are in the form of Adnectins. Adnectins refer to a class of targeted biologics derived from human fibronectin, an abundant extracellular protein that naturally binds to other proteins. See, for example, U.S. Patent Applications Nos. 2007 / 0082365; 2008 / 0139791; and 2008 / 0220049, which are incorporated by reference. Adnectins typically consist of a natural fibronectin backbone and multiple targeting domains of specific portions of human fibronectin. The targeting domains can be engineered to enable the Adnectin to specifically recognize an IL-11Rα polypeptide or an epitope thereof.

[0071] In some embodiments, the antibodies or antigen-binding fragments described herein are in the form of anticalins. Anticalins refer to a class of antibody mimics typically synthesized from human lipocalins, a family of binding proteins with hypervariable loop regions supported by a structurally rigid framework. See, for example, U.S. Patent Application No. 2006 / 0058510. Anticalins typically have a size of approximately 20 kDa. Anticalins can be characterized by a barrel structure formed by eight antiparallel β-strands (a stable β-barrel scaffold) connected in pairs by four peptide loops and attached α-helices. In certain aspects, conformational deviations are created in the hypervariable loop regions to achieve specific binding. See, for example, Skerra, FEBS J. 275:2677-83, 2008, incorporated by reference.

[0072] In some embodiments, the antibodies or antigen-binding fragments described herein are in the form of designed ankyrin repeat proteins (DARPins). DARPins comprise a class of non-immunoglobulin proteins that may offer advantages over antibodies in target binding in drug discovery and development. Among other applications, DARPins are ideally suited for in vivo imaging or delivery of toxins or other therapeutic payloads due to their favorable molecular properties, including small size and high stability. Low-cost production in bacteria and rapid generation of many target-specific DARPins make the DARPin approach useful for drug discovery. In addition, DARPins can be easily produced in multispecific formats, offering the potential to target effector DARPins to specific organs or target multiple receptors with a single molecule composed of several DARPins. See, e.g., Stumpp et al., Curr Opin Drug Discov Devel. 10:153-159, 2007; U.S. Patent Application No. 2009 / 0082274; and PCT / EP2001 / 10454, which are incorporated by reference.

[0073] Also included are heavy chain dimers, such as antibodies from camelids and sharks. Camelid and shark antibodies contain two homodimeric pairs of V-like and C-like domains (neither of which has a light chain). The V of heavy chain dimers in camelids is H Because the heavy chains do not need to make hydrophobic interactions with the light chains, the regions of the heavy chains that normally contact the light chains are changed to hydrophilic amino acid residues in camelids. The VH domains of heavy chain dimer IgGs are called VHH domains. Shark Ig-NARs contain a homodimer of one variable domain (called the V-NAR domain) and five C-like constant domains (C-NAR domains).

[0074] In camelids, the diversity of the antibody repertoire is determined by complementarity-determining regions (CDRs) 1, 2, and 3 in the VH or VHH regions. CDR3 in camelid VHH regions is characterized by its relatively long length, averaging 16 amino acids (Muyldermans et al., 1994, Protein Engineering 7(9):1129). This contrasts with the CDR3 regions of antibodies from many other species. For example, the CDR3 of mouse VH has an average of 9 amino acids. Libraries of camelid-derived antibody variable regions maintain the in vivo diversity of camelid variable regions and can be generated, for example, by the method disclosed in U.S. Patent Application No. 20050037421, published February 17, 2005.

[0075] In certain embodiments, the antibody or antigen-binding fragment thereof is humanized. These embodiments generally refer to chimeric molecules, prepared using recombinant techniques, having an antigen-binding site derived from an immunoglobulin from a non-human species and the remaining immunoglobulin structure of the molecule based on the structure and / or sequence of a human immunoglobulin. The antigen-binding site may comprise either a complete variable domain fused onto a constant domain, or only CDRs (whole or part) grafted onto appropriate framework regions in the variable domain. The epitope-binding site may be wild-type or modified by one or more amino acid substitutions. This eliminates the constant region as an immunogen in human individuals, although the possibility of an immune response to the foreign variable region remains (LoBuglio et al., PNAS USA 86:4220-4224, 1989; Queen et al., PNAS USA. 86:10029-10033, 1988; Riechmann et al., Nature. 332:323-327, 1988). Exemplary methods for antibody humanization include those described in US Pat. No. 7,462,697.

[0076] Another approach focuses not only on providing human-derived constant regions, but also on modifying the variable regions and reshaping them as closely as possible to human form. Both heavy and light chain variable regions are known to contain three complementarity-determining regions (CDRs) that vary in response to the epitope in question and determine binding ability, flanked by four framework regions (FRs) that are relatively conserved in a given species and presumably provide a scaffold for the CDRs. When a non-human antibody is prepared for a specific epitope, the variable region can be reshaped or humanized by grafting CDRs derived from the non-human antibody onto the FRs present in the modified human antibody. Application of this approach to various antibodies has been reviewed by Sato et al., Cancer Res. 53:851-856, 1993; Riechmann et al., Nature 332:323-327, 1988; Verhoeyen et al., Science 239:1534-1536, 1988; Kettleborough et al., Protein Engineering. 4:773-3783, 1991; Maeda et al., Human Antibodies Hybridoma 2:124-134, 1991; Gorman et al., PNAS USA. 88:4181-4185, 1991; Tempest et al., Bio / Technology 9:266-271, 1991; Co et al., PNAS USA. 88:2869-2873, 1991; Carter et al., PNAS USA. 89:4285-4289, 1992; and Co et al., J. Immunol. 148:1149-1154, 1992. In some embodiments, a humanized antibody retains all CDR sequences (e.g., a humanized mouse antibody containing all six CDRs from the mouse antibody). In some embodiments, only a portion of the CDR sequences are transplanted from a non-human antibody (Bowers et al., J. Biol. Chem. 288:7688-7696, 2013).In certain embodiments, a humanized antibody has one or more CDRs (one, two, three, four, five, six) that are altered relative to the original antibody, also referred to as one or more CDRs "derived from" one or more CDRs of the original antibody.

[0077] In certain embodiments, the antibody is a chimeric antibody. In this regard, a chimeric antibody is composed of an antigen-binding fragment of an antibody operably linked or otherwise fused to a heterologous Fc portion of a different antibody. In certain embodiments, the Fc domain or heterologous Fc domain is of human origin. In certain embodiments, the Fc domain or heterologous Fc domain is of murine origin. In other embodiments, the heterologous Fc domain can be from an Ig class different from that of the parent antibody, including IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), and IgM. In further embodiments, the heterologous Fc domain can be composed of CH2 and CH3 domains derived from one or more of the different Ig classes. As described above for humanized antibodies, an antigen-binding fragment of a chimeric antibody can include only one or more of the CDRs of an antibody described herein (e.g., one, two, three, four, five, or six CDRs of an antibody described herein), or can include the entire variable domain (VL, VH, or both).

[0078] The term "bond" refers to a direct association between two molecules, for example, due to covalent, electrostatic, hydrophobic, and ionic and / or hydrogen-bonding interactions, including, for example, salt bridges and water bridges.

[0079] By "coding sequence" is meant any nucleic acid sequence that contributes to the code for the polypeptide product of a gene. In contrast, the term "non-coding sequence" refers to any nucleic acid sequence that does not directly contribute to the code for the polypeptide product of a gene.

[0080] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer or group of elements or integers.

[0081] "Consisting of" means including, but not limited to, everything that follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or essential, and that no other elements will be present. By "consisting essentially of," it is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or function specified in this disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or essential, but that other elements are optional and may or may not be present depending on whether they substantially affect the activity or function of the listed elements.

[0082] The term "effector function" in the context of an antibody, or "ADCC effector function," refers to the antibody's ability to interact with other arms of the immune system, including, for example, activation of the classical complement pathway or through Fc receptor engagement. The complement-dependent pathway is primarily driven by the interaction of C1q with the C1 complex and the clustered antibody Fc domain. Antibody-dependent cellular cytotoxicity (ADCC) is primarily driven by the interaction of Fc receptors (FcRs) on the surface of effector cells (natural killer cells, macrophages, monocytes, and eosinophils) that bind to the Fc region of IgG, which itself binds to the target cell. Fc receptors (FcRs) are key immunoregulatory receptors that connect antibody-mediated (humoral) immune responses to cellular effector functions. Receptors for all classes of immunoglobulins have been identified, including FcγR (IgG), FcεRI (IgE), FcαRI (IgA), FcμR (IgM), and FcδR (IgD). There are at least three receptor classes for human IgG found on leukocytes: CD64 (FcγRI), CD32 (FcγRIIa, FcγRIIb, and FcγRIIc), and CD16 (FcγRIIIa and FcγRIIIb). FcγRI is a high-affinity receptor (nanomolar range K D ), whereas FcγRII and FcγRIII have low to intermediate affinity (micromolar range K D Upon Fc binding, signaling pathways are triggered, leading to the secretion of various substances, such as lytic enzymes, perforin, granzymes, and tumor necrosis factor, which mediate the destruction of target cells. The level of ADCC effector function varies for human IgG subtypes. This is dependent on the allotype and the specific FcvR, but in simple terms, ADCC effector function is "high" for human IgG1 and IgG3, and "low" for IgG2 and IgG4.

[0083] The terms "endotoxin-free" or "substantially endotoxin-free" generally refer to compositions, solvents, and / or containers containing only trace amounts of endotoxin (e.g., amounts that have no clinically adverse physiological effects in a subject), and preferably undetectable amounts of endotoxin. Endotoxins are toxins associated with certain microorganisms, such as bacteria, typically gram-negative bacteria, although endotoxins can also be found in gram-positive bacteria, such as Listeria monocytogenes. The most common endotoxins are lipopolysaccharides (LPS) or lipooligosaccharides (LOS), found in the outer membrane of various gram-negative bacteria, which represent central pathogenic features in the ability of these bacteria to cause disease. Small amounts of endotoxin in humans can produce fever, a drop in blood pressure, and activation of inflammation and coagulation, among other adverse physiological effects.

[0084] Therefore, in pharmaceutical production, it is often desirable to remove most or all traces of endotoxin from the drug product and / or drug container, since even small amounts can cause adverse effects in humans. Dehydrogenation ovens can be used for this purpose, since temperatures above 300°C are typically required to decompose most endotoxins. For example, based on primary packaging materials such as syringes or vials, a glass temperature of 250°C in combination with a 30-minute hold time is often sufficient to achieve a 3-log reduction in endotoxin levels. Other methods of removing endotoxin are contemplated, including, for example, chromatography and filtration methods described herein and known in the art.

[0085] Endotoxin can be detected using routine techniques known in the art. For example, the Limulus amebocyte lysis assay utilizes blood from horseshoe crabs and is a highly sensitive assay for detecting the presence of endotoxin. In this test, very low levels of LPS can cause detectable clotting of the Limulus lysate due to a powerful enzyme cascade that amplifies this reaction. Endotoxin can also be quantified by enzyme-linked immunosorbent assay (ELISA). To be substantially endotoxin-free, endotoxin levels can be less than about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.08, 0.09, 0.1, 0.5, 1.0, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, or 10 EU / mg of active compound. Typically, 1 ng of lipopolysaccharide (LPS) corresponds to approximately 1-10 EU.

[0086] The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specific binding to an immunoglobulin or T-cell receptor. An epitope comprises the region of an antigen bound by an antibody. In certain embodiments, epitopic determinants include chemically active surface groupings of molecules, such as amino acids, sugar side chains, phosphoryls, or sulfonyls, and in certain embodiments, may have specific three-dimensional structural characteristics and / or specific charge characteristics. An epitope can be continuous or discontinuous with respect to the primary structure of an antigen, e.g., an IL-11Rα polypeptide. In certain embodiments, an epitope comprises, consists of, or consists essentially of about, at least about, or no more than about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids (i.e., a linear epitope) or non-contiguous amino acids (i.e., a conformational epitope) of a reference sequence (e.g., see Table B1) or target molecule described herein.

[0087] An "epitope" includes that portion of an antigen or other macromolecule that interacts with the variable region binding pocket of a binding protein and is capable of forming a binding interaction. Such a binding interaction may manifest as intermolecular contact with one or more amino acid residues of a CDR. Antigen binding may involve a CDR3 or CDR3 pair. An epitope can be a linear peptide sequence (i.e., "continuous") or can be composed of a discontinuous amino acid sequence (i.e., "conformational" or "discontinuous"). A binding protein can recognize more than one amino acid sequence; therefore, an epitope can define more than one distinct amino acid sequence. Epitopes recognized by binding proteins can be determined by peptide mapping and sequence analysis techniques well known to those skilled in the art. A "cryptic epitope" or "cryptic binding site" is an epitope or binding site of a protein sequence that is not exposed or is substantially protected from recognition in an unmodified polypeptide, but that can be recognized by a binding protein in a denatured or proteolytic polypeptide. The amino acid sequence that is not exposed or only partially exposed in the unmodified polypeptide structure is a potential cryptic epitope.If an epitope is not exposed or only partially exposed, then it is likely to be buried inside the polypeptide.Candidate cryptic epitopes can be identified, for example, by examining the three-dimensional structure of unmodified polypeptide.

[0088] The term "half maximum effective concentration" or "EC 50 " refers to the concentration of an agent (e.g., antibody) described herein that induces a response halfway between baseline and maximum after some specified exposure time; EC of a graded dose-response curve. 50 Therefore, EC50 represents the concentration of a compound at which 50% of its maximum effect is observed. EC50 also represents the plasma concentration required to obtain 50% of the maximum effect in vivo. Similarly, "EC 90 " refers to the concentration of an agent or composition at which 90% of its maximum effect is observed. 90 " is "EC 50and the Hill slope, or it can be determined directly from the data using routine knowledge in the art. In some embodiments, the EC 50 is less than about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, or 500 nM. In some embodiments, the agent has an EC50 value of about 1 nM or less.

[0089] "Immune response" refers to any immunological response derived from the immune system, including responses from the cellular and humeral, innate, and adaptive immune systems. Exemplary cellular immune cells include, for example, lymphocytes, macrophages, T cells, B cells, NK cells, neutrophils, eosinophils, dendritic cells, mast cells, monocytes, and all subsets thereof. Cellular responses include, for example, effector functions, cytokine release, phagocytosis, efferocytosis, translocation, trafficking, proliferation, differentiation, activation, suppression, cell-cell interactions, apoptosis, and the like. Humoral responses include, for example, IgG, IgM, IgA, IgE, responses, and their corresponding effector functions.

[0090] The "half-life" of a drug, such as an antibody, can refer to the time it takes for the drug to lose half of its pharmacological, physiological, or other activity, relative to such activity at the time of administration to the serum or tissues of an organism, or relative to any other defined time point. "Half-life" can also refer to the time it takes for the amount or concentration of the drug to decrease by half of the starting amount administered to the serum or tissues of an organism, relative to such amount or concentration at the time of administration to the serum or tissues of an organism, or relative to any other defined time point. Half-life can be measured in serum and / or in any one or more selected tissues.

[0091] The terms "modulating" and "altering" include "increasing," "enhancing," or "stimulating," as well as "decreasing," "reducing," or "inhibiting," typically in a statistically significant or physiologically significant amount or degree compared to a control. An "increased," "stimulated," or "enhanced" amount is typically a "statistically significant" amount and can include an increase that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more (e.g., 500, 1000-fold) (including all integers and ranges therebetween, e.g., 1.5, 1.6, 1.7, 1.8) than the amount produced by no composition (e.g., absence of agent) or a control composition. A "decreased" or "reduced" or "inhibited" amount is typically a "statistically significant" amount and can include a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease (including all integers and ranges therebetween) in the amount produced by no composition (e.g., absence of agent) or a control composition. Examples of comparisons and "statistically significant" amounts are described herein.

[0092] The terms "polypeptide," "protein," and "peptide" are used interchangeably and refer to a polymer of amino acids, not limited to any particular length. The term "enzyme" includes polypeptide or protein catalysts. This term includes modifications, such as myristoylation, sulfation, glycosylation, phosphorylation, and the addition or deletion of a signal sequence. The term "polypeptide" or "protein" refers to one or more chains of amino acids, where each chain contains amino acids covalently linked by peptide bonds, and where the polypeptide or protein can contain multiple chains noncovalently and / or covalently linked together by peptide bonds, including native proteins, i.e., proteins produced by natural cells and specific non-recombinant cells, or genetically engineered or recombinant cells, and includes molecules having the amino acid sequence of a native protein or molecules with deletions from, additions to, and / or substitutions of one or more amino acids from the native sequence. In certain embodiments, a polypeptide is a "recombinant" polypeptide produced by a recombinant cell containing one or more recombinant DNA molecules, which are typically made from heterologous polynucleotide sequences or combinations of polynucleotide sequences not otherwise found in the cell.

