Anti-IL-11Ralpha antibodies for treatment of thyroid eye diseases

Abstract

The present invention provides methods of treating thyroid eye disease (TED) by administering an antibody, or and an antigen-binding fragment thereof, that binds to human interleukin-11 receptor subunit alpha (IL-11R alpha).

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 437,607 filed on January 6, 2023, U.S. Provisional Patent Application No. 63 / 444,492 filed on February 9, 2023, and U.S. Provisional Patent Application No. 63 / 466,112 filed on May 12, 2023, and U.S. Provisional Patent Application No. 63 / 529,910 filed on July 31, 2023, and U.S. Provisional Patent Application No. 63 / 529,910 filed on July 31, 2023 U.S. Provisional Patent Application No. 63 / 537,030, filed September 7, 2023, and U.S. Provisional Patent Application No. 63 / 592,899, filed October 24, 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 entirety. Background Art

[0003] Interleukin-11 (IL-11) is a member of the IL-6 family and plays an important role in chronic inflammation, autoimmunity, cancer and other diseases. It also plays a key role in pathological wound healing.

[0004] Thyroid eye disease (TED), also known as Graves' ophthalmopathy, is an autoimmune inflammatory disorder of the orbit and periorbital tissues characterized by upper eyelid retraction, eyelid hysteresis, swelling, redness (erythema), conjunctivitis, and proptosis (bulging eyes) (see, e.g., Bahn, The New England Journal of Medicine. 362(8):726-738, 2010). Treatments include topical lubrication of the eye 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 therapeutic approaches to treat TED. Provided herein are compositions and methods that address this need. Summary of the Invention

[0005] Embodiments of the present disclosure include methods 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) (see, e.g., PCT / US2022 / 075680, which is incorporated by reference in its entirety). In specific embodiments, the anti-IL-11Rα antibody or antigen-binding fragment thereof antagonizes or inhibits the 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.

[0006] 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 the group consisting of: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

[0007] In certain embodiments, the patient's Clinical Activity Score (CAS) is 3 or higher, or 4 or higher, 5 or higher, or 6 or higher, wherein the CAS includes one point 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 plica semilunaris. In some embodiments, the patient's VISA (vision, inflammation, strabismus, appearance / exposure) score is 4 or higher, 5 or higher, 6 or higher, 7 or higher, or 8 or higher. 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 elevated levels of thyroid stimulating immunoglobulin (TSI). In some embodiments, the patient suffers from Graves' disease.

[0008] 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 sex, middle-aged age, smoking, and current or past radioactive iodine treatment. In some embodiments, the patient has elevated levels of IL-11Rα and / or IL-11 in the blood or tissue surrounding the eye, such as in orbital fibroblasts. In some embodiments, the patient has elevated circulating IL-11 levels.

[0009] Some embodiments include the following steps:

[0010] (a) determine whether the patient has TED; and

[0011] (b) If the patient suffers from TED, administering the pharmaceutical composition to the patient.

[0012] In some embodiments, (a) comprises measuring one or more clinical signs of TED, optionally selected from: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability of the eyelid to fully close); extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

[0013] Some embodiments include the following steps:

[0014] (a) determine the patient's CAS; and

[0015] (b) if the CAS is 3 or higher, or 4 or higher, 5 or higher, or 6 or higher, administering a pharmaceutical composition to the patient.

[0016] Some embodiments include the following steps:

[0017] (a) determining the patient's VISA score; and

[0018] (b) administering the pharmaceutical composition to the patient if the VISA score is 4 or higher, 5 or higher, 6 or higher, 7 or higher, or 8 or higher.

[0019] Some embodiments include the following steps:

[0020] (a) determine the patient's thyroid function; and

[0021] (b) If the patient has abnormal thyroid function, optionally hyperthyroidism, administering the pharmaceutical composition to the patient.

[0022] Some embodiments include the following steps:

[0023] (a) determining the patient's thyroid stimulating immunoglobulin (TSI) level; and

[0024] (b) administering the pharmaceutical composition to the patient if the patient's TSI level is elevated relative to a control or reference standard.

[0025] Some embodiments include the following steps:

[0026] (a) determining the level of IL-11Rα and / or IL-11 in the patient's blood or tissue surrounding the eye, such as orbital fibroblasts; and

[0027] (b) administering the pharmaceutical composition to the patient if the level of IL-11Rα and / or IL-11 in the patient's blood or tissue surrounding the eye (eg, in orbital fibroblasts) is elevated relative to a control or reference standard.