[0093] The term "isolated" polypeptide or protein, as referred to herein, means that the subject protein (1) is free from at least some other proteins with which it would typically be found in nature; (2) is essentially free from other proteins from the same source, e.g., from the same species; (3) is expressed by cells from a different species; (4) is separated from at least about 50 percent of the polynucleotides, lipids, carbohydrates, or other materials with which it is naturally associated; (5) is not associated (by covalent or non-covalent interactions) with portions of proteins with which it is naturally associated; (6) is operably associated (by covalent or non-covalent interactions) with polypeptides with which it is not naturally associated; or (7) does not occur in nature. Such isolated proteins may be encoded by genomic DNA, cDNA, mRNA, or other RNA, may be of synthetic origin, or any combination thereof. In certain embodiments, an isolated protein is substantially free from proteins or polypeptides found in its natural environment or other contaminants that would interfere with its use (therapeutic, diagnostic, preventative, research, or otherwise).

[0094] In certain embodiments, the purity of any given agent (e.g., an antibody) in a composition can be defined. For example, a particular composition may include an agent that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure on a protein basis or weight-by-weight basis, including, for example, all decimal points measured and ranges therebetween, and is not limited by any means by high performance liquid chromatography (HPLC), a well-known form of column chromatography frequently used in biochemistry and analytical chemistry to separate, identify, and quantify compounds.

[0095] The term "reference sequence" generally refers to a nucleic acid coding sequence, or amino acid sequence, to which another sequence is compared. All polypeptide and polynucleotide sequences described herein are included as reference sequences, including those described by name and in the tables and sequence listing.

[0096] Certain embodiments include biologically active "variants" and "fragments" of the polypeptides (e.g., antibodies) described herein, as well as polynucleotides encoding the same. "Variant" includes one or more substitutions, additions, deletions, and / or insertions relative to a reference polypeptide or polynucleotide (see, e.g., Tables and Sequence Listing). A variant polypeptide or polynucleotide, as described herein, comprises an amino acid or nucleotide sequence with at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity or similarity or homology to a reference sequence and substantially retains the activity of the reference sequence. Also included are sequences that consist of a reference sequence or that differ from a reference sequence by the addition, deletion, insertion, or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, or more amino acids or nucleotides, and that substantially retain the activity of the reference sequence. In certain embodiments, the additions or deletions include C-terminal and / or N-terminal additions and / or deletions.

[0097] The term "sequence identity" or, as used herein, includes, for example, "at least 50% identical sequence", refers to the degree to which sequences are identical on a nucleotide-by-nucleotide basis or on an amino acid-by-amino acid basis over a comparison window.Thus, "sequence identity percentage" can be calculated by: comparing two optimally aligned sequences over a comparison window; determining the number of positions where identical nucleic acid bases (e.g., A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) occur in both sequences, resulting in the number of identical positions; dividing the number of identical positions by the total number of positions in the comparison window (i.e., window size), and multiplying the result by 100 to obtain the percentage of sequence identity. Optimal alignment of sequences for aligning a comparison window can be performed by computerized implementations of algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive, Madison, Wis., USA), or by inspection and best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by any of a variety of selected methods. Reference can also be made to the BLAST family of programs, for example, as disclosed by Altschul et al., Nucl. Acids Res. 25:3389, 1997.

[0098] The term "solubility" refers to the ability of an agent (e.g., an antibody) provided herein to dissolve in a liquid solvent to form a homogeneous solution. Solubility is typically expressed as a concentration by mass of solute per unit volume of solvent (e.g., g of solute per kg of solvent, g per dL (100 mL), mg / mL, etc.), molarity, molar concentration, molar fraction, or other similar descriptions of concentration. The maximum equilibrium amount of solute that can be dissolved per volume of solvent is the solubility of the solute in that solvent under specific conditions, including temperature, pressure, pH, and solvent properties. In certain embodiments, solubility is measured at physiological pH or other pHs, such as pH 5.0, pH 6.0, pH 7.0, pH 7.4, pH 7.6, pH 7.8, or pH 8.0 (e.g., about pH 5-8). In certain embodiments, solubility is measured in water or a physiological buffer, such as PBS or NaCl (with or without NaPO). In certain embodiments, solubility is measured at a relatively low pH (e.g., pH 6.0) and a relatively high salt (e.g., 500 mM NaCl and 10 mM NaPO). In certain embodiments, solubility is measured in a biological fluid (solvent), such as blood or serum. In certain embodiments, the temperature can be about room temperature (e.g., about 20, 21, 22, 23, 24, 25°C) or about body temperature (37°C). In certain embodiments, the agent has a solubility of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg / ml at room temperature or 37°C.

[0099] A "subject" or "subject in need thereof" or a "patient" or "patient in need thereof" includes mammalian subjects, such as human subjects.

[0100] "Substantially" or "essentially" means nearly entirely or completely, for example, 95%, 96%, 97%, 98%, 99%, or more of a given amount of some substance.

[0101] By " statistically significant ", it means that the result is unlikely to occur by chance. Statistical significance can be determined by any method known in the art. Commonly used significance measures include p-value, which is the frequency or probability that the observed event will occur if the null hypothesis is true. If the obtained p-value is smaller than the significance level, then the null hypothesis is rejected. In simple cases, the significance level is defined as a p-value of 0.05 or less.

[0102] "Therapeutic response" refers to an improvement in symptoms (whether sustained or not) following administration of one or more therapeutic agents.

[0103] As used herein, the term "therapeutically effective amount," "therapeutic dose," "prophylactically effective amount," or "diagnostically effective amount" is the amount of an agent (e.g., an anti-IL-11RαP antibody) required to elicit a desired biological response following administration.

[0104] As used herein, "treatment" of a subject (e.g., a mammal, such as a human) or cell is any type of intervention used in an attempt to alter the natural course of a disease or disorder. Treatment includes, but is not limited to, the administration of a pharmaceutical composition and can be performed either prophylactically or following the initiation of a pathological event or contact with a pathogenic agent. Also included is prophylactic treatment, which can be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset. "Treatment" or "prevention" does not necessarily indicate complete eradication, cure, or prevention of the disease or condition, or its associated symptoms.

[0105] The term "wild-type" refers to a gene or gene product (eg, a polypeptide) that is most frequently observed in a population and is thus arbitrarily designed as the "normal" or "wild-type" form of the gene.

[0106] Each embodiment herein should be applied mutatis mutandis to all other embodiments unless expressly stated otherwise.

[0107] Therapeutic methods, antibodies, and pharmaceutical compositions Embodiments of the present disclosure relate to a method of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody, or antigen-binding fragment thereof, that binds to human interleukin-11 receptor subunit alpha (IL-11Rα). Thyroid eye disease is the most common inflammatory orbital disorder and is associated with autoimmune thyroid dysfunction. The disorder is a progressive disorder with symptoms and signs that can cause significant facial disfigurement and visual impairment, but rarely leads to blindness.

[0108] In some cases, TED is characterized by orbital inflammation due to fibroblast activation (see, e.g., Li et al., Curr Opin Ophthalmol. 29(6):528-534, 2018). Research has demonstrated the importance of orbital CD34+ fibroblasts (see, e.g., Meyer et al., Clinical pathophysiology of thyroid eye disease: The Cone Model. Eye (Lond). 33(2):244-253, 2019). In response to molecular signaling, these fibroblasts differentiate into adipocytes and myofibroblasts. CD34+ fibroblasts express thyroglobulin, thyroid-stimulating hormone (TSH), and other thyroid-related peptides. These signaling molecules stimulate the TSH receptor and insulin-like growth factor I (IGF-1) complex, which in turn cascades to intraorbital adipogenesis and fibroblast hyaluronan synthesis (ibid.). Increased orbital adipose tissue and sequestration of glycosaminoglycans within the EOM expand the soft tissue volume, resulting in increased intraorbital congestion and pressure associated with the pathological manifestations of TED.

[0109] Women have a higher incidence of TED, while men are more likely to have severe TED (see, e.g., Douglas et al., J Clin Endocrinol Metab. 95(1):430-8, 2010; and Lazarus, Best Pract Res Clin Endocrinol Metab. 26(3):273-9, 2012). Research has shown that patients with TED do not have a specific genetic predisposition, and the disease is largely due to environmental influences and epigenetic changes (see, e.g., Yin et al., Thyroid. 22(7):730-6, 2012). There are many risk factors for TED, including female gender, middle age, and smoking, which not only increase the incidence of TED but also reduce the effectiveness of treatment (see, e.g., Wang et al., Ther Clin Risk Manag. 15:1305-1318, 2019). Treatment with radioactive iodine is another example of a risk factor for TED (see, e.g., Sikder and Weinberg, Ophthalmologica. 224(4):199-203, 2010).

[0110] Typically, the diagnosis of TED is made by one of two criteria (see, e.g., Bartley and Gorman, Am J Ophthalmol. 119(6):792-5, 1995). For example, if eyelid retraction is evident, after exclusion of confounding factors, the presence of additional thyroid dysfunction or dysregulation, exophthalmos, ophthalmic nerve dysfunction, or extraocular muscle (EOM) involvement provides the diagnosis. In the absence of eyelid retraction, the diagnosis is made via exophthalmos, optic nerve dysfunction, or EOM involvement against the backdrop of thyroid dysfunction or dysregulation. TED is often associated with Graves' disease.

[0111] Thus, in certain embodiments, the patient has one or more clinical signs of TED. The most common clinical sign of TED is upper eyelid retraction, which can be unilateral or bilateral (see, e.g., Bartley et al., Am J Ophthalmol. 121(3):284-290, 1996; and Smith and Hegedus, N Engl J Med. 375(16):1552-1565, 2016). Wide-open eye appearance leads to eye exposure, especially during sleep. Initially, such signs may be associated with foreign body sensation, dryness, and tearing. Over time, severe keratopathy may occur, which increases the risk of corneal scarring, ulcers, perforation, and endophthalmitis (see, e.g., Douglas, Eye (Lond). 33(2):183-190, 2019). Exophthalmos, or bulging of the eyeball, is the second most common clinical sign of TED and is primarily due to increased EOM and / or fat, which may also increase the risk of exposure. Lagophthalmos, or incomplete eye closure, is also observed in some patients with TED (e.g., Smith and Hegedus, supra). Elevation of the lateral portion of the upper eyelid contour or primary inflammation is also frequently observed. Dysfunction of the EOM is observed in many patients, and diplopia often occurs when ocular misalignment occurs (e.g., Smith and Hegedus, supra). The inferior and medial rectus muscles are most commonly affected, potentially inducing hypotropia (downward deviation), esotropia (inward deviation), and / or limiting eye movement if the muscles become fibrotic. Many patients experience eye pain that feels like a dull pressure. Eyelid edema and erythema, conjunctival hyperemia, and chemosis (swelling of the conjunctiva) are also observed. Fibrinous inflammatory reactions may also be present in orbital tissue, and activated Thy1 + and Thy1 -The relative proportion of OF may determine whether excessive extracellular matrix accumulation or lipogenesis predominates in TED (see, e.g., Shan et al., Journal of Neuro-Ophthalmology. 34(2):177-185, 2014). Achromatopsia (color vision loss) or visual loss secondary to compressive optic neuropathy is observed in very few cases but indicates severe disease. TED can be unilateral or highly asymmetric. Thus, in some instances, one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

[0112] The Clinical Activity Score (CAS) system assesses the activity of TED using findings from the medical history and external examination. In some cases, patients are scored at the initial visit, receiving one point for each of the following symptoms: spontaneous orbital pain, gaze-induced orbital pain, eyelid swelling, eyelid erythema, conjunctival hyperemia, chemosis, and inflammation of the caruncle or semilunar fold (see, e.g., Mourits et al., Clin Endocrinol (Oxf). 47(1):9-14, 1997; and Clin Endocrinol (Oxf). 47(5):632, 1997). A CAS score of 3 or greater at the initial visit is considered active disease. In some cases, at follow-up, patients are given additional points for each criterion: a 2mm or greater increase in proptosis, a 5° or greater decrease in motility in either eye, or a 1 Snellen line or greater decrease in visual acuity (see, e.g., ibid.). A score of 4 or greater indicates active disease. Thus, in certain embodiments, a patient in need thereof has a Clinical Activity Score (CAS) of 3 or greater, or 4 or greater, 5 or greater, or 6 or greater.

[0113] The VISA (Vision, Inflammation, Strabismus, Appearance / Exposure) classification assesses severity and activity (see, e.g., Dolman and Rootman, Ophthalmic Plast Reconstr Surg. 22(5):319-324, 2006). The vision component excludes optic neuropathy by assessing visual acuity, color vision deficits, pupillary reflex, and optic nerve appearance. The inflammation component modifies the CAS criteria described above by excluding inflammation of the colliculus / meniscal fold (including subconjunctival chemosis) and grading chemosis and eyelid edema on a scale of 0 to 2. Retrobulbar pain is graded as 0 = no pain, 1 = pain with movement, and 2 = pain at rest. Conjunctival and eyelid hyperemia are graded as present or absent, and the worst-scored eyelid score (ranging from 0 to 8) is recorded. The strabismus component tracks the progression of EOM functional impairment and diplopia. The appearance / exposure section assesses symptomatic exophthalmos, eyelid retraction, and dryness. In some embodiments, patients in need thereof have a VISA score of 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater.

[0114] In certain embodiments, the patient in need thereof has a thyroid dysfunction, e.g., hyperthyroidism. In some examples, the patient has autoantibody stimulation of the thyroid-stimulating hormone receptor (TSHR). Thyroid-stimulating immunoglobulin (TSI) is a TSHR antibody that directly correlates with the severity and activity of TED (see, e.g., Lytton et al., J Clin Endocrinol Metab. 95(5):2123-2131, 2010) and can be used as a biomarker for the disease. Thus, in some embodiments, the patient in need thereof has an increased level of TSI, for example, compared to a control or reference. In some embodiments, the patient has Graves' disease.

[0115] In some embodiments, the patient has one or more risk factors associated with TED. Examples of the one or more risk factors include being female, being middle-aged (e.g., over 40-60 years old), being a smoker, and currently undergoing or having undergone radioactive iodine therapy. In certain embodiments, the patient in need thereof has increased levels of IL-11Rα and / or IL-11 in the blood or tissues around the eye (e.g., orbital blood, orbital tissue, e.g., orbital fibroblasts), e.g., compared to a healthy control or reference. In some embodiments, the patient in need thereof has increased levels of circulating IL-11.

[0116] Certain embodiments include diagnosing TED in a patient before administering a pharmaceutical composition as described herein. For example, certain embodiments include (a) determining whether the patient has TED, and (b) administering a pharmaceutical composition to the patient if the patient has TED. Determining whether the patient has TED can utilize any one or more of the diagnostic procedures described herein and known in the art. For example, in some instances, step (a) includes measuring one or more clinical signs of TED, including upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in orbital tissues, and chemosis (swelling of the conjunctiva).

[0117] Certain embodiments include (a) determining the patient's CAS and (b) administering a pharmaceutical composition to the patient if the CAS is 3 or greater, or 4 or greater, 5 or greater, or 6 or greater. Also included are (a) determining the patient's VISA score and (b) administering a pharmaceutical composition to the patient if the VISA score is 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater. Some embodiments include (a) determining the patient's thyroid function and (b) administering a pharmaceutical composition to the patient if the patient has a thyroid dysfunction, e.g., hyperthyroidism. Certain embodiments include (a) determining the patient's TSI level and (c) administering a pharmaceutical composition to the patient if the TSI level in the patient is increased compared to a control or reference standard. Some embodiments include (a) determining the level of IL-11Rα and / or IL-11 (e.g., protein expression, mRNA expression) in the patient's blood or tissues around the eye (e.g., orbital blood, orbital tissues, e.g., orbital fibroblasts, etc.), and (b) administering a pharmaceutical composition to the patient if the level of IL-11Rα and / or IL-11 in the patient's blood or tissues around the eye is increased compared to a control or reference standard. Certain embodiments include (a) determining the patient's level of circulating IL-11, and (b) administering a pharmaceutical composition to the patient if the level of circulating IL-11 is increased compared to a control or reference standard. Antibodies and antigen-binding fragments thereof of the present disclosure can be used to determine the protein expression level of IL-11Rα in a patient's blood or tissues.

[0118] The methods provided herein can be combined with any one or more diagnostic procedures to arrive at a diagnosis of TED prior to treatment with a pharmaceutical composition comprising an anti-IL-11Rα antibody or antigen-binding fragment thereof.

[0119] Certain embodiments include obtaining or receiving a biological sample from a subject and performing a diagnostic assay on the sample. In some embodiments, the tissue sample is a liquid biopsy (e.g., a blood sample), surgical sample, or other biopsy sample obtained from the patient, including a blood or tissue sample from around the patient's eye (e.g., an orbital blood or tissue sample, such as an orbital fibroblast). Certain embodiments of step (a) include performing thyroid function tests on the blood or other biological sample by measuring TSH, T4, and / or T3 levels and determining whether the patient has a thyroid dysfunction, such as hyperthyroidism. Some embodiments of step (a) include performing a bioassay on the blood or other biological sample obtained from the patient (e.g., comparing cyclic adenosine monophosphate (cAMP) production obtained from thyrotropin (TSH)-responsive cells upon exposure to patient serum with the same cells after exposure to normal control serum) to determine whether the patient has increased TSH levels compared to a reference or control. See Preissner et al., Clin Chem. 49(8):1402-1404, 2003). Certain embodiments include performing a bioassay on blood or other biological sample obtained from a patient (e.g., a circulating blood sample, an orbital blood sample, or an orbital tissue sample, such as orbital fibroblasts, etc.) to determine whether the patient has increased levels of IL-11Rα and / or IL-11 (e.g., circulating IL-11) compared to a reference or control. Examples of a "reference" include a value, amount, sequence, or other characteristic obtained from a database. A "reference" also includes a value, amount, sequence, or other characteristic obtained from one or more control tissues, e.g., healthy tissues of one or more controls, e.g., one or more control subjects (e.g., a population of control healthy subjects).

[0120] In some embodiments, the patient is treatment-naive to a TED treatment. A "treatment-naive" patient has not previously received a prior TED treatment, e.g., as described herein. In some embodiments, the patient has chronic TED.

[0121] In some embodiments, the patient is undergoing or has previously undergone TED treatment and is intolerant, relapsed, and / or refractory to the (prior) TED treatment. "Relapse" refers to a return to a previous condition or disease state, e.g., after a period of treatment-related dormancy or disease inactivity. In some embodiments, a patient with relapsed TED is identified by an initial response to a previous TED treatment, as measured by a decrease in exophthalmos, followed by regression after a period of time despite continued treatment with the same TED treatment. In some embodiments, the decrease in exophthalmos is greater than about 2 mm. In some embodiments, regression of exophthalmos is an increase in exophthalmos returning to pre-treatment baseline measurements. In some embodiments, regression of exophthalmos is an increase in exophthalmos from a maximal response to a previous TED treatment. In some embodiments, a patient with relapsed TED is identified by an initial response to a previous TED treatment, as measured by a decrease in CAS score, followed by regression after a period of time despite continued treatment with the same TED treatment. A patient who is "refractory" to a previous TED treatment is a patient who has not responded meaningfully, previously failed to respond, or become non-responsive (e.g., by selection) to a previous TED treatment. In some embodiments, a refractory patient is identified by a lack of improvement in exophthalmos. In some embodiments, a lack of improvement in exophthalmos is less than about 2 mm. In some embodiments, a refractory patient is identified by little or no change in CAS score. A patient who is "intolerant" refers to an adverse event (AE) profile that previously required or indicates that cessation of TED treatment is advisable. In some embodiments, an intolerant, relapsed, and / or refractory patient has active TED. In some instances, the patient has progressive TED. In certain embodiments, a patient with an intolerant / relapsed / refractory disease state has TED that progresses more aggressively in the patient than it did before TED treatment.In some embodiments, progression of TED is indicated by a worsening of one or more clinical signs of TED, an increase in CAS score, and / or a worsening VISA score compared to the clinical signs, CAS score, and / or VISA score prior to TED treatment. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanisms of action may provide a clinical benefit in the treatment of progressive disease states, including more aggressive and progressive disease states, compared to previous (now refractory) TED treatments.

[0122] In some embodiments, the (previous) TED treatment is selected from insulin-like growth factor-1 receptor (IGF-1R) inhibitor therapy, FcRn inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy, including combinations thereof (e.g., steroid + ORT therapy). In certain embodiments, the IGF-1R inhibitor therapy is a small molecule. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody. In certain embodiments, the IGF-1R inhibitor antibody is selected from the following therapies: teprotumumab, ganitumumab, dalotuzumab, cixutumumab, and figitumumab. In some embodiments, the FcRn inhibitor therapy is selected from the following therapies: batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab. In certain embodiments, the IL-6 inhibitor therapy is selected from the following therapies: clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab. In some embodiments, the steroid therapy is selected from the following therapies: methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone).In certain embodiments, the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapies. In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0123] In some embodiments, the patient is receiving or has previously received teprotumumab treatment and is intolerant, relapsed, and / or refractory to the (prior) teprotumumab treatment. "Relapse" refers to a return to a previous condition or disease state, for example, after a period of treatment-related dormancy or disease inactivity. In some embodiments, a patient with relapsed TED is identified by an initial response to previous teprotumumab treatment, as measured by a decrease in exophthalmos, followed by regression after a period of time despite continued treatment with the same teprotumumab treatment. In some embodiments, the decrease in exophthalmos is greater than about 2 mm. In some embodiments, regression of exophthalmos is an increase in exophthalmos returning to pre-treatment baseline measurements. In some embodiments, regression of exophthalmos is an increase in exophthalmos from a maximal response to previous teprotumumab treatment. In some embodiments, patients with relapsed TED are identified by an initial response to previous teprotumumab treatment, as measured by a decrease in CAS score, followed by reversal after a period of time despite continued treatment with the same teprotumumab treatment. Patients who are "refractory" to previous teprotumumab treatment are patients who do not meaningfully respond, have previously failed to respond, or have become non-responsive (e.g., by selection) to previous teprotumumab treatment. In some embodiments, refractory patients are identified by a lack of improvement in exophthalmos. In some embodiments, a lack of improvement in exophthalmos is less than about 2 mm. In some embodiments, refractory patients are identified by little or no change in CAS score. In some embodiments, intolerant, relapsed, and / or refractory patients have active TED. In some instances, the patient has progressive TED. In certain embodiments, patients with intolerant / relapsed / refractory disease states have TED that progresses more aggressively in the patient than it did before teprotumumab treatment. In some embodiments, progression of TED is indicated by a worsening of one or more clinical signs of TED, an increase in CAS score, and / or a worsening VISA score compared to the clinical signs, CAS score, and / or VISA score before teprotumumab treatment.In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanisms of action compared to previous (now refractory) teprotumumab treatment may provide clinical benefit in the treatment of progressive disease states, including more aggressive disease states. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered one teprotumumab half-life from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered two teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered three teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered four teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 5 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 6 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 7 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 8 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 9 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered 10 teprotumumab half-lives from the last administration of teprotumumab. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof of the present disclosure is administered more than 10 teprotumumab half-lives from the last administration of teprotumumab.

[0124] Certain embodiments include combination therapy, in which the method comprises administering a pharmaceutical composition (comprising an anti-IL-11Rα antibody or antigen-binding fragment thereof described herein) in combination with at least one additional TED therapy.

[0125] In some embodiments, at least one additional TED therapy is administered prior to administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered simultaneously with administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered sequentially with administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered in the same composition as an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, at least one additional TED therapy is administered in a separate composition from an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure.

[0126] In some embodiments, the at least one additional TED therapy is selected from IGF-1R inhibitor therapy, FcRn inhibitor therapy, IL-6 inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy, including combinations thereof (e.g., steroid plus ORT therapy). In certain embodiments, the IGF-1R inhibitor therapy is an antibody therapy. In some embodiments, the IGF-1R inhibitory antibody therapy is selected from teprotumumab, ganitumumab, dalotuzumab, cixutumumab, and figitumumab therapies. In some embodiments, the FcRn inhibitor therapy is selected from the following therapies: batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab. In some embodiments, the IL-6 inhibitor therapy is selected from the following therapies: clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab. In certain embodiments, the steroid therapy is selected from the following therapies: methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone). In some embodiments, the CD20 inhibitor therapy is selected from the following therapies: ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab.In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0127] In some embodiments, the at least one additional TED therapy is an IGF-1R inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody, such as, for example, teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered simultaneously with the administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered before the administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered sequentially with the administration of an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered in the same composition as the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered in a separate composition from the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 2 times during treatment with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 3 times during treatment with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 4 times during treatment with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 5 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, IGF-1R inhibitor therapy (e.g., an IGF-1R antibody) is administered about 1 to about 6 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the present disclosure.In some embodiments, IGF-1R inhibitor therapy (eg, IGF-1R antibody) is administered from about 1 to about 7 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the disclosure.

[0128] In certain embodiments, the methods and compositions described herein are sufficient to result in stable disease. In certain embodiments, the methods and compositions described herein are sufficient to result in a clinically relevant reduction or improvement in symptoms indicative of a particular disease known to a skilled clinician. Administering the pharmaceutical composition to the patient improves one or more clinical signs of TED. For example, in certain embodiments, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in orbital tissues, and chemosis (swelling of the conjunctiva). In certain embodiments, administering the pharmaceutical composition to a patient improves the patient's Clinical Activity Score (CAS), optionally by at least 1, 2, 3, 4, or 5 points, optionally to a CAS of 3 or less, 2 or less, or 1 or less. In certain embodiments, administering the pharmaceutical composition to a patient improves the patient's VISA score, optionally by at least 1, 2, 3, 4, or 5 points, optionally to a VISA of 4 or less, 3 or less, 2 or less, or 1 or less. In some embodiments, administering the pharmaceutical composition to a patient reduces the level of IL-11Rα and / or IL-11 in the blood or tissues around the patient's eye (e.g., orbital blood, orbital tissues, such as orbital fibroblasts). In certain embodiments, administering the pharmaceutical composition to a patient reduces the level of circulating IL-11 in the patient.

[0129] As discussed above, the methods and compositions described herein utilize one or more antibodies and antigen-binding fragments thereof that bind to interleukin-11 receptor subunit alpha (IL-11Rα). In some embodiments, the antibody or antigen-binding fragment thereof modulates (e.g., interferes with, antagonizes, inhibits) the binding of IL-11Rα to its ligand, interleukin-11 (IL-11). In certain embodiments, the antibody or antigen-binding fragment thereof binds to the complementarity-determining region V H CDR1, V H CDR2, and V H The heavy chain variable region (V H ), and complementarity-determining region V L CDR1, V L CDR2, and V L The light chain variable region (V L ) characterized by or including them. H Array, V H CDR1 sequence, V H CDR2 sequence, V H CDR3 sequence, V L Array, V L CDR1 sequence, V L CDR2 sequence, and V L The CDR3 sequences are provided in Tables A1 and A2 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0130] Thus, in certain embodiments, the antibody or antigen-binding fragment thereof comprises a V complementarity determining region selected from Table A1.H CDR1 sequence, V H CDR2 sequence, and V H V containing the CDR3 sequence H sequences, and variants thereof that bind to IL-11Rα, and V of the complementarity determining region selected from Table A1 L CDR1 sequence, V L CDR2 sequence, and V L V containing the CDR3 sequence L In certain embodiments, the antibody comprises the sequence V H CDR1 sequence, V H CDR2 sequence, and V H V containing the CDR3 sequence H Sequence, and V L CDR1 sequence, V L CDR2 sequence, and V L V containing the CDR3 sequence L sequences, in which all of the CDR sequences are derived from one named antibody (e.g., mAb1) in Table A1.

[0131] In certain embodiments, the CDR sequences are as follows: V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 1 to 3, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 4 to 6, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 7 to 9, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 10 to 12, respectively; V H CDR1 sequence, V H CDR2 sequence, and V HThe CDR3 sequences include SEQ ID NOs: 13 to 15, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 16 to 18, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 19 to 21, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 22 to 24, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 25 to 27, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 28 to 30, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 31 to 33, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 34 to 36, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 37 to 39, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 40 to 42, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 43 to 45, respectively, and V L CDR1 sequence, V L CDR2 sequence, and VL the CDR3 sequences comprise SEQ ID NOs: 46 to 48, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 49 to 51, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 52 to 54, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 55 to 57, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 58 to 60, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 61 to 63, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 64 to 66, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 67 to 69, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 70 to 72, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 73 to 75, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 76 to 78, respectively; V H CDR1 sequence, VH CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 79 to 81, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 82 to 84, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 85 to 87, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 88 to 90, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 91 to 93, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 94 to 96, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 97 to 99, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 100 to 102, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 103 to 105, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 106-108, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 109 to 111, respectively, and VL CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 112-114, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 115 to 117, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 118-120, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 121 to 123, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 124 to 126, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 127 to 129, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 130 to 132, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 133 to 135, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 136 to 138, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences comprise SEQ ID NOs: 139 to 141, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V Lthe CDR3 sequences comprise SEQ ID NOs: 142 to 144, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 145 to 147, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 148 to 150, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 151 to 153, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 154 to 156, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 157 to 159, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 160 to 162, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 163 to 165, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 166-168, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 169 to 171, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 172 to 174, respectively; V HCDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 175 to 177, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 178-180, respectively; V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 181 to 183, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L the CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or V H CDR1 sequence, V H CDR2 sequence, and V H The CDR3 sequences include SEQ ID NOs: 187 to 189, respectively, and V L CDR1 sequence, V L CDR2 sequence, and V L The CDR3 sequences include SEQ ID NOs: 190 to 192, respectively.

[0132] Also included are minor variants of the aforementioned CDRs. Exemplary variants bind to IL-11Rα and have minor variants in any one or more of the individual CDRs, e.g., the V and V sequences described herein. H CDR1, V H CDR2, V H CDR3, V L CDR1, V L CDR2, and / or V L Any one or more of the CDR3 sequences may have a total of 1, 2, or 3 changes. Exemplary "changes" include amino acid substitutions, additions, and deletions.

[0133] Exemplary V H and V L The sequences are provided in Table A2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0134] Thus, in certain embodiments, the antibody, or antigen-binding fragment thereof, binds to IL-11Rα and is selected from Table A2. H Array and corresponding V L In certain embodiments, V H includes a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, e.g., V H has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in one or more framework regions. L includes a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, e.g., V L has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in one or more framework regions. H comprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, and V L comprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, and V H In certain embodiments, the V region is derived from the same named antibody (e.g., mAb1). H comprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, and V Lcomprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, and is derived from the same one named antibody (e.g., mAb1) as the VH region, where there are no changes in the underlined CDRs of Table A2. Thus, an antibody can have a VH region that is at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to each sequence from one named antibody (e.g., mAb1) of Table A2. H Array and V L The antibody may comprise a sequence, in which case the antibody comprises the CDRs of one of the named antibodies (e.g., mAb1) listed in Table A1.

[0135] In some embodiments, the V of the antibody or antigen-binding fragment H and V L is as follows: V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and V Lcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; V Hcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and V Lcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250; V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; V Hcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and V L comprises a sequence that is at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:256.

[0136] Also, variants thereof that bind to IL-11Rα, such as the aforementioned V H Sequence and / or V L These are variants having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in any one or more framework regions of the sequence. Exemplary "changes" include amino acid substitutions, additions, and deletions.

[0137] As described above, the antibodies or antigen-binding fragments thereof described herein bind to IL-11Rα, e.g., membrane-bound IL-11Rα. In certain embodiments, the antibodies or antigen-binding fragments thereof bind to human IL-11Rα or a region or fragment thereof. The amino acid sequence of human IL-11Rα is provided in Table B1 below. [Table 3]

[0138] Thus, in certain embodiments, the antibody or antigen-binding fragment thereof binds to an IL-11Rα sequence in Table B1, e.g., a human IL-11Rα sequence. In certain embodiments, the antibody or antigen-binding fragment thereof binds to mature IL-11Rα. In certain embodiments, the antibody or antigen-binding fragment thereof binds to soluble IL-11Rα. In certain embodiments, the antibody or antigen-binding fragment thereof binds to the IL-11Rα membrane precursor.