[0028] Some embodiments include the following steps:

[0029] (a) determining the patient's circulating IL-11 level; and

[0030] (b) administering the pharmaceutical composition to the patient if the circulating IL-11 level is elevated relative to a control or reference standard.

[0031] In some embodiments, the patient is not receiving TED therapy, including patients with chronic TED.

[0032] In some embodiments, the patient is undergoing or has previously undergone TED therapy and is intolerant, relapsed, and / or refractory to the (previous) TED therapy. In some embodiments, recurrent TED patients are identified by an initial response to the previous TED therapy as measured by a decrease in proptosis, followed by a recovery of proptosis over a period of time despite continued treatment with the same TED therapy. In some embodiments, the decrease in proptosis is greater than about 2 mm. In some embodiments, recovery of proptosis is an increase in proptosis back to a pre-treatment baseline measurement. In some embodiments, recovery of proptosis is an increase in proptosis compared to the maximum response to the previous TED therapy. In some embodiments, recurrent TED patients are identified by an initial response to TED therapy as measured by a decrease in CAS score, followed by a reversal over a period of time despite continued treatment with the same TED therapy. In some embodiments, refractory patients are identified by insufficient improvement in proptosis. In some embodiments, insufficient improvement in proptosis is less than about 2 mm. In some embodiments, refractory patients are identified by minimal or no change in CAS score. In some embodiments, intolerant, recurrent, and / or refractory patients have active TED. In some cases, the patient's TED is progressing. In certain embodiments, TED in a patient in an intolerant / relapsed / refractory disease state progresses more aggressively in the patient than before TED therapy. In some embodiments, TED progression is indicated by worsening of one or more clinical signs of TED, an increase in CAS score, and / or an increase in VISA score compared to the clinical signs, CAS score, and / or VISA score before TED therapy. In certain such and related embodiments, the potency of the presently claimed antibodies and / or their different mechanism of action relative to prior (now inadequately responsive) TED therapies may provide a clinical advantage in treating progressive disease states, including more aggressive progressive disease states.

[0033] In some embodiments, the (prior) TED therapy 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 teixumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy. In some embodiments, the FcRn inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapy. In specific embodiments, the IL-6 inhibitory therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy. In some embodiments, the steroid therapy is selected from methylprednisolone (optionally, IV methylprednisolone sodium succinate), prednisolone (optionally, oral prednisolone), and prednisone (optionally, oral prednisone) therapy. In certain embodiments, the CD20 inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy. In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0034] In some embodiments, the patient is undergoing or has previously undergone tadalafil therapy and is intolerant, relapsed, and / or refractory to the (previous) tadalafil therapy. In some embodiments, recurrent TED patients are identified by measuring an initial response to the previous tadalafil therapy by a reduction in the degree of proptosis, followed by a recovery of the degree of proptosis after a period of time despite continued treatment with the same tadalafil therapy. In some embodiments, the reduction in the degree of proptosis is greater than about 2 mm. In some embodiments, the recovery of the degree of proptosis is an increase in the degree of proptosis back to the pre-treatment baseline measurement. In some embodiments, the recovery of the degree of proptosis is an increase in the degree of proptosis compared to the maximum response to the previous tadalafil therapy. In some embodiments, the initial response to tadalafil therapy is measured by a decrease in the CAS score, followed by a reversal after a period of time despite continued treatment with the same tadalafil therapy. In some embodiments, refractory patients are identified by insufficient improvement in proptosis. In some embodiments, insufficient improvement in proptosis is less than about 2 mm. In some embodiments, refractory patients are identified by minimal or no change in the CAS score. In some embodiments, the intolerant, relapsed, and / or refractory patient has active TED. In some cases, the patient's TED is progressing. In certain embodiments, the progression of TED in a patient in an intolerant / relapsed / refractory disease state is more aggressive than before tadalafil therapy. In some embodiments, TED progression is indicated by worsening of one or more clinical signs of TED, an increase in CAS score, and / or an increase in VISA score compared to the clinical signs, CAS score, and / or VISA score before tadalafil therapy. In certain such and related embodiments, the efficacy of the presently claimed antibodies and / or their different mechanism of action relative to prior (now inadequately responsive) tadalafil therapy can provide a clinical advantage in treating progressive disease states, including more aggressive progressive disease states. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for one half-life of tadalafil from the last dose of tadalafil. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for two half-lives of tadalafil from the last dose of tadalafil. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for three half-lives of tiuximab starting from the last dose of tiuximab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for four half-lives of tiuximab starting from the last dose of tiuximab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for five half-lives of tiuximab starting from the last dose of tiuximab.In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 6 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 7 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 8 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 9 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 10 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for more than 10 half-lives of Titumumab from the last dose of Titumumab.