[0139] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to a conformational epitope on IL-11Rα.

[0140] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to a linear epitope on IL-11Rα.

[0141] In certain embodiments, the antibody or antigen-binding fragment thereof binds to the first fibronectin type III domain in human IL-11Rα (also referred to herein as the second extracellular domain of IL-11Rα), which comprises residues 90-197 of SEQ ID NO: 260.

[0142] In certain embodiments, an IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope spanning residues 115 to 134 of mature IL-11Rα. In certain embodiments, exemplary antibodies of the disclosure that exhibit such binding include those comprising the V and V sequences of CDRs 25 to 27 of SEQ ID NOS: 115 to 27, respectively. H CDR1, V H CDR2, and V H CDR3 sequences, and V sequences of SEQ ID NOs: 28 to 30, respectively L CDR1, V L CDR2, and V L In certain embodiments, an example of an antibody of the disclosure that exhibits such binding comprises the CDR3 sequence V of SEQ ID NO: 201. H Sequence number 202, and V L Contains arrays.

[0143] In certain embodiments, an IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope comprising residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261). In certain embodiments, an IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope comprising a subset of residues located within residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261). In certain embodiments, exemplary antibodies of the present disclosure that exhibit such binding include those comprising the V and V sequences of CDRs 25-27 of SEQ ID NOs: 25-27, respectively. H CDR1, V H CDR2, and V HCDR3 sequences, and V sequences of SEQ ID NOs: 28 to 30, respectively L CDR1, V L CDR2, and V L In certain embodiments, an example of an antibody of the disclosure that exhibits such binding comprises the CDR3 sequence V of SEQ ID NO: 201. H Sequence number 202, and V L Contains arrays.

[0144] In some embodiments, the antibody or antigen-binding fragment thereof binds to human IL-11Rα with a binding affinity of about 1 pM to about 10 pM to about 500 pM, or about, at least about, or less than about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, or 500 pM, or optionally less than about 1 pM ~about 500pM, about 1pM to about 400pM, about 1pM to about 300pM, about 1pM to about 200pM, about 1pM to about 100pM, about 1pM to about 50pM, about 1pM to about 40pM, about 1pM to about 30pM, about 1pM Approximately 20 pM, approximately 1 pM to approximately 10 pM, approximately 1 pM to approximately 5 pM, approximately 5 pM to approximately 500 pM, approximately 5 pM to approximately 400 pM, approximately 5 pM to approximately 300 pM, approximately 5 pM to approximately 200 pM, approximately 5 pM to approximately 100 pM, approximately 5 pM to approximately 50 pM, about 5 pM to about 40 pM, about 5 pM to about 30 pM, about 5 pM to about 20 pM, about 5 pM to about 10 pM, about 10 pM to about 500 pM, about 10 pM to about 400 pM, about 10 pM to about 300 pM, about 10 pM to about 2 00pM, about 10pM to about 100pM, about 10pM to about 50pM, about 10pM to about 40pM, about 10pM to about 30pM, about 10pM to about 20pM, or about 20pM to about 500pM, about 20pM to about 400pM , about 20 pM to about 300 pM, about 20 pM to about 200 pM, about 20 pM to about 100 pM, about 20 pM to about 50 pM, about 20 pM to about 40 pM, about 20 pM to about 30 pM, or about 30 pM to about 500 pM, about 30 pM to about 400 pM, about 30 pM to about 300 pM, about 30 pM to about 200 pM, about 30 pM to about 100 pM, about 30 pM to about 50 pM, or about 30 pM to about 40 pM. In certain embodiments, the antibody or antigen-binding fragment thereof has increased binding affinity for human IL-11Rα compared to the TS7 antibody and the 8E2 antibody (see, e.g., U.S. Patent Nos. 9,796,782; 9,340,618).

[0145] In some embodiments, the antibody, or antigen-binding fragment thereof, is an IL-11Rα antagonist. In some examples, the antibody, or antigen-binding fragment thereof, antagonizes binding and / or signaling activity between IL-11Rα and its ligand, IL-11. In some embodiments, the antibody, or antigen-binding fragment thereof, antagonizes or reduces binding and / or signaling activity between IL-11Rα and IL-11 by about or at least about 10-1000% (e.g., about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000% or more), e.g., in a cell-based assay. In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof reduces IL-11-mediated STAT3 phosphorylation. In an exemplary assay, cells expressing IL-11Rα and gp130 are cultured in the presence of IL-11, with or without an IL-11Rα binding protein. The level of STAT3 phosphorylation is then assessed by Western blotting or FACS using an antibody specific for phosphorylated STAT3. An exemplary assay using FACS is described in Dams-Kozlowska et al., BMC Biotechnol, 12:8, 2012. In certain embodiments, the antibody or antigen-binding fragment thereof has increased potency as an IL-11 signaling antagonist compared to the TS7 antibody and the 8E2 antibody (see, e.g., U.S. Patent Nos. 9,796,782; 9,340,618). In certain embodiments, the antibody or antigen-binding fragment thereof has no detectable agonistic activity with respect to IL-11 signaling.

[0146] In some embodiments, the antibody, or antigen-binding fragment thereof, inhibits or otherwise reduces IL-11Rα dimerization or complex formation, e.g., with gp130. In certain embodiments, the antibody, or antigen-binding fragment thereof, inhibits or otherwise reduces IL-11Rα dimerization or complex formation by about or at least about 10-1000% (e.g., about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000% or more), e.g., in a cell-based assay.

[0147] In some embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof reduces the proliferation of cells expressing IL-11Rα and gp130 (e.g., BaF3 cells, B9 cells, T10 cells) (e.g., cells that naturally express or have been engineered to express both proteins) cultured in the presence of IL-11. Methods for assessing cell proliferation are known in the art, including, for example, MTT reduction and / or thymidine incorporation. Assays using B9 or T10 cells have been described (see Dams-Kozlowska et al., BMC Biotechnol, 12:8, 2012; and Yokote et al., J AOAC, 83:1053-1057, 2000). For T10 cells, proliferation can be measured by colorimetrically detecting a decrease in the tetrazolium compound, 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzenedisulfonate (WST-1). An IL-11Rα binding protein that reduces the level of proliferation compared to that observed in the absence of the IL-11Rα binding protein is considered to reduce or otherwise reduce IL-11R signaling.

[0148] For illustrative purposes only, the binding interaction between IL-11Rα and an antibody or antigen-binding fragment thereof, or the binding / signaling between IL-11Rα and IL-11, as described herein, can be detected and quantified using a variety of routine methods, including Biacore® assays (e.g., coupled to a sensor chip using an appropriately tagged soluble reagent), FACS analysis using cells (either natural or recombinant) expressing IL-11Rα on their cell surface, immunoassays, fluorescent staining assays, ELISA assays, and microcalorimetry approaches, such as ITC (isothermal titration calorimetry). Similarly, the functional properties of anti-IL-11Rα antibodies can be evaluated using a variety of methods known to those skilled in the art, including affinity / binding assays (e.g., surface plasmon resonance, competitive inhibition assays); cytotoxicity assays, cell survival assays, cell proliferation or differentiation assays, and cancer cell and / or tumor growth inhibition using in vitro or in vivo models. Other assays may be used to test the ability of the antibodies described herein to block normal IL-11Rα-mediated responses. The antibodies described herein may be tested for in vitro and in vivo efficacy. Such assays may be performed using well-established protocols known to those skilled in the art (see, e.g., Current Protocols in Molecular Biology (Greene Publ. Assoc. Inc. & John Wiley & Sons, Inc., NY, NY); Current Protocols in Immunology (Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober 2001 John Wiley & Sons, NY, NY); or commercially available kits.

[0149] In certain embodiments, the Fc region of the antibody, or antigen-binding fragment thereof, comprises, consists of, or consists essentially of an IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or a hybrid and / or variant thereof. In certain embodiments, the heavy chain constant region or Fc region comprises, consists of, or consists essentially of a heavy chain constant region or Fc derived from human IgG1 or IgG4 (see, e.g., Allberse and Schuurman, Immunology. 105:9-19, 2002), or a fragment or variant thereof. Table F1 below provides exemplary heavy chain constant region sequences (CH1, hinge (underlined), CH2, and CH3 regions) derived from human IgG4. Examples of variant IgG4 sequences that may be employed include the S228P / S241P variant. [Table 4]

[0150] Table F2 below provides an example of a heavy chain sequence for mAb5. [Table 5]

[0151] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a variant or otherwise modified Fc region, including one with altered properties or biological activity compared to a wild-type Fc region. Examples of modified Fc regions include regions having a mutated sequence, e.g., by substitution, insertion, deletion, or truncation of one or more amino acids relative to the wild-type sequence, hybrid Fc polypeptides composed of domains from different immunoglobulin classes / subclasses, Fc polypeptides with altered glycosylation / sialylation patterns, and Fc polypeptides that are modified or derivatized, e.g., by biotinylation (see, e.g., U.S. Patent Application Publication No. 2010 / 0209424), phosphorylation, sulfation, etc., or any combination of the foregoing. Such modifications can affect the binding properties of the Fc region to one or more specific FcRs (e.g., FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, FcγRIIIb, FcRn), its pharmacokinetic properties (e.g., stability or half-life, bioavailability, tissue distribution, volume of distribution, concentration, elimination rate constant, elimination rate, area under the curve (AUC), clearance, C max , t max , C min , wander mutations), its immunogenicity, its complement fixation or activation, and / or CDC / ADCC / ADCP-related activity of the Fc region compared to the corresponding wild-type Fc sequence of an antibody or antigen-binding fragment thereof. Included are modified Fc regions of human and / or murine origin.

[0152] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a hybrid Fc region, e.g., an Fc region comprising a combination of Fc domains (e.g., hinge, CH2, CH3, CH4) from immunoglobulins of different species (e.g., human, mouse), different Ig classes, and / or different Ig subclasses. Also included are antibodies or antigen-binding fragments thereof comprising derivatized or otherwise modified Fc regions. In certain aspects, the Fc region is modified, e.g., by phosphorylation, sulfation, acylation, glycosylation, methylation, farnesylation, acetylation, amidation, and the like, relative to a wild-type or native Fc region. In certain embodiments, the Fc region comprises a wild-type or native glycosylation pattern, or alternatively, it comprises increased glycosylation relative to the native form, decreased glycosylation relative to the native form, or it is completely deglycosylated. As an example of an altered Fc glycoform, reduced glycosylation of the Fc region reduces binding to the C1q region of the first complement component C1, decreases ADCC-related activity, and / or decreases CDC-related activity. Certain embodiments thus employ deglycosylated or aglycosylated Fc regions. For exemplary production of aglycosylated Fc regions, see, e.g., WO 2005 / 047337. Another example of an Fc region glycoform is generated by substituting a cysteine ​​residue at position Q295 according to the Kabat et al. numbering system (see, e.g., U.S. Patent Application No. 2010 / 0080794). Certain embodiments include Fc regions in which approximately 80-100% of the glycoproteins in the Fc region comprise a mature core carbohydrate structure lacking fucose (see, e.g., U.S. Patent Application No. 2010 / 0255013). Some embodiments include Fc regions that are optimized by substitutions or deletions to reduce the level of fucosylation, e.g., to increase affinity for FcγRI, FcγRIa, or FcγRIIIa, and / or to improve phagocytosis by FcγRIIa-expressing cells (see U.S. Patent Applications Nos. 2010 / 0249382 and 2007 / 0148170).

[0153] As another example of a modified Fc glycoform, the Fc region of an antibody or antigen-binding fragment thereof may comprise oligomannose-type N-glycans, optionally having one or more of the following: increased ADCC effector activity, increased binding affinity for FcγRIIIA (and certain other FcRs), similar or increased binding specificity for a target of an IL-11Rα polypeptide, similar or higher binding affinity for a target of an IL-11Rα polypeptide, and / or similar or lower binding affinity for the mannose receptor, relative to a corresponding Fc region comprising complex-type N-glycans (see, e.g., U.S. Patent Application Publication No. 2007 / 0092521 and U.S. Patent No. 7,700,321). As another example, increased affinity of the Fc region for FcγRs has been achieved using engineered glycoforms generated by expression of the antibody in engineered or variant cell lines (see, e.g., Umana et al., Nat Biotechnol. 17:176-180, 1999; Davies et al., Biotechnol Bioeng. 74:288-294, 2001; Shields et al., J Biol Chem. 277:26733-26740, 2002; Shinkawa et al., 2003, J Biol Chem. 278:3466-3473, 2003; and U.S. Patent Application No. 2007 / 0111281). Certain Fc region glycoforms contain an increased proportion of N-glycosidically linked complex glycans that do not have the 1-position of fucose attached to the 6-position of the N-acetylglucosamine at the reducing end of the glycan (see, e.g., U.S. Patent Application Publication No. 2010 / 0092997). Certain embodiments may include an IgG Fc region that is glycosylated with at least one galactose moiety linked to each terminal sialic acid moiety by an α-2,6 linkage, optionally wherein the Fc region has greater anti-inflammatory activity than the corresponding wild-type Fc region (see, e.g., U.S. Patent Application Publication No. 2008 / 0206246).Some of these and related altered glycosylation approaches, as described herein, have produced substantial enhancements in the ability of Fc regions to selectively bind to FcRs, such as FcγRIII, mediate ADCC, and modify other properties of the Fc region.

[0154] Particular variant, fragment, hybrid, or otherwise modified Fc regions of antibodies or antigen-binding fragments thereof may have altered binding to one or more FcRs and / or corresponding changes in effector function compared to the corresponding wild-type Fc sequence (e.g., same species, same Ig class, same Ig subclass). For example, such Fc regions may have increased binding to one or more Fcγ receptors, Fcα receptors, Fcε receptors, and / or neonatal Fc receptors compared to the corresponding wild-type Fc sequence. In other embodiments, variant, fragment, hybrid, or modified Fc regions may have decreased binding to one or more Fcγ receptors, Fcα receptors, Fcε receptors, and / or neonatal Fc receptors compared to the corresponding wild-type Fc sequence. Particular FcRs are described elsewhere herein.

[0155] In some embodiments, the antibody comprises an Fc domain comprising one or more mutations to increase binding to one or more Fcγ receptors, Fcα receptors, Fcε receptors, and / or neonatal Fc receptors relative to the corresponding wild-type Fc sequence. In some embodiments, the antibody comprises an IgG1 or IgG3 Fc domain comprising one or more mutations to increase binding to one or more Fcγ receptors, Fcα receptors, Fcε receptors, and / or neonatal Fc receptors relative to the corresponding wild-type Fc sequence. In some embodiments, the antibody comprises an Fc domain comprising one or more mutations to increase effector function. In some embodiments, at least one antibody comprises an Fc domain selected from human IgG1 and human IgG3, optionally comprising one or more mutations to increase effector function.

[0156] In some embodiments, the antibody comprises an Fc domain comprising one or more mutations to reduce binding to one or more Fcγ receptors, Fcα receptors, Fcε receptors, and / or neonatal Fc receptors compared to the corresponding wild-type Fc sequence. In some embodiments, the antibody comprises an IgG1 or IgG3 Fc domain comprising one or more mutations to reduce binding to one or more Fcγ receptors, Fcα receptors, Fcε receptors, and / or neonatal Fc receptors compared to the corresponding wild-type Fc sequence. In some embodiments, the antibody comprises an Fc domain comprising one or more mutations to reduce effector function. In some embodiments, the antibody comprises an Fc domain selected from human IgG2 and human IgG4 comprising one or more mutations to reduce effector function.

[0157] Specific examples of Fc variants with altered (e.g., increased, decreased) effector function / FcR binding are described, for example, in U.S. Patent Nos. 5,624,821 and 7,425,619; U.S. Patent Application Nos. 2009 / 0017023, 2009 / 0010921, and 2010 / 0203046; and WO2000 / 42072 and WO2004 / 016750. Specific examples include human Fc regions with one or more substitutions at positions 298, 333, and / or 334, e.g., S298A, E333A, and / or K334A (based on the EU index numbering of Kabat et al.), which have been shown to increase binding to the activating receptor FcγRIIIa and decrease binding to the inhibitory receptor FcγRIIb. These mutations can be combined to produce double and triple mutant variants with further improvements in FcR binding. Particular embodiments include the S298A / E333A / K334A triple mutant, which increases binding to FcγRIIIa, decreases binding to FcγRIIb, and increases ADCC (see, e.g., Shields et al., J. Biol. Chem. 276:6591-6604, 2001; and Presta et al., Biochem. Soc. Trans. 30:487-490, 2002). See also Umana et al. (supra); and engineered Fc glycoforms with increased FcR binding, as disclosed in U.S. Pat. No. 7,662,925. Some embodiments include an Fc region comprising one or more substitutions selected from 434S, 252Y / 428L, 252Y / 434S, and 428L / 434S, based on the EU index of Kabat et al. (see U.S. Patent Application Nos. 2009 / 0163699 and 20060173170).

[0158] Certain variant, fragment, hybrid, or modified Fc regions may have altered effector function compared to the corresponding wild-type Fc sequence. For example, such Fc regions may have increased complement fixation or activation, increased Clq binding affinity, increased CDC-related activity, increased ADCC-related activity, and / or increased ADCP-related activity compared to the corresponding wild-type Fc sequence. In other embodiments, such Fc regions may have decreased complement fixation or activation, decreased Clq binding affinity, decreased CDC-related activity, decreased ADCC-related activity, and / or decreased ADCP-related activity compared to the corresponding wild-type Fc sequence. As merely one illustrative example, the Fc region may include deletions or substitutions in complement binding sites, such as C1q binding sites, and / or deletions or substitutions in ADCC sites. Examples of such deletions / substitutions are described, for example, in U.S. Patent No. 7,030,226. Many Fc effector functions, such as ADCC, can be assayed according to routine techniques in the art (see, e.g., Zuckerman et al., CRC Crit Rev Microbiol. 7:1-26, 1978). Useful effector cells for such assays include, but are not limited to, natural killer (NK) cells, macrophages, and other peripheral blood mononuclear cells (PBMCs). Alternatively, or additionally, certain Fc effector functions can be assessed in vivo by using animal models, such as those described in Clynes et al. PNAS. 95:652-656, 1998.

[0159] Certain variant hybrids or modified Fc regions may have altered stability or half-life compared to the corresponding wild-type Fc sequence. In certain embodiments, such Fc regions may have an increased half-life compared to the corresponding wild-type Fc sequence. In other embodiments, variant hybrids or modified Fc regions may have a decreased half-life compared to the corresponding wild-type Fc sequence. Half-life can be measured in vitro (e.g., under physiological conditions) or in vivo according to routine techniques in the art, such as radiolabeling, ELISA, or other methods. In vivo measurements of stability or half-life can be measured in one or more body fluids, including blood, serum, plasma, urine, or cerebrospinal fluid, or in a given tissue, such as liver, kidney, muscle, central nervous system tissue, bone, etc. As an example, modifications to an Fc region that alter its ability to bind to FcRn can alter its half-life in vivo. Non-limiting examples of assays for measuring in vivo pharmacokinetic properties (e.g., in vivo mean elimination half-life) and Fc modifications that alter their binding to FcRn are described, for example, in U.S. Pat. Nos. 7,217,797 and 7,732,570; and U.S. Patent Application Nos. US2010 / 0143254 and 2010 / 0143254.

[0160] Additional non-limiting examples of stability- or half-life-altering modifications include substitutions / deletions at one or more amino acid residues selected from 251-256, 285-290, and 308-314 of the CH2 domain, and 385-389 and 428-436 of the CH3 domain, according to the numbering system of Kabat et al. See U.S. Patent Application Publication No. 2003 / 0190311. Specific examples include substitutions with leucine at position 251, tyrosine, tryptophan, or phenylalanine at position 252, threonine or serine at position 254, arginine at position 255, glutamine, arginine, serine, threonine, or glutamic acid at position 256, threonine at position 308, proline at position 309, serine at position 311, aspartic acid at position 312, leucine at position 314, arginine, asparagine at position 385, and the like. substitution with threonine or proline at position 386, with arginine or proline at position 387, with proline, asparagine, or serine at position 389, with methionine or threonine at position 428, with tyrosine or phenylalanine at position 434, with histidine, arginine, lysine, or serine at position 433, and / or with histidine, tyrosine, arginine, or threonine at position 436, including any combination thereof. Such modifications optionally increase the affinity of the Fc region for FcRn, thereby increasing the half-life compared to the corresponding, wild-type Fc region.

[0161] Certain variant hybrids or modified Fc regions may have altered solubility compared to the corresponding wild-type Fc sequence. In certain embodiments, such Fc regions may have increased solubility compared to the corresponding wild-type Fc sequence. In other embodiments, variant hybrids or modified Fc regions may have decreased solubility compared to the corresponding wild-type Fc sequence. Solubility can be measured, for example, in vitro (e.g., under physiological conditions) according to routine techniques in the art. Exemplary solubility measurements are described elsewhere herein.

[0162] The variant Fc region can also have one or more mutant hinge regions, for example, as described in U.S. Patent Application Publication No. 2003 / 0118592. For example, one or more cysteines in the hinge region can be deleted or substituted with different amino acids. The mutant hinge region can contain no cysteine ​​residues, or it can contain one, two, or three fewer cysteine ​​residues than the corresponding wild-type hinge region. In some embodiments, Fc regions with this type of mutant hinge region exhibit reduced dimerization ability compared to the wild-type Ig hinge region.

[0163] In certain embodiments, the antibody or antigen-binding fragment thereof is incubated for about or at least about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 20 hours, about 24 hours, about 36 hours, about 40 hours, about 50 hours, about 60 hours, about 70 hours, about 80 hours, about 90 hours, about 100 hours, about 120 hours, about 160 hours, about 180 hours, about 240 hours, about 280 hours, about 360 hours, about 380 hours, about 400 hours, about 400 hours, about 500 hours, about 600 hours, about 700 hours, about 800 hours, about 900 hours, about 1000 hours, about 1200 hours, about 1400 hours, about 1600 hours, about 1800 hours, about 2000 hours, about 24 ... A biological half-life of 4 hours, about 30 hours, about 36 hours, about 40 hours, about 48 hours, about 50 hours, about 60 hours, about 70 hours, about 72 hours, about 80 hours, about 84 hours, about 90 hours, about 96 hours, about 120 hours, or about 144 hours or more, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks or more, or any intervening half-life, including all ranges therebetween.

[0164] In some embodiments, the antibody or antigen-binding fragment thereof has a T of about or at least about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75°C. m In some embodiments, the antibody or antigen-binding fragment thereof has a T of about 65° C. or higher, for example, in PBS (phosphate buffered saline). m It has.

[0165] For in vivo use, certain embodiments include pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof described herein and a pharmaceutically acceptable carrier. To prepare a therapeutic or pharmaceutical composition, an effective or desired amount of one or more agents is mixed with any pharmaceutical carrier or excipient known to those of skill in the art to be appropriate for the particular agent and / or mode of administration. The pharmaceutical carrier may be liquid, semi-liquid, or solid. Solutions or suspensions used for parenteral, intradermal, intraocular, subcutaneous, direct instillation into the bladder, or topical application may contain, for example, sterile diluents (such as water), saline (e.g., phosphate-buffered saline; PBS), fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents (such as benzyl alcohol and methylparabens); antioxidants (such as ascorbic acid and sodium bisulfite) and chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); buffers (such as acetates, citrates, and phosphates). If administered intravenously (e.g., by IV infusion), suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof.

[0166] Administration of the agents described herein, in pure form or in suitable therapeutic or pharmaceutical compositions, can be via any of the accepted modes of administration for agents that perform similar functions. Therapeutic or pharmaceutical compositions can be prepared by combining the agent-containing composition with a suitable physiologically acceptable carrier, diluent, or excipient, and can be formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Other pharmaceutically active ingredients (including other small molecules described elsewhere herein) and / or suitable excipients, such as salts, buffers, and stabilizers, can also be present in the composition, but need not be.

[0167] Administration can be achieved by a variety of different routes, including oral, parenteral, nasal, intravenous, intraocular, intradermal, intramuscular, subcutaneous, placement in the bladder, or topical. The preferred mode of administration depends on the nature of the condition being treated or prevented. Certain embodiments include administration by IV infusion.

[0168] Carriers can include, for example, pharmaceutically or physiologically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers, such as phosphate, citrate, other organic acids, and the like; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, histidine, and / or lysine, and the like; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or non-ionic surfactants, such as polysorbate 20 (TWEEN™), polyethylene glycol (PEG), poloxamer (PLURONICS™), and the like.

[0169] In some embodiments, one or more agents can be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980). The particles or liposomes may further comprise other therapeutic or diagnostic agents.

[0170] The exact dosage and duration of treatment are a function of the disease being treated and can be determined empirically using known test protocols or by testing the composition in a model system known in the art and extrapolating from there.Controlled clinical trials can also be carried out.Dosage can also vary depending on the severity of the condition to be alleviated.Pharmaceutical compositions are generally formulated and administered to exert therapeutically useful effects while minimizing undesirable side effects.The composition can be administered once or divided into multiple smaller doses that are administered at regular intervals.For any particular subject, the specific dosage regimen can be adjusted over time according to individual needs.

[0171] Typical routes of administration of these and related therapeutic or pharmaceutical compositions thus include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, ocular, rectal, vaginal, and intranasal. As used herein, the term "parenteral" includes subcutaneous injection, intravenous, intravesical, intramuscular, intrasternal injection, or infusion techniques. Therapeutic or pharmaceutical compositions according to certain embodiments of the present disclosure are formulated so that the active ingredients contained therein are bioavailable upon administration of the composition to a subject or patient. The composition administered to a subject or patient may take the form of one or more dosage units, where, for example, a tablet may be a single dosage unit and a container of a drug described herein in aerosol form may hold multiple dosage units. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The compositions to be administered typically contain a therapeutically effective amount of an agent described herein for treatment of the disease or condition of interest.

[0172] Therapeutic or pharmaceutical compositions can be in solid or liquid form.In some embodiments, the carrier is particulate, and the composition is, for example, in tablet or powder form.The carrier can be liquid, and the composition is, for example, oral oil, injectable liquid, or aerosol, which is useful, for example, in inhalation administration.When intended for oral administration, pharmaceutical compositions are preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension, and gel form are included in the form considered herein as either solid or liquid.Certain embodiments include sterile injection solutions.

[0173] As a solid composition for oral administration, the pharmaceutical composition may be formulated into powder, granules, gel, compressed tablets, pills, capsules, chewing gum, wafers, or the like. Such solid compositions typically contain one or more inert diluents or edible carriers. One or more of the following may also be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, and the like; lubricants such as magnesium stearate or Stereotex; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as peppermint, methyl salicylate, or orange flavor; and coloring agents. When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to the above materials, a liquid carrier such as polyethylene glycol or oil.

[0174] Therapeutic or pharmaceutical compositions may be in the form of a liquid, such as an elixir, syrup, solution, gel, emulsion, or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to the compound, one or more of a sweetener, a preservative, a dye / colorant, and a flavor enhancer. In compositions intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffer, a stabilizer, and an isotonic agent may be included.

[0175] Liquid therapeutic or pharmaceutical compositions, whether in solution, suspension, or other similar form, may contain one or more of the following adjuvants: sterile diluents, such as water for injection, saline, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils, such as synthetic mono- or diglycerides, polyethylene glycols, glycerin, propylene glycol, or other solvents that serve as solvents or suspending media; antibacterial agents, such as benzyl alcohol or methylparabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, phosphates, and agents for adjusting tonicity, such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Pharmaceutical compositions for injection are preferably sterilized.

[0176] Liquid therapeutic or pharmaceutical compositions intended for either parenteral, ocular, or oral administration should contain an amount of agent such that an appropriate dosage will be obtained. Typically, this amount is at least 0.01% of the agent of interest in the composition. When intended for oral administration, this amount can vary to be between 0.1 and about 70% by weight of the composition. Certain oral therapeutic or pharmaceutical compositions contain between about 4% and about 75% of the agent of interest. In certain embodiments, therapeutic or pharmaceutical compositions and preparations are prepared so that a parenteral dosage unit contains between 0.01 and 10% by weight of the agent of interest before dilution.

[0177] Therapeutic or pharmaceutical compositions may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, or gel base. The base may comprise, for example, one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may also be present in therapeutic or pharmaceutical compositions for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or iontophoresis device.

[0178] Therapeutic or pharmaceutical compositions may be intended for rectal administration, for example, in the form of suppositories that dissolve in the rectum and release the drug.Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient.Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0179] Therapeutic or pharmaceutical compositions may contain various materials that modify the physical form of a solid or liquid dosage unit. For example, the composition may contain a material that forms a coating shell around the active ingredient. The material that forms the coating shell is typically inert and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule. Therapeutic or pharmaceutical compositions in solid or liquid form may contain a component that binds to the drug and thereby assists in the delivery of the compound. Suitable components that can act in this capacity include monoclonal or polyclonal antibodies, one or more proteins, or liposomes.

[0180] Therapeutic or pharmaceutical compositions may consist essentially of dosage units that can be administered as an aerosol. The term "aerosol" is used to refer to a variety of systems, ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by liquefied or compressed gas or by an appropriate pump system that dispenses the active ingredient. The aerosol may be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient. Aerosol delivery includes the necessary containers, activators, valves, subcontainers, and the like, which may together form a kit. One skilled in the art can determine a preferred aerosol without undue experimentation.

[0181] The compositions described herein may be prepared with carriers that protect the agent against rapid elimination from the body, such as slow release formulations or coatings. Such carriers include controlled release formulations, including, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and others known to those skilled in the art.

[0182] Pharmaceutical compositions can be prepared by methods well known in the pharmaceutical arts. For example, therapeutic or pharmaceutical compositions intended to be administered by injection may contain one or more salts, buffers and / or stabilizers, along with sterile distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with drugs to promote the dissolution or homogeneous suspension of the drug in an aqueous delivery system.

[0183] Therapeutic or pharmaceutical compositions may be administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound used; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the subject; the mode and time of administration; the excretion rate; the drug combination; the severity of the particular disorder or condition; and the subject being treated. In some examples, a therapeutically effective daily dose is from about 0.001 mg / kg (i.e., 0.07 mg) to about 100 mg / kg (i.e., 7.0 g) (for a mammal weighing 70 kg); preferably, a therapeutically effective dose is from about 0.01 mg / kg (i.e., 0.7 mg) to about 50 mg / kg (i.e., 3.5 g) (for a mammal weighing 70 kg); more preferably, a therapeutically effective amount is from about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g) (for a mammal weighing 70 kg). In some embodiments, the therapeutically effective dose is administered weekly, biweekly, or monthly. In certain embodiments, the therapeutically effective dose is administered weekly, biweekly, or monthly, e.g., at a dose of about 1-10 or 1-5 mg / kg, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg.

[0184] Also provided are antibodies, antigen-binding fragments thereof, or pharmaceutical compositions of the present disclosure for use as pharmaceuticals. The antibodies, fragments thereof, or pharmaceutical compositions of the present disclosure may be for use in any of the therapeutic methods disclosed herein. In certain embodiments, the antibodies, fragments thereof, or pharmaceutical compositions of the present disclosure may be for use in methods for treating TED, ameliorating the symptoms of TED, and / or slowing the progression of TED.

[0185] The methods and compositions provided herein can be combined with other therapeutic modalities for the treatment of TED, including supportive care (e.g., improving thyroid function, smoking cessation, selenium supplementation, etc.), corticosteroids, radiation therapy, and surgical management, such as eyelid retraction correction, strabismus surgery, and orbital decompression.

[0186] Also included are patient care kits comprising (a) an antibody or antigen-binding fragment thereof that binds to IL-11Rα, as described herein; and, optionally, (b) at least one additional therapeutic agent. In certain kits, (a) and (b) are in separate therapeutic compositions. In some kits, (a) and (b) are in the same therapeutic composition.

[0187] The kits herein may also include one or more additional therapeutic agents or other components appropriate or desirable for the indication being treated or for the desired diagnostic application. The kits herein may also include one or more syringes or other components necessary or desirable to facilitate the intended mode of delivery (e.g., stent, implantable depot, etc.).

[0188] In some embodiments, the patient care kit contains separate containers, dividers, or compartments for the composition and informational material. For example, the composition may be contained in a bottle, vial, or syringe, and the informational material can be included in association with the container. In some embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial, or syringe having informational material in the form of a label attached thereto. In some embodiments, the kit contains multiple (e.g., packs) individual containers, each containing one or more unit dosage forms of the antibody (e.g., dosage forms described herein) and, optionally, at least one additional therapeutic agent. For example, the kit contains multiple syringes, ampoules, foil packets, or blister packs, each containing a single unit dose of the antibody and, optionally, at least one additional therapeutic agent. The containers of the kit can be airtight, waterproof (e.g., impermeable to changes in moisture or evaporation), and / or light-tight.