[0035] Certain embodiments include combination therapies, wherein the method comprises administering a pharmaceutical composition comprising an anti-IL-11Rα antibody or antigen-binding fragment thereof and at least one other TED therapy.

[0036] In some embodiments, the at least one other TED therapy is administered prior to administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the at least one other TED therapy is administered concurrently with administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, administration of the at least one other TED therapy and administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure are performed sequentially. In some embodiments, the at least one other TED therapy is administered in the same composition as the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the at least one other TED therapy is administered in a separate composition from the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure.

[0037] In some embodiments, the at least one other 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 teitutumumab, ganitutumumab, darotolumab, citumumab, and phentolumab therapy. In some embodiments, the FcRn inhibitory therapy is selected from bartolimumab (IMVT-1401), agamod, nicallimab, onorimab, and lorixizumab therapy. In some embodiments, the IL-6 inhibitor therapy is selected from clatuzumab, ecitumomab, levitra, olotumumab, sarrellumab, siltuximab, sirukumab, and tocilizumab therapy. In certain embodiments, the steroid therapy is selected from methylprednisolone (optionally, IV methylprednisolone sodium succinate), prednisolone (optionally, oral prednisolone), and prednisone (optionally, oral prednisone) therapy. In some embodiments, the CD20 inhibitor therapy is selected from isobetamin, obinutuzumab, octomel, ofavumab, rituximab, and utoximab therapy. In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.

[0038] In some embodiments, the at least one other TED therapy is an IGF-1R inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody, such as teixumab, ganituzumab, darotolumab, cixitumumab, or phentolumab therapy. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered concurrently with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered prior to the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the administration of the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) and the administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure are performed sequentially. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) and the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure are administered in the same composition. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered in a composition separate from the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., 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., 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., 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, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered about 1 to about 5 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., IGF-1R antibody) is administered about 1 to about 6 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the disclosure. In some embodiments, IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered about 1 to about 7 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the disclosure.

[0039] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to fibronectin domain III of human IL-11Rα, or 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.

[0040] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof binds to an epitope spanning residues 115-134 of IL-11Rα. In certain embodiments, exemplary antibodies of the present disclosure that exhibit such binding comprise V represented by SEQ ID NOs: 25-27, respectively. H CDR1, V H CDR2 and V H CDR3 sequences, and V sequences represented by SEQ ID NOs: 28-30, respectively. L CDR1, V L CDR2 and V L In certain embodiments, exemplary antibodies of the present disclosure that exhibit such binding comprise a CDR3 sequence of SEQ ID NO: 201. H Sequence and V of SEQ ID NO: 202 L sequence.

[0041] 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 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 further comprises crosslinks at positions S138, S147, K151, S162, and T165.

[0042] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (V H ), which comprises a complementarity determining region V selected from Table A1 H CDR1, V H CDR2 and V H CDR3 sequences and their variants that specifically bind to IL-11Rα; and light chain variable region (V L ), which comprises a complementarity determining region V selected from Table A1 L CDR1, V L CDR2 and V L CDR3 sequences and their variants that specifically bind to IL-11Rα.

[0043] In a specific embodiment:

[0044] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 1-3, respectively, and the V LCDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 4-6, respectively;

[0045] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 7-9, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 10-12, respectively;

[0046] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 13-15, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 16-18, respectively;

[0047] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 19-21, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 22-24, respectively;

[0048] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 25-27, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 28-30, respectively;

[0049] The V H CDR1 sequence, the V H CDR2 sequence and the V HThe CDR3 sequences comprise SEQ ID NOs: 31-33, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 34-36, respectively;

[0050] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 34-39, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 40-42, respectively;

[0051] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 43-45, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 46-48, respectively;

[0052] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 49-51, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 52-54, respectively;

[0053] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 55-57, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 58-60, respectively;