[0189] The patient care kit optionally includes a device suitable for administering the composition, such as a syringe, inhaler, dropper (e.g., eye dropper), swab (e.g., cotton swab or wooden swab), or any such delivery device. In some embodiments, the device is an implantable device that dispenses a metered dose of the agent. Also included are methods of providing the kit, for example, by combining the components described herein.

[0190] Although the foregoing embodiments have been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in view of the teachings of the present disclosure that certain changes and modifications can be made without departing from the spirit or scope of the appended claims. The following examples are provided by way of illustration only, and not by way of limitation. Those of ordinary skill in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially similar results.

[0191] Enumerated Embodiments Non-limiting example embodiments of the present disclosure are provided herein.

[0192] Embodiment I-1. A method for treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody, or antigen-binding fragment thereof, that binds to human interleukin-11 receptor subunit alpha (IL-11Rα).

[0193] Embodiment I-2. The method of embodiment I-1, wherein the patient has one or more clinical signs of TED.

[0194] Embodiment I-3. The method of embodiment I-2, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), dysfunction of the extraocular muscles (EOM), optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

[0195] Embodiment I-4. The method of any one of embodiments I-1 to I-3, wherein the patient has a Clinical Activity Score (CAS) of 3 or greater, or 4 or greater, or 5 or greater, or 6 or greater, where the CAS is assigned a score of 1 for each of spontaneous orbital pain, gaze-induced orbital pain, eyelid swelling, eyelid erythema, conjunctival hyperemia, chemosis, and inflammation of the caruncle and semilunar folds.

[0196] Embodiment I-5. The method according to any one of embodiments I-1 to I-4, wherein the patient has a VISA (Vision, Inflammation, Strabismus, Appearance / Exposure) score of 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater.

[0197] Embodiment I-6. The method according to any one of embodiments I-1 to I-5, wherein the patient has a thyroid dysfunction, optionally hyperthyroidism.

[0198] Embodiment I-7. The method according to any one of embodiments I-1 to I-6, wherein the patient has autoantibody stimulation of the thyroid stimulating hormone receptor (TSHR).

[0199] Embodiment I-8. The method according to any one of embodiments I-1 to I-7, wherein the patient has an increased level of thyroid-stimulating immunoglobulin (TSI).

[0200] Embodiment I-9. The method according to any one of embodiments I-1 to I-8, wherein the patient has Graves' disease.

[0201] Embodiment I-10. The method according to any one of embodiments I-1 to I-9, wherein the patient has one or more risk factors associated with TED.

[0202] Embodiment I-11. The method of embodiment I-10, wherein the one or more risk factors are selected from female gender, middle age, smoking, and undergoing or having undergone treatment with radioactive iodine.

[0203] Embodiment I-12. The method of any one of embodiments I-1 to I-11, wherein the patient has increased levels of IL-11Rα and / or IL-11 in the blood or tissues around the eye, optionally in orbital fibroblasts, and / or the patient has increased levels of circulating IL-11.

[0204] Embodiment I-13. a. Determining whether the patient has TED; and b. The method of any one of embodiments I-1 to I-12, comprising administering the pharmaceutical composition to the patient if the patient has TED.

[0205] Embodiment I-14. The method of embodiment I-13, wherein (a) optionally comprises measuring one or more clinical signs of TED selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in orbital tissues, and chemosis (swelling of the conjunctiva).

[0206] Embodiment I-15. a. Determining the patient's CAR; and b. The method of embodiment I-13 or I-14, comprising administering to the patient a pharmaceutical composition if the CAS is 3 or greater, or 4 or greater, or 5 or greater, or 6 or greater.

[0207] Embodiment I-16. a. Determining the patient's VISA score; and b. The method of any one of embodiments I-13 to I-15, comprising administering a pharmaceutical composition to the patient if the VISA score is 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater.

[0208] Embodiment I-17. a. Determining thyroid function in a patient; and b. The method of any one of embodiments I-13 to I-16, comprising administering to the patient, if the patient has a thyroid dysfunction, optionally hyperthyroidism, the pharmaceutical composition.

[0209] Embodiment I-18. a. Determining the level of thyroid-stimulating immunoglobulin (TSI) in the patient; and b. The method of any one of embodiments I-13 to I-17, comprising administering to the patient the pharmaceutical composition if the level of TSI in the patient is increased compared to a control or reference standard.

[0210] Embodiment I-19. a. determining the levels of IL-11Rα and / or IL-11 in the patient's peripheral eye blood or tissue, and optionally in orbital fibroblasts; and b. The method of any one of embodiments I-1 to I-18, comprising administering the pharmaceutical composition to the patient if the level of IL-11Rα and / or IL-11 in the blood or tissues around the eye of the patient (optionally, in orbital fibroblasts) is increased compared to a control or reference standard.

[0211] Embodiment I-20. The method of any one of embodiments I-1 to I-19, wherein the patient is treatment-naive to TED treatment and, optionally, is a chronic TED patient.

[0212] Embodiment I-21. The method of any one of embodiments I-1 to I-19, wherein the patient is undergoing or has previously undergone TED treatment and is relapsed / refractory / intolerant to TED treatment, and optionally has active TED.

[0213] Embodiment I-22. The method of embodiment I-21, wherein TED has progressed in the patient, optionally as indicated by a worsening of one or more clinical signs of TED, an increase in CAS score, and / or a worsening VISA score compared to the clinical signs or scores before TED treatment, wherein TED has progressed more aggressively in the patient than before TED treatment.

[0214] Embodiment I-23. The method of any one of embodiments I-20 to I-22, wherein the TED treatment is selected from insulin-like growth factor-1 receptor (IGF-1R) inhibitor therapy, FcRn inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy.

[0215] Embodiment I-24. The method of embodiment I-23, wherein the IGF-1R inhibitory antibody therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and fizitumumab therapies.

[0216] Embodiment I-25. The method of embodiment I-23, wherein the FcRn inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapies.

[0217] Embodiment I-26. The method of embodiment I-23, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, revilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapies.

[0218] Embodiment I-27. The method of embodiment I-23, wherein the steroid therapy is selected from the following therapies: methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone).

[0219] Embodiment I-28. The method of embodiment I-23, wherein the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0220] Embodiment I-29. The method of embodiment I-23, wherein the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0221] Embodiment I-30. The method according to any one of embodiments I-1 to I-29, comprising administering the pharmaceutical composition in combination with at least one additional TED treatment.

[0222] Embodiment I-31. The method of embodiment I-30, wherein the at least one additional TED treatment is selected from IGF-1R inhibitor therapy, FcRn inhibitor therapy, IL-6 inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy.

[0223] Embodiment I-32. The method of embodiment I-31, wherein the IGF-1R inhibitor therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and fizitumumab therapy.

[0224] Embodiment I-33. The method of embodiment I-32, wherein the IGF-1R inhibitor therapy is administered 1 to 7 times simultaneously with or consecutively with the administration of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or antigen-binding fragment thereof that binds to human IL-11Rα.

[0225] Embodiment I-34. The method of embodiment I-31, wherein the FcRn inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapies.

[0226] Embodiment I-35. The method of embodiment I-31, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, revilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapies.

[0227] Embodiment I-36. The method of embodiment I-31, wherein the steroid therapy is selected from the following therapies: methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone).

[0228] Embodiment I-37. The method of embodiment I-31, wherein the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0229] Embodiment I-38. The method of embodiment I-31, wherein the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0230] Embodiment I-39. The method of any one of embodiments I-1 to I-38, wherein the antibody or antigen-binding fragment thereof binds to fibronectin domain III of human IL-11Rα or to about residues 90-197 of SEQ ID NO:260.

[0231] Embodiment I-40. The method of any one of embodiments I-1 to I-38, wherein the antibody or antigen-binding fragment thereof binds to the second extracellular domain of IL-11Rα.

[0232] Embodiment I-41. The method of embodiments I to 39, wherein the antibody or antigen-binding fragment thereof recognizes an epitope comprising the amino acid sequence of SEQ ID NO: 261.

[0233] Embodiment I-42. The method of embodiments I-41, wherein the epitope comprises residues S116, S125, K129, S140 and T143 of SEQ ID NO: 260.

[0234] Embodiment I-43. The antibody or antigen-binding fragment thereof may be a. V of a complementarity-determining region selected from Table A1 H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The heavy chain variable region (V H ), and variants thereof that specifically bind to IL-11Rα; and b. V of a complementarity-determining region selected from Table A1 L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L The light chain variable region (V) containing the CDR3 amino acid sequence L ), as well as variants thereof that specifically bind to IL-11Rα.

[0235] Embodiment I-44. V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 1 to 3, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 4 to 6, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 7 to 9, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 10 to 12, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 13 to 15, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 16 to 18, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 19 to 21, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 22 to 24, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 25 to 27, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 28 to 30, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 31 to 33, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 34 to 36, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 34 to 39, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and VL the CDR3 amino acid sequences include SEQ ID NOs: 40 to 42, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 43 to 45, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 46 to 48, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 49 to 51, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 52 to 54, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 55 to 57, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 58 to 60, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 61 to 63, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 64 to 66, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 67 to 69, respectively, and V LCDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 70 to 72, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 73 to 75, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 76 to 78, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 79 to 81, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 82 to 84, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 85 to 87, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 88 to 90, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 91 to 93, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 94 to 96, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V HThe CDR3 amino acid sequences include SEQ ID NOs: 97 to 99, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 100 to 102, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 103 to 105, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 106 to 108, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 109 to 111, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 112 to 114, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 115 to 117, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 118 to 120, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 121 to 123, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 124 to 126, respectively; VH CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 127 to 129, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 130 to 132, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 133 to 135, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 136 to 138, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 139 to 141, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 142 to 144, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 145 to 147, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 148 to 150, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 151 to 153, respectively, and V L CDR1 amino acid sequence, V LCDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 154 to 156, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 157 to 159, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 160 to 162, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 163 to 165, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 166 to 168, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 169 to 171, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 172 to 174, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 175 to 177, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences include SEQ ID NOs: 178 to 180, respectively; V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V HThe CDR3 amino acid sequences include SEQ ID NOs: 181 to 183, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 184-186, respectively; or V H CDR1 amino acid sequence, V H CDR2 amino acid sequence, and V H The CDR3 amino acid sequences include SEQ ID NOs: 187 to 189, respectively, and V L CDR1 amino acid sequence, V L CDR2 amino acid sequence, and V L The method of embodiment I-43, wherein the CDR3 amino acid sequences comprise SEQ ID NOs: 190-192, respectively.

[0236] Embodiment I-45. V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to an amino acid sequence selected from Table A2, and optionally V H The method of embodiment I-43 or I-44, wherein the amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in the framework regions.

[0237] Embodiment I-46. V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to an amino acid sequence selected from Table A2, and optionally V L The method of any one of embodiments I-43 to I-45, wherein the amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in the framework regions.

[0238] Embodiment I-47. V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and V Lcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218; V Hcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and VL comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and V Lcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and V LThe method of any one of embodiments I-43 to I-46, wherein the amino acid sequence is at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 256.

[0239] Embodiment I-48. The antibody, or antigen-binding fragment thereof, has the following characteristics: a. optionally, has increased binding affinity for human IL-11Rα compared to the 340 antibody, as measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells, and increased functional potency compared to the 340 antibody; b. has a binding affinity for human IL-11Rα of less than about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 30 pM, optionally having increased binding affinity for human IL-11Rα compared to the TS7 and 8E2 antibodies; c. antagonizes the binding and / or signaling activity between IL-11Rα and IL-11, and optionally has increased potency as an IL-11 signaling antagonist compared to the TS7 and 8E2 antibodies; d. optionally, reducing IL-11Rα / gp130 dimerization or complex formation in a cell-based assay; and / or e. Optionally, V compared to TS7 antibody and 8E2 antibody L The method according to any one of embodiments I-1 to I-47, wherein the CDR3 has one or more of:

[0240] Embodiment I-49. The method of any one of embodiments I-1 to I-48, wherein the antibody or antigen-binding fragment thereof comprises an IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or hybrids and / or variants thereof.

[0241] Embodiment I-50. The method of embodiment I-49, wherein the antibody or antigen-binding fragment thereof comprises an IgG Fc domain with enhanced effector function in humans, optionally an IgG1 or IgG3 Fc domain.

[0242] Embodiment I-51. The method of embodiment I-49, wherein the antibody or antigen-binding fragment thereof comprises an IgG Fc domain with reduced effector function in humans, optionally an IgG2 or IgG4 Fc domain.

[0243] Embodiment I-52. The method of embodiment I-49, wherein the antibody or antigen-binding fragment thereof optionally comprises a human IgG1 or IgG4 Fc domain selected from Table F1.

[0244] Embodiment I-53. The method of any one of embodiments I-1 to I-52, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody.

[0245] Embodiment I-54. The method of any one of embodiments I-1 to I-53, wherein the antibody, or antigen-binding fragment thereof, is a humanized antibody, optionally wherein the antibody, or antigen-binding fragment thereof, is a humanized monoclonal antibody comprising a human IgG4 Fc domain with a S228P mutation (EU numbering).

[0246] Embodiment I-55. The method of any one of embodiments I-1 to I-53, wherein the antibody, or antigen-binding fragment thereof, is selected from an Fv fragment, a single-chain Fv (scFv) polypeptide, an adnectin, an anticalin, an aptamer, an avimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.

[0247] Embodiment I-56. The method of any one of embodiments I-1 to I-55, wherein the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the at least one antibody or antigen-binding fragment, and is substantially free of aggregates and endotoxin.

[0248] Embodiment I-57. The composition optionally comprises V L The method of any one of embodiments I-1 to I-56, wherein the CDR3 sequences have reduced or undetectable heterogeneity in N-linked glycosylation (optionally compared to the TS7 and 8E2 antibodies).

[0249] Embodiment I-58. The method of any one of embodiments I-1 to I-57, wherein the pharmaceutical composition is optionally a sterile injectable solution suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.

[0250] Embodiment I-59. The method of any one of embodiments I-1 to I-58, wherein administering the pharmaceutical composition to the patient ameliorates one or more clinical symptoms of TED.

[0251] Embodiment I-60. The method of embodiment I-59, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), dysfunction of the extraocular muscles (EOM), optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

[0252] Embodiment I-61. The method of any of embodiments I-59 or I-60, wherein administering the pharmaceutical composition to the patient improves the patient's Clinical Activity Score (CAS), optionally by at least 1, 2, 3, 4, or 5 points, optionally to a CAS of 3 or less, 2 or less, or 1 or less.

[0253] Embodiment I-62. The method of any one of embodiments I-59 to I-61, wherein administering the pharmaceutical composition to the patient optionally improves the patient's VISA score by at least 1, 2, 3, 4, or 5 points, optionally to a VISA of 4 or less, 3 or less, 2 or less, or 1 or less.

[0254] Embodiment I-63. The method of any one of embodiments I-1 to I-62, wherein administering the pharmaceutical composition to the patient reduces the levels of IL-11Rα and / or IL-11 in the blood or tissue around the patient's eye, and optionally in orbital fibroblasts.

[0255] Embodiment I-64 The method of any one of embodiments I-1 to I-63, wherein administering the pharmaceutical composition to the patient reduces the level of circulating IL-11 in the patient. [Example]

[0256] Example 1: IL-11Rα expression is elevated in TED-induced fibroblasts. Flow cytometry was performed to compare IL-11Rα expression on primary fibroblasts derived from the orbital tissue of patients with thyroid eye disease (TED) with that of primary fibroblasts derived from the ocular tissue of patients without TED. mAb5 antibody was used to detect IL-11R levels on the cell surface. As shown in Figures 1A-1C, higher levels of IL-11Rα expression were detected on fibroblasts derived from diseased tissue compared with fibroblasts derived from normal tissue (Figure 1C). This result indicates that inhibitory anti-IL-11Rα antibodies may be therapeutically useful for treating TED, for example, by inhibiting the activity of IL-11Rα in the periocular tissue of TED patients.

[0257] Example 2: Anti-IL-11Rα antibody blocks IL-11-stimulated HA release and cell proliferation in orbital cells from TED patients. To evaluate the role of IL-11 in thyroid eye disease, fibroblasts were isolated from orbital tissue of patients with thyroid eye disease (TED) and then stimulated in culture with recombinant human IL-11 in the presence or absence of the IL-11Rα-blocking antibody, mAb 5. The effects of these treatments were measured on hyaluronic acid (HA) release and cell proliferation, two events related to the pathogenesis of TED.

[0258] material and method Cell isolation Orbital fat / connective tissue was isolated from TED patients during orbital decompression. Donor information is provided in Table E1 below. [Table 6]

[0259] After isolation, the tissue was minced into 1-2 mm pieces and placed in a 6-well culture dish containing 3 mL of growth medium (high-glucose Dulbecco's Modified Eagle Medium (DMEM) supplemented with 20% fetal bovine serum and 1% penicillin / streptomycin, all from Gibco Laboratories, New York, USA) and incubated at 37°C in 5% CO. The culture medium was refreshed every 3-4 days, and the tissue was maintained in culture for 2-3 weeks to allow orbital fibroblasts to migrate out of the tissue.

[0260] Cell proliferation and HA releaseAfter isolation, orbital fibroblasts (<5 passages) were seeded onto black, clear, flat-bottom 96-well plates (Corning Costar, catalog no. 3603) at a density of 10,000 cells / well in growth medium and maintained overnight at 37°C and 5% CO in a humidified incubator. The next day, the medium was replaced with 100 μL of starvation medium (high-glucose Dulbecco's Modified Eagle Medium (DMEM) supplemented with 1% fetal bovine serum and 1% penicillin / streptomycin, all from Gibco Laboratories, New York, USA) for 24 hours to synchronize the cells. The next day, the medium was replaced with fresh serum starvation medium, and cells were preincubated for 1 hour with medium alone (vehicle, no antibody control), mAb5 (at the indicated concentrations), teprotumumab (ichorbio, ICH5128, 10 ng / mL), and / or isotype control (10 ng / mL). They were then stimulated with human recombinant IL-11 (1.1, 3.3, or 10 ng / mL) for an additional 96 hours. After 96 hours of stimulation, aliquots of medium were removed and frozen at -80°C for analysis of HA release. To measure cell proliferation, 10 μL of WST-1 cell proliferation reagent (Sigma-Aldrich, catalog no. 11644807001) was added to each well. After 2 hours of incubation, cell proliferation was assessed by measuring OD 450 on a Spectramax iD5 plate reader (Molecular Devices, San Jose, CA). HA release was measured using Duoset ELISA (R&D Systems, Cat. No. DY3614) according to the manufacturer's recommendations.

[0261] result As shown in Figure 2, recombinant IL-11 stimulated a dose-dependent increase in hyaluronan release from orbital fibroblasts (gray bars). This release was inhibited by mAb5 at all IL-11 doses (hatched bars). Similarly, as shown in Figure 3, recombinant IL-11 stimulated fibroblast proliferation at all doses. These effects were blocked by the addition of mAb5.

[0262] Figures 4A-4C show the dose-dependent effect of IL-11 with and without mAb5 (10 ng / mL, hatched lines) on hyaluronan release from orbital fibroblasts from patient sample #2 (Figure 4A, no previous TED treatment), patient sample #1 (Figure 4B, previous teprotumumab treatment), and patient sample #3 (Figure 4C, previous corticosteroid treatment). Figures 5A-5C show the effect of mAb5 at 3, 10, 30, and 100 μg / mL on IL-11 (10 ng / mL)-induced HA release from orbital fibroblasts from patient samples #2, #4, and #5 (Figure 5A, no previous TED treatment), patient sample #1 (Figure 5B, previous teprotumumab treatment), and patient sample #3 (Figure 5C, previous corticosteroid treatment).

[0263] Figures 6A-6C show the comparative inhibitory effects of mAb5, teprotumumab, and an isotype control (all at 10 μg / mL) on HA release from orbital fibroblasts of TED patients induced by 10 ng / mL IL-11. Figure 6A shows the effect on naive patient samples (no prior TED treatment, n=4). Figure 6B shows the effect on a patient sample previously treated with teprotumumab (n=1). Figure 6C shows the effect on a patient sample previously treated with corticosteroids (n=2). Figures 7A-7C show the comparative effects of mAb5, teprotumumab (and an isotype control antibody (all at 10 μg / mL)) on the expansion of orbital fibroblasts of TED patients induced by 10 ng / mL IL-11. Figure 7A shows the effect on naive patient samples (no prior TED treatment, n=4). Figure 7B shows the effect on a patient sample previously treated with teprotumumab (n=1). FIG. 7C shows the effect on patient samples previously treated with corticosteroids (n=2).

[0264] Activation of the IGF-1 receptor (IGF-1R) is a disease-causing factor in TED and is the target of the currently approved TED treatment, the anti-IGF-1R mAb teprotumumab (TEPEZZA) (Lee and Kahaly, Best Pract Res Clin Endocrinol Metab. 37(2):101620, 2023). Based on our data demonstrating crosstalk between the IL-11 and IGF-1 pathways, we performed experiments to measure the effects of mAb5, teprotumumab (ichorbio, ICH5128), and their combination (mAb5 / teprotumumab) on hyaluronan release in orbital fibroblasts from TED patients stimulated with IGF-1 (100 ng / mL) and IL-11 (10 ng / mL). Orbital fibroblasts were stimulated with a combination of IL-11 and IGF-1, and HA release in response to increasing concentrations of teprotumumab (1, 3, and 10 μg / mL) and mAb5 was measured. As shown in Figure 10, combination treatment with increasing doses of teprotumumab (solid gray bars) and mAb5 dose-dependently increased the inhibition of HA release compared to mAb5 or teprotumumab alone (black and crosshatched bars). These data indicate that treating patients with the anti-IL11Rα antibodies described herein in addition to the standard of care agent teprotumumab may have additional therapeutic benefit compared to treatment with either agent alone.

[0265] Increased HA production is a key pathology of TED, causing orbital tissue edema and exophthalmos (eye swelling). Preclinical studies demonstrated that teprotumumab inhibited HA release by orbital fibroblasts, providing important translational information and correlating with clinical efficacy in TED. Canonical IL-11 signaling leads to phosphorylation of STAT3 (pSTAT3), and IL-11 stimulation of orbital fibroblasts promotes HA release. For this reason, we examined the dose-dependent effects of mAb5 on IL-11-stimulated pSTAT3 and HA release in orbital fibroblasts to determine the IC50 and IC90 values ​​for IL-11R inhibition. Figures 11A-11B show that mAb5 inhibits pSTAT3 (Figure 11A). The IC50 and IC90 values ​​are 0.007 and 0.06 μg / mL, respectively. They also showed blocking of HA release (Figure 11B), with IC50 and IC90 values ​​of 0.05 and 0.48 μg / mL, respectively. These data confirm the efficacy of the anti-IL-11Rα antibodies described herein on IL-11 pathway activation in orbital fibroblasts and in reducing clinically relevant endpoints in TED, such as HA release.

[0266] One of the etiologies of TED, which is not effectively addressed by the current standard of care (teprotumumab), is the accumulation of excess extracellular matrix in orbital tissues. Based on the role of IL-11 in this fibro-inflammatory response outside the eye and the fact that TGFβ, a highly potent profibrotic growth factor, can stimulate massive IL-11 release, we investigated the effect of mAb5 on TGFβ-stimulated procollagen I production and compared it with teprotumumab. Figures 12A-12B show that TGFβ stimulation increased procollagen I release by more than threefold (Figure 12A). The addition of mAb5 significantly inhibited this increase (Figure 12B).

[0267] Overall, these results demonstrate that the anti-IL11Rα antibodies described herein can robustly inhibit hyaluronan release from and proliferation of orbital fibroblasts in TED patients, including those who have received previous TED treatments (teprotumumab therapy, corticosteroid therapy) and therefore may be expected to have more aggressive disease characteristics. These results also support a role for IL-11 and the IL-11Rα antibodies described herein in mediating excessive extracellular matrix accumulation in orbital tissue.

[0268] They demonstrate the clinical utility of IL-11Rα-based therapies with distinct mechanisms of action compared to previous or other TED therapies, such as teprotumumab and corticosteroid therapy, and also demonstrate the beneficial effects of combination therapy with teprotumumab and the anti-IL-11Rα antibodies described herein.

[0269] Example 3: Comparison of affinity and potency Experiments were performed to evaluate the binding affinity and / or potency of mAb5 and mAb29 compared to an anti-ILRα monoclonal antibody (antibody 340) with an HC of SEQ ID NO:58 / LC of SEQ ID NO:59, described in U.S. Patent Application Publication No. 2020 / 0270340. Binding kinetics were measured by Octet® Biolayer Interferometry (BLI), and potency was measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells. As shown in Figures 8A-8B, mAb5 has a binding affinity of approximately 37 pm for human IL-11Rα (Figure 8A), while the 340 antibody has a significantly weaker (approximately 35-fold weaker) binding affinity of approximately 1.3 nM for human IL-11Rα (Figure 8B). As shown in Figures 9A-9C, mAb5 (Figure 9A) and mAb29 (Figure 9B) had strong functional potency as measured by pSTAT3 inhibition. In contrast, the 340 antibody (Figure 9C) showed no functional activity in this assay.

[0270] Example 4: Blocking IL-11Rα inhibits the production of inflammatory cytokines in orbital fibroblasts from TED patients Immune cell infiltration is a key pathological feature of TED and an area of ​​ongoing therapeutic research. In particular, upregulation of cytokines, including TNFα, IL-6, IL-8, and MCP-1 / CCL2, is thought to promote the activation of immune cells, including T cells and B cells, and orbital fibroblasts, which then lead to the expansion and remodeling of orbital tissue (Fallahy et al., Front Endocrinol (Lausanne). 12:654473 (2021); Lee et al., Best Pract Res Clin Endocrinol Metab. 37(2):101620 (2023); Zhang et al., J Immunol Res. 2528046 (2022)). We compared the inhibitory effects of mAb5 with teprotumumab, an approved treatment for TED, on a broad panel of cytokines after 96 hours of stimulation of patient-derived orbital fibroblasts with IL-11 and IGF-1. We then stimulated orbital fibroblasts with IL-11 or a combination of IL-11 and IGF-1 to assess the extent of inhibition of IL-6 and MCP-1 / CCL2 release by mAb5 and teprotumumab. Both of these cytokines are upregulated in TED and are thought to play a role in the pathogenesis of TED (Fallahy et al., Front Endocrinol (Lausanne). 12:654473 (2021)).

[0271] For the cytokine panel experiments, orbital fibroblasts were stimulated with the IL-11 + IGF-1 combination for 96 hours, and a panel of 96 cytokines was measured by multiplex analysis in response to inhibition by mAb5 or teprotumumab (Figure 13). ELISA was then used under similar treatment conditions to measure the specific effects of mAb5 and teprotumumab on the release of IL-6 and MCP-1 / CCL2 after stimulation with IL-11 alone or the IL-11 + IGF-1 combination (Figure 14).

[0272] As a single agent, IL-11 stimulated the release of both IL-6 and MCP-1 / CCL2 (Figures 14A and 14C). Combination stimulation with IL-11 and IGF-1 did not significantly increase release. Notably, mAb5 inhibited IL-6 and MCP-1 / CCL2 release under all treatment conditions, whereas teprotumumab had no effect (Figure 14). The ability of IL-11 to stimulate IL-6 and MCP-1 / CCL2 to the same extent as the combination treatment, combined with the lack of inhibition by teprotumumab, demonstrates that IL-11 is the primary inducer of IL-6 and MCP-1 / CCL2 release by orbital fibroblasts under these treatment conditions. These data also suggest that IL-11 is upstream of IL-6 as an inflammatory mediator in TED. This finding has important clinical implications given current efforts to therapeutically target the IL-6 pathway in TED. Taken together, these data provide evidence for a pathological role of IL-11 in inducing inflammation-mediated orbital tissue remodeling in TED.

[0273] Example 5: Comparison of mAb5 with commercially available antibodies against IL-11 and IL-11R A panel of commercially available antibodies against IL-11 and IL-11R were tested in comparison to mAb 5 for their ability to block HA production in orbital fibroblasts from TED patients. The antibodies tested are listed in Table E2 below. [Table 7]

[0274] These antibodies were directly compared to mAb5 using TED orbital fibroblasts stimulated with IL-11 and IGF-1, using the assay conditions described in Example 2. Cells from 12 separate tissue donors were used for all antibodies except MM09, which used six donors. Results are presented as fold average over vehicle conditions. The results, shown in Figure 15, clearly demonstrate that mAb5 is more effective against IL-11 or IL-11R than commercially available antibodies.

[0275] Example 6: Epitope mapping of mAb5 The epitope of mAb5 was determined by two mass spectrometry methods: hydrogen-deuterium exchange (HDX) and cross-linking / high-resolution mass spectrometry (XL-MS). This experiment was performed using a method developed by CovalX AG (Pimenova et al., J. Mass Spectrometry 43:185 (2008)). Briefly, human IL-11Rα was conjugated to mAb5 and cross-linked with a heterobifunctional linker. The resulting complex was digested with five different proteases (trypsin, chymotrypsin, ASP-N, elastase, and thermolysin), and the resulting peptides, whether cross-linked or not, were analyzed by high-resolution mass spectrometry. For HDX mapping, IL-11Rα was deuterium-labeled before and after complexation with mAb5, and the sites of differential deuterium labeling were determined by mass spectrometry.

[0276] The results indicated that mAb5 recognizes an epitope on the second extracellular domain of IL-11R. HDX mapping localized the binding epitope of mAb5 to the sequence ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261), spanning residues 115-134 in mature IL-11Rα (SEQ ID NO: 260). XL-MS mapping localized the epitope to amino acid residues in IL-11Rα that overlap and extend the epitope. As shown in Figure 16, cross-linking was confirmed at positions S116, S125, K129, S140, and T143. These results confirmed the binding of mAb5 to the second extracellular domain of IL-11R.

[0277] Example 7: Blocking IL-11 signaling using anti-IL-11Rα antibodies is effective in inhibiting IL-11 signaling in both cis and trans. It has been reported that IL-11 not only binds to IL-11Rα (in cis) on the same cell, forming a complex with the coreceptor gp130, but also signals in trans. In trans, soluble IL-11Rα forms a complex with IL-11 and signals to gp130-bearing cells (which may or may not bear IL-11Rα) (Lokau et al., BBA Mol. Cell Res. 1864, 2105-2117 (2017)). Therefore, to completely block IL-11 signaling, it is necessary to inhibit both cis and trans signaling. To achieve this, we tested the inhibition of IL-11 signaling in a cell-based pSTAT3 reporter assay to compare the potency of mAbs against IL-11 and IL-11R. In this assay, pSTAT3 stimulation was achieved by IL-11 (Figure 17A) or by a soluble IL-11R / IL-11 complex (Figure 17B). The soluble complex of IL-11R and IL-11 was achieved using a fusion protein of IL-11 and soluble IL-11R known as hyper-IL-11 (Dams-Kozlowska et al., BMC Biotechnol. 12:8 (2012)).

[0278] The STAT3 reporter (Luc)-HEK293 cell line was purchased from BPS Bioscience, catalog number 79800-P, and transfected with recombinant IL-11Rα. Cells were selected for IL-11Rα expression, and stable clones were isolated and used for further experiments. Cells were expanded, passaged, and assayed according to BPS Bioscience's protocol. Cells were plated at 25,000 cells per well in 96-well microtiter dishes and incubated at 37°C in 5% CO2 humidified air for 30–45 minutes. mAbs were added in duplicate to the rows or columns in serial dilutions, and the plate was returned to the incubator for an additional hour at 37°C. Then, 40 ng / mL IL-11 or hyper-IL-11 was added to each well to initiate the signaling cascade and luciferase production. Plates were incubated at 37°C for 18–24 h, and luciferase was detected using the One-Step Luciferase Assay System (BPS Bioscience, Cat. No. 60690-1) according to the manufacturer's instructions.

[0279] The results shown in Figure 17 indicate that when pSTAT3 signaling was initiated by IL-11, both mAb5 (anti-IL-11R) and anti-IL-11 mAb were approximately equally potent (IC50 5.6 nM for mAb5 and 4.2 nM for anti-IL-11). However, when stimulated with hyper-IL-11, mAbs against IL-11 were ineffective, whereas the potency of mAb5 remained unchanged (IC50 5.4 nM). This data confirms that mAb5 is effective in blocking IL-11 signaling both in cis and trans.