[0054] The V H CDR1 sequence, the V Hthe CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 61-63, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 64-66, respectively;

[0055] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 67-69, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 70-72, respectively;

[0056] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 73-75, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 76-78, respectively;

[0057] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 79-81, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 82-84, respectively;

[0058] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 85-87, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 88-90, respectively;

[0059] the V Hthe CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 91-93, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 94-96, respectively;

[0060] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 97-99, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 100-102, respectively;

[0061] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 103-105, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 106-108, respectively;

[0062] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 109-111, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 112-114, respectively;

[0063] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 115-117, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 118-120, respectively;

[0064] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 121-123, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 124-126, respectively;

[0065] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 127-129, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 130-132, respectively;

[0066] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 133-135, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 136-138, respectively;

[0067] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 139-141, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 142-144, respectively;

[0068] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 145-147, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the VL The CDR3 sequences comprise SEQ ID NOs: 148-150, respectively;

[0069] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 151-153, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 154-156, respectively;

[0070] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 157-159, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 160-162, respectively;

[0071] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 163-165, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 166-168, respectively;

[0072] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 169-171, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 172-174, respectively;

[0073] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 175-177, respectively, and the VL CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 178-180, respectively;

[0074] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 181-183, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or

[0075] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 187-189, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 190-192, respectively.

[0076] In certain embodiments, the V H comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from Table A2, optionally wherein said V H There are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 changes in the framework regions. In certain embodiments, the V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from Table A2, optionally wherein said V L There are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 alterations in the framework regions.

[0077] In a specific embodiment:

[0078] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 193, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 194;

[0079] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 195, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 196;

[0080] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 197, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 198;

[0081] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 199, and wherein said V L comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 200;

[0082] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 201, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 202;

[0083] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 203, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 204;

[0084] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 205, and wherein said V Lcomprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 206;

[0085] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 207, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 208;

[0086] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 209, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 210;

[0087] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 211, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 212;

[0088] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 213, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 214;

[0089] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 215, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 216;

[0090] The V Hcomprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 217, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 218;

[0091] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 219, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 220;

[0092] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 221, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 222;

[0093] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 223, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 224;

[0094] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 225, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 226;

[0095] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 227, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 228;

[0096] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 229, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 230;

[0097] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 231, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 232;

[0098] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 233, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 234;

[0099] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 235, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 236;

[0100] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 237, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 238;

[0101] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 239, and wherein said V Lcomprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 240;

[0102] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 241, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 242;

[0103] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 243, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 244;

[0104] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 245, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 246;

[0105] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 247, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 248;

[0106] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 249, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 250;

[0107] The V Hcomprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 251, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 252;

[0108] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 253, and wherein said V L comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 254; or

[0109] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 255, and wherein said V L Comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO:256.

[0110] In certain embodiments, the antibodies or antigen-binding fragments thereof have one or more of the following characteristics:

[0111] the isolated antibody or antigen-binding fragment thereof has a binding affinity for human IL-11Rα of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM or 30 pM, and optionally has an increased binding affinity for human IL-11Rα relative to the binding affinity of the TS7 antibody and the 8E2 antibody;

[0112] The isolated antibody or antigen-binding fragment thereof antagonizes the binding and / or signaling activity between IL-11Rα and IL-11, and optionally the isolated antibody or antigen-binding fragment thereof has increased potency as an IL-11 signaling antagonist relative to the potency of the TS7 antibody and the 8E2 antibody;

[0113] The isolated antibody or antigen-binding fragment thereof reduces IL-11Rα / gp130 dimerization or complex formation, optionally in a cell-based assay; and / or

[0114] Optionally, the isolated antibody or antigen-binding fragment thereof is at V relative to the TS7 antibody and the 8E2 antibody.L N-linked glycosylation in CDR3 is reduced.

[0115] In some embodiments, the IL-11Rα antibody or its antigen-binding fragment 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 certain embodiments, the antibody or its antigen-binding fragment comprises an IgG Fc domain with high effector function in humans, optionally an IgG1 or IgG3 Fc domain. In some embodiments, the antibody or its antigen-binding fragment comprises an IgG Fc domain with low effector function in humans, optionally an IgG2 or IgG4 Fc domain. In certain embodiments, the antibody or its antigen-binding fragment comprises a human IgG1 or IgG4 Fc domain, optionally selected from Table F1.