[0280] Example 8: mAb5 inhibits HA production stimulated by autoantibodies to TSHR Agonistic autoantibodies against TSHR are thought to be an important inducer of TED (Lee & Kahaly, Best Pract Res Clin Endocrinol Metab. 37(2):101620(2023)). M22 is an agonistic monoclonal autoantibody and has been widely used in experimental studies as a patient-derived autoantibody (Krieger et al., J. Clin. Endocrinol. Metab. 101, 2340-2347(2016)). Orbital fibroblasts from TED patients were cultured and tested as described in Example 2, except that PDGF was added to the culture medium to increase the cellular level of TSHR, as reported (van Steensel et al., J. Clin. Endocrinol. Metab. 97, E944-E953(2012)). M22 induced HA production in orbital fibroblasts from three donors. This production was effectively inhibited by both mAb5 and the positive control antibody teprotumumab (Figure 18). mAb5 appeared to be more potent and effective than teprotumumab in this experiment.

[0281] Example 9: Additional experiments performed Further experiments will be performed to determine the effect of using anti-IL11Rα antibodies on the secretion of HA, IL-11, and IL-6 from activated orbital fibroblasts and to determine whether the effect is equivalent to, synergistic with, or additive to IGF1R blockade.

[0282] Orbital fibroblasts from TED patients were stimulated with an anti-thyroid stimulating hormone receptor (TSHR) monoclonal antibody (the sequence corresponds to M22 from Kronus Bio) alone or in combination with IL-11, in the presence and absence of an anti-IL-11Rα antibody, teprotumumab, or both, to determine the effects on HA, IL-11, and IL-6. Supernatants were collected after 4 days for HA, IL-11, and IL-6 measurement by ELISA. IL-11R levels on orbital fibroblasts were determined by immunoblotting or staining.

[0283] Additional experiments will be conducted to evaluate the effects of TGFβ at 0.03, 0.3, and 3 ng / mL (as well as other doses) on orbital fibroblasts, as well as the ability of anti-IL11R antibodies to block these effects. Orbital fibroblast proliferation / myofibroblast formation by SMA, collagen, fibronectin, and IL-11R will be further evaluated 24-96 hours after treatment or 48-72 hours after treatment. Furthermore, supernatants will be collected at various time points between 48 and 72 hours, and inflammatory cytokines will be measured via ELISA, including IL-6, IL-8, procollagen, HA, and IL-11.

[0284] To compare IL-11 concentrations in serum / plasma from TED patients with those from healthy individuals, and to examine differences in IL-11 and IL-11R expression in ocular tissues from TED patients compared with normal ocular tissues, specifically in fibroblasts, myoblasts, and other relevant cell types.

Claims

1. 1. A method of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody, or antigen-binding fragment thereof, that binds to human interleukin-11 receptor subunit alpha (IL-11Rα).

2. 10. The method of claim 1, wherein the patient has one or more clinical signs of TED.

3. 3. The method of claim 2, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), dysfunction of the extraocular muscles (EOM), optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

4. 4. The method of claim 1, wherein the patient has a Clinical Activity Score (CAS) of 3 or greater, or 4 or greater, or 5 or greater, or 6 or greater, where the CAS is assigned a score of 1 for each of spontaneous orbital pain, gaze-induced orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and inflammation of the caruncle and semilunar folds.

5. 5. The method of any one of claims 1 to 4, wherein the patient has a VISA (Vision, Inflammation, Strabismus, Appearance / Exposure) score of 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater.

6. The method of any one of claims 1 to 5, wherein the patient has a thyroid dysfunction, optionally hyperthyroidism.

7. The method of any one of claims 1 to 6, wherein the patient has autoantibody stimulation of the thyroid stimulating hormone receptor (TSHR).

8. The method of any one of claims 1 to 7, wherein the patient has an increased level of thyroid-stimulating immunoglobulin (TSI).

9. The method of any one of claims 1 to 8, wherein the patient has Graves' disease.

10. The method of any one of claims 1 to 9, wherein the patient has one or more risk factors associated with TED.

11. 11. The method of claim 10, wherein the one or more risk factors are selected from female gender, middle age, smoking, and undergoing or having undergone treatment with radioactive iodine.

12. 12. The method of any one of claims 1 to 11, wherein the patient has increased levels of IL-11Rα and / or IL-11 in the blood or tissues around the eye, optionally in orbital fibroblasts, and / or the patient has increased levels of circulating IL-11.

13. a. determining whether the patient has TED, and b) administering said pharmaceutical composition to said patient if said patient has TED.

14. 14. The method of claim 13, wherein (a) optionally comprises measuring one or more clinical signs of TED selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in orbital tissues, and chemosis (swelling of the conjunctiva).

15. a. determining the CAS of the patient; and b) administering the pharmaceutical composition to the patient if the CAS is 3 or more, or 4 or more, or 5 or more, or 6 or more.

16. a. determining the VISA score of the patient; and b. The method of any one of claims 13 to 15, comprising administering the pharmaceutical composition to the patient if the VISA score is 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater.

17. a. determining thyroid function in said patient; and b) administering to said patient said pharmaceutical composition if said patient has thyroid dysfunction, optionally hyperthyroidism.

18. a. determining the level of thyroid-stimulating immunoglobulin (TSI) in said patient; and b) administering to the patient the pharmaceutical composition if the level of TSI in the patient is increased compared to a control or reference standard.

19. a. determining the levels of IL-11Rα and / or IL-11 in the blood or tissue surrounding the eye of said patient, and optionally in orbital fibroblasts; and b) administering to the patient the pharmaceutical composition if the level of IL-11Rα and / or IL-11 in the blood or tissues around the eye of the patient (optionally, orbital fibroblasts) is increased compared to a control or reference standard.

20. The method of any one of claims 1 to 19, wherein the patient is treatment-naive to a TED treatment and, optionally, is a chronic TED patient.

21. 20. The method of any one of claims 1 to 19, wherein the patient is undergoing or has previously undergone TED treatment and is relapsed / refractory / intolerant to said TED treatment, optionally an active TED patient.

22. 22. The method of claim 21, wherein the TED is progressing in the patient as indicated by a worsening of one or more clinical signs of TED, an increase in CAS score, and / or a worsening VISA score, optionally compared to the clinical signs or scores before the TED treatment, and optionally the TED is progressing more aggressively in the patient than before the TED treatment.

23. 23. The method of any one of claims 20 to 22, wherein the TED treatment is selected from insulin-like growth factor-1 receptor (IGF-1R) inhibitor therapy, FcRn inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-α (TNF-α) inhibitor therapy.

24. 24. The method of claim 23, wherein the IGF-1R inhibitor therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and fizitumumab therapies.

25. 24. The method of claim 23, wherein the FcRn inhibitory therapy is selected from the following therapies: batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab.

26. 24. The method of claim 23, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, revilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapies.

27. 24. The method of claim 23, wherein the steroid therapy is selected from methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapies.

28. 24. The method of claim 23, wherein the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

29. 24. The method of claim 23, wherein the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

30. 30. The method of any one of claims 1 to 29, comprising administering said pharmaceutical composition in combination with at least one additional TED treatment.

31. 31. The method of claim 30, wherein the at least one additional TED therapy is selected from IGF-1R inhibitor therapy, FcRn inhibitor therapy, IL-6 inhibitor therapy, corticosteroid therapy, orbital radiation therapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-alpha (TNF-α) inhibitor therapy.

32. 32. The method of claim 31 , wherein the IGF-1R inhibitor therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and fizitumumab therapies.

33. 33. The method of claim 32, wherein the IGF-1R inhibitor therapy is administered 1 to 7 times simultaneously with or consecutively with the administration of the pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or antigen-binding fragment thereof that binds to human IL-11Rα.

34. 32. The method of claim 31, wherein the FcRn inhibitory therapy is selected from the following therapies: batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab.

35. 32. The method of claim 31 , wherein the IL-6 inhibitor therapy is selected from clazakizumab, elcilimomab, revilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapies.

36. 32. The method of claim 31 , wherein the steroid therapy is selected from methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapies.

37. 32. The method of claim 31, wherein the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

38. 32. The method of claim 31, wherein the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

39. The method of any one of claims 1 to 38, wherein the antibody or antigen-binding fragment thereof binds to fibronectin domain III of human IL-11Rα or binds to about residues 90 to 197 of SEQ ID NO:

260.

40. The method of any one of claims 1 to 38, wherein the antibody or antigen-binding fragment thereof binds to the second extracellular domain of IL-11Rα.

41. 40. The method of claim 39, wherein the antibody or antigen-binding fragment thereof recognizes an epitope comprising the amino acid sequence of SEQ ID NO:

261.

42. 42. The method of claim 41, wherein the epitope comprises residues S116, S125, K129, S140 and T143 of SEQ ID NO:

260.

43. the antibody or antigen-binding fragment thereof a. V of a complementarity determining region selected from Table A1 Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The heavy chain variable region (V) containing the CDR3 amino acid sequence Ｈ ), and variants thereof that specifically bind to IL-11Rα; and b. V of a complementarity determining region selected from Table A1 Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ A light chain variable region (V) containing the CDR3 amino acid sequence Ｌ 43. The method of any one of claims 1 to 42, comprising the antibody or antibody fragment thereof that specifically binds to IL-11Rα.

44. a. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 1 to 3, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 4-6, respectively; b. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 7 to 9, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 10-12, respectively; c. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 13-15, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 16-18, respectively; d. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 19-21, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 22-24, respectively; e. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 25-27, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 28-30, respectively; f. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 31-33, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 34-36, respectively; g. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 34-39, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 40-42, respectively; h. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 43-45, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 46-48, respectively; i. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 49-51, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 52-54, respectively; j. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 55-57, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 58-60, respectively; k. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 61-63, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 64-66, respectively; l. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 67-69, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs:70-72, respectively; m. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 73-75, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 76-78, respectively; n. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 79-81, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 82-84, respectively; o. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 85-87, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 88-90, respectively; p. V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 91-93, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ CDR3 amino acid sequences include SEQ ID NOs:94-96, respectively; q. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences include SEQ ID NOs: 97-99, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 100-102, respectively; r. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 103-105, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 106-108, respectively; s. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 109-111, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 112-114, respectively; t. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 115-117, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 118-120, respectively; u. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 121-123, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 124-126, respectively; v. The above V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 127-129, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 130-132, respectively; w. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 133-135, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 136-138, respectively; x. The above V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 139-141, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 142-144, respectively; y. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 145-147, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 148-150, respectively; Z. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 151-153, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 154-156, respectively; dd. The above V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 157-159, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 160-162, respectively; ee. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 163-165, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 166-168, respectively; ff. The above V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 169-171, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 172-174, respectively; gg. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 175-177, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 178-180, respectively; hh. Said V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 181-183, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ the CDR3 amino acid sequences comprise SEQ ID NOs: 184-186, respectively; or ii. The V Ｈ CDR1 amino acid sequence, V Ｈ CDR2 amino acid sequence, and V Ｈ The CDR3 amino acid sequences comprise SEQ ID NOs: 187-189, respectively, and Ｌ CDR1 amino acid sequence, V Ｌ CDR2 amino acid sequence, and V Ｌ 44. The method of claim 43, wherein the CDR3 amino acid sequences comprise SEQ ID NOs: 190-192, respectively.

45. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to an amino acid sequence selected from Table A2, and optionally said V Ｈ 45. The method of claim 43 or 44, wherein said amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in the framework regions.

46. The V Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to an amino acid sequence selected from Table A2, and optionally said V Ｌ 46. ​​The method of any one of claims 43 to 45, wherein said amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 changes in the framework regions.

47. a. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; b. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196; c. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; d. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; e. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:202; f. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:204; g. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; h. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; i. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:210; j. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:211, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:212; k. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:214; l. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:216; m. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:218; n. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; o. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; p. V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; q. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; r. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228; s. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; t. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:232; u. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:234; v. The above V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:236; w. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:238; x. The above V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:240; y. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:242; z. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:244; dd. The above V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:246; ee. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:248; ff. The above V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250; gg. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; hh. Said V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and Ｌ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or ii. The V Ｈ comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and Ｌ 47. The method of any one of claims 43-46, wherein said sequence comprises an amino acid sequence that is at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO:

256.

48. The antibody, or antigen-binding fragment thereof, has the following characteristics: a. optionally, has increased binding affinity for human IL-11Rα compared to the 340 antibody, as measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells, and has increased functional potency compared to the 340 antibody; b. has a binding affinity for human IL-11Rα of less than about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 30 pM, optionally having an increased binding affinity for human IL-11Rα compared to the TS7 and 8E2 antibodies; c. antagonize the binding and / or signaling activity between IL-11Rα and IL-11, and optionally have increased potency as an IL-11 signaling antagonist compared to the TS7 and 8E2 antibodies; d. optionally, reducing IL-11Rα / gp130 dimerization or complex formation in a cell-based assay; and / or e. Optionally, V compared to TS7 and 8E2 antibodies Ｌ The method of any one of claims 1 to 47, wherein the CDR3 has reduced N-linked glycosylation.

49. 49. The method of any one of claims 1 to 48, wherein the antibody or antigen-binding fragment thereof comprises an IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or hybrids and / or variants thereof.

50. 50. The method of claim 49, wherein the antibody or antigen-binding fragment thereof comprises an IgG Fc domain, optionally an IgG1 or IgG3 Fc domain, that has enhanced effector function in humans.

51. 50. The method of claim 49, wherein the antibody or antigen-binding fragment thereof comprises an IgG Fc domain, optionally an IgG2 or IgG4 Fc domain, with reduced effector function in humans.

52. 50. The method of claim 49, wherein the antibody or antigen-binding fragment thereof optionally comprises a human IgG1 or IgG4 Fc domain selected from Table F1.

53. The method of any one of claims 1 to 52, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody.

54. 54. The method of any one of claims 1 to 53, wherein the antibody, or antigen-binding fragment thereof, is a humanized antibody, and optionally, the antibody, or antigen-binding fragment thereof, is a humanized monoclonal antibody comprising a human IgG4 Fc domain with a S228P mutation (EU numbering).

55. 54. The method of any one of claims 1 to 53, wherein the antibody, or antigen-binding fragment thereof, is selected from an Fv fragment, a single-chain Fv (scFv) polypeptide, an adnectin, anticalin, an aptamer, an avimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.

56. 56. The method of any one of claims 1 to 55, wherein the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the at least one antibody or antigen-binding fragment, and is substantially free of aggregates and endotoxins.

57. The composition optionally comprises the V Ｌ 57. The method of any one of claims 1 to 56, wherein the CDR3 sequences have reduced or undetectable heterogeneity in N-linked glycosylation (optionally compared to the TS7 and 8E2 antibodies).

58. 58. The method of any one of claims 1 to 57, wherein the pharmaceutical composition is optionally a sterile injectable solution suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.

59. 59. The method of any one of claims 1 to 58, wherein administering the pharmaceutical composition to the patient improves one or more clinical symptoms of TED.

60. 60. The method of claim 59, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyeball), lagophthalmos (incomplete eye closure), dysfunction of the extraocular muscles (EOM), optionally hypotropia (downward deviation) and / or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival hyperemia, excessive extracellular matrix accumulation in the orbital tissues, and chemosis (swelling of the conjunctiva).

61. 61. The method of any of claims 59 or 60, wherein administering the pharmaceutical composition to the patient improves the patient's Clinical Activity Score (CAS), optionally by at least 1, 2, 3, 4, or 5 points, optionally to a CAS of 3 or less, 2 or less, or 1 or less.

62. 62. The method of any one of claims 59-61, wherein administering the pharmaceutical composition to the patient improves the patient's VISA score, optionally by at least 1, 2, 3, 4, or 5 points, optionally to a VISA of 4 or less, 3 or less, 2 or less, or 1 or less.

63. 63. The method of any one of claims 1 to 62, wherein administering said pharmaceutical composition to said patient reduces the level of IL-11Rα and / or IL-11 in the blood or tissue surrounding the eye of said patient, and optionally in orbital fibroblasts.

64. 64. The method of any one of claims 1 to 63, wherein administering said pharmaceutical composition to said patient reduces the level of circulating IL-11 in said patient.

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