[0116] 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, including wherein the antibody or antigen-binding fragment thereof is a humanized monoclonal antibody comprising a human IgG4 Fc domain having an S228P mutation (EU numbering).

[0117] In certain embodiments, the IL-11Rα antibody or antigen-binding fragment thereof is selected from an Fv fragment, a single-chain Fv (scFv) polypeptide, fibronectin, anticalin, an aptamer, a high-affinity multimer, a camel antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a monoclonal antibody.

[0118] In certain embodiments, the composition is at least about 80%, 85%, 90%, 95%, 98% or 99% pure on a protein basis relative to the antibody or antigen-binding fragment and is substantially free of aggregates and endotoxins. L The composition has reduced or undetectable heterogeneity of N-linked glycosylation in the CDR3 sequence (optionally relative to the TS7 antibody and the 8E2 antibody). In certain embodiments, the pharmaceutical composition is a sterile injectable solution, optionally suitable for intravenous, intramuscular, subcutaneous or intraperitoneal administration.

[0119] In certain embodiments, administration of the pharmaceutical composition to a patient improves one or more clinical signs of TED. In some embodiments, the one or more clinical signs are selected from the group consisting of: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

[0120] In certain embodiments, administration of the pharmaceutical composition to a patient can improve the patient's Clinical Activity Score (CAS), optionally by at least one, two, three, four, or five points, optionally to a CAS of 3 or less, 2 or less, or 1 or less. In some embodiments, administration of the pharmaceutical composition to a patient can improve the patient's VISA score, optionally by at least one, two, three, four, or five points, optionally to a VISA of 4 or less, 3 or less, 2 or less, or 1 or less. In specific embodiments, administration of the pharmaceutical composition to a patient can reduce the level of IL-11Rα or IL-11 in the blood or tissue around the patient's eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] Figures 1A-1C Cell surface expression on fibroblasts from orbital tissue of TED patients compared to healthy (non-TED) patients is shown. Figure 1A Display CD90 expression, Figure 1B exhibit CD45 expression, and Figure 1C IL-11Rα expression using mAb5 antibody is shown. Healthy control (dashed line); TED (black line); unstained / secondary Ab alone (light grey line).

[0122] Figure 2 Hyaluronic acid release from orbital fibroblasts pre-incubated with medium alone (no antibody control) or mAb5 (10 μg / mL) for 1 hour, followed by restimulation with human recombinant IL-11 (1.1, 3.3, or 10 ng / mL) for 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 cells treated with mAb5 using one-way ANOVA and Dunnet's post hoc multiple comparison test.

[0123] Figure 3Cell proliferation of orbital fibroblasts pre-incubated with medium alone (no antibody control) or mAb5 (10 μg / mL) for 1 hour followed by restimulation with human recombinant IL-11 (1.1, 3.3, or 10 ng / mL) for 96 hours is shown. 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 cells treated with mAb5 using one-way ANOVA with Dunnet's post hoc multiple comparison test.

[0124] Figures 4A-4C Shown are the dose-dependent effects of IL-11 on hyaluronan release from orbital fibroblasts from patient sample #2 ( in the presence of mAb5 (10 ng / mL, hatched) and in the absence of mAb5 (solid). Figure 4A , no prior TED therapy), patient sample #1 ( Figure 4B , prior titumomab therapy) and patent sample #3 ( Figure 4C , previous corticosteroid therapy).

[0125] Figures 5A-5C The effects of 3, 10, 30, and 100 μg / mL of mAb5 on IL-11 (10 ng / mL)-induced HA release from orbital fibroblasts from patient samples #2, #4, and #5 ( Figure 5A , no prior TED therapy), patient sample #1 ( Figure 5B , prior tiuximab therapy) and patient sample #3 ( Figure 5C , previous corticosteroid therapy).

[0126] Figures 6A-6C Comparative inhibitory effects of mAb5, tetumumab, and isotype control (all at 10 μg / mL) on HA release induced by 10 ng / mL IL-11 in orbital fibroblasts from TED patients are shown; Figure 6A Effects are shown on naive patient samples (no prior TED therapy, n=4), Figure 6B Demonstrate effects on samples of patients previously treated with teixumab (n=1), and Figure 6C Effects are shown for samples of patients previously treated with corticosteroids (n=2).

[0127] Figures 7A-7C The comparative effects of mAb5, teituzumab, and an isotype control antibody (all at 10 μg / mL) on the proliferation of orbital fibroblasts from TED patients induced by 10 ng / mL IL-11 are shown; Figure 7AEffects are shown on naive patient samples (no prior TED therapy, n=4), Figure 7B Demonstrate effects on samples of patients previously treated with teixumab (n=1), and Figure 7C Effects are shown for samples of patients previously treated with corticosteroids (n=2).

[0128] Figures 8A-8B mAb5 was shown to have a binding affinity of approximately 37 pM for human IL-11Rα ( Figure 8A ), and the 340 antibody has a significantly weaker (approximately 35-fold) binding affinity of approximately 1.3 nM for human IL-11Rα ( Figure 8B ).

[0129] Figures 9A-9C Display 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.

[0130] Figure 10 The combined effect of mAb5 and telostatin on HA release following stimulation with IL-11 + IGF-1 in orbital fibroblasts is shown. Data are from n≥8 donors from two separate studies. #### indicates p<0.0001 relative to vehicle, *** indicates p<0.001; **** indicates p<0.0001 relative to IGF-1 + IL-11, Ф indicates p<0.05 relative to the combination of telostatin + mAb5, as determined 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 telostatin (10 μg / mL).

[0131] Figures 11A-11B The dose response curve of mAb5 is shown as shown by its effect on pSTAT3 in orbital fibroblasts from TED patients ( Figure 11A ) and HA release ( Figure 11B ) is measured by the effect of

[0132] Figure 12A Procollagen I release (ng / mL) from orbital fibroblasts from n=6 TED donors stimulated with TGFβ (5 ng / mL) for 96 hours is shown. Figure 12BDemonstrates inhibition of TGFβ-stimulated procollagen I release from orbital fibroblasts from n=6 TED donors, pre-incubated for 1 hour with mAb5 (3 μg / mL) or teixumab (10 μg / mL), followed by restimulation with human recombinant TGFβ (5 ng / mL) for 96 hours. ### indicates p<0.001 relative to vehicle; ** indicates p<0.01 relative to TGFβ control, as determined by one-way ANOVA with Dunnett's post hoc multiple comparison test.

[0133] Figure 13 mAb5 is shown to reduce multiple cytokines in orbital fibroblasts after stimulation with IL-11 + IGF-1. Cytokine release from human orbital fibroblasts was pre-incubated with mAb5 (3 μg / mL) or tetumumab (10 μg / mL) for 1 hour and then restimulated with a combination of human recombinant IL-11 + IGF-1 (100 ng / mL) for 96 hours. Cell supernatants were measured by multiplex analysis by Eve Technologies (Calgary, CAN), and data are presented as individual replicates of n=6 TED patients per treatment.

[0134] Figures 14A-14D mAb5 was shown to be more effective than tetoclax in inhibiting the release of IL-6 and MCP-1 / CCL2 in human orbital fibroblasts. Figure 14A and B) and MCP-1( Figure 14C and D) release, the orbital fibroblasts were preincubated with mAb5 (3 μg / mL) or tetumumab (10 μg / mL) for 1 h and then treated with human recombinant IL-11 (10 ng / mL; Figure 14A and C) or IL-11+IGF-1 combination (100 ng / mL; Figure 14B and D) restimulation for 96 hours. Data represent mean ± SEM of n = 6 TED patients, as compared by one-way ANOVA with Dunnett's post hoc test. ### indicates p < 0.001, #### indicates p < 0.0001 relative to vehicle. **** indicates p < 0.05, ** indicates p < 0.01, **** indicates p < 0.0001 relative to isotype-only control, as determined by one-way ANOVA with Dunnett's post hoc multiple comparison test.

[0135] Figure 15A panel of commercially available antibodies against IL-11 and IL-11Rα is shown, and their ability to inhibit HA production by TED donor orbital fibroblasts stimulated with IL-11 and IGF-1 is compared to mAb 5. Antibodies against IL-11 are shown in dark grey bars, and antibodies against IL-11Rα are shown in black bars.

[0136] Figure 16 A partial sequence of IL-11Rα is shown, and the epitope of mAb5 is shown. Two mass spectrometry methods were used to map the epitope of mAb5. The epitope identified by HDX-MS is shown in bold, spanning residues 115-134 of mature IL-11Rα. Crosslinks identified by XL-MS are indicated at positions S138, S147, K151, S162, and T165, indicating that these residues are located at or near the mAb5 epitope.

[0137] Figures 17A-17B This indicates that anti-IL-11Rα mAb5 effectively inhibits IL11 and hyper IL-11 signaling.A luciferase reporter gene assay was used to test the inhibition of STAT3 phosphorylation. Figure 17A The inhibition of IL-11 signaling induced by the addition of IL-11 is shown. The solid line and circular symbols are data for mAb5, and the dotted line and triangular symbols are data for anti-IL-11 mAb. Figure 17B Demonstrates inhibition of STAT3 phosphorylation induced by super IL-11. Symbols and lines for each antibody are as follows: Figure 17A mAb5 effectively inhibited signaling in both assays, whereas anti-IL-11 mAb effectively inhibited signaling induced only by IL-11 but not by super-IL-11 (soluble receptor IL-11 complex).

[0138] Figure 18 The ability of mAb5 to reduce M22-stimulated HA production in TED orbital fibroblasts is demonstrated. HA release from human orbital fibroblasts was pre-incubated for 1 hour with mAb5 (1 or 10 μg / mL) or tebuconazole (10 μg / mL) followed by stimulation with the TSHR agonist antibody M22. Three donors were used, and data are presented as mean HA levels (ng / mL). The stimulation window for M22 is indicated by the dotted line. DETAILED DESCRIPTION

[0139] The present disclosure relates to 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). In some embodiments, the antibody or antigen-binding fragment thereof binds to the fibronectin domain III of human IL-11Rα or the second extracellular domain of IL-11Rα and antagonizes the binding and / or signaling activity between IL-11Rα and IL-11. Exemplary antibodies and antigen-binding fragments thereof are described herein.

[0140] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of virology, immunology, microbiology, molecular biology and recombinant DNA techniques within the skill of the art, many of which are described below for the purpose of illustration. Such techniques are fully explained in the literature. See, e.g., Current Protocols in Molecular Biology or Current Protocols in Immunology, John Wiley & Sons, New York, N.Y. (2009); Ausubel, et al., Short Protocols in Molecular Biology, 3rdEd., Wiley & Sons, 1995; Sambrook and Russell, Molecular Cloning: A Laboratory Manual (3rdEd., 2001); Maniatis et al., Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A Practical Approach, Volumes 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.

[0141] Definitions

[0142] As used in this specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise.

[0143] “About” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by up to 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% relative to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0144] The term "antigen" refers to a molecule or a part of a molecule that can be bound by a selective binding agent such as an antibody and can additionally be used in an animal to produce an antibody that can bind to the epitope of the antigen. An antigen can have one or more epitopes. As used herein, the term "antigen" includes substances that can induce an immune response to a substance under appropriate conditions and can react with the product of the immune response. For example, an antigen can be recognized by an antibody (humoral immune response) or a sensitized T lymphocyte (helper T cell or cell-mediated immune response) or both. An antigen can be a soluble substance (such as toxins and foreign proteins) or a particle (such as bacteria and tissue cells); however, only the part of a protein or polysaccharide molecule that is called an antigenic determinant (epitope) is combined with a specific receptor on an antibody or lymphocyte. More broadly speaking, the term "antigen" includes any substance to which an antibody binds or requires an antibody, regardless of whether the substance is immunogenic. For such antigens, antibodies can be identified by recombinant methods, which has nothing to do with any immune response.

[0145] "Antagonist" refers to an agent (e.g., an antibody) that interferes with or otherwise weakens the physiological effects of another agent or molecule. In some cases, an antagonist specifically binds to another agent or molecule. Both full and partial antagonists are included.

[0146] "Agonist" refers to an agent (e.g., an antibody) that increases or enhances the physiological effects of another agent or molecule. In some cases, an agonist specifically binds to another agent or molecule. This includes both full and partial agonists.

[0147] As used herein, the term "amino acid" is intended to refer to naturally occurring and non-naturally occurring amino acids, as well as amino acid analogs and mimetics. For example, naturally occurring amino acids include the 20 (L)-amino acids used during protein biosynthesis, as well as other amino acids such as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, homocysteine, citrulline, and ornithine. Non-naturally occurring amino acids include, for example, (D)-amino acids, norleucine, norvaline, p-fluorophenylalanine, ethionine, and the like, known to those skilled in the art. Amino acid analogs include modified forms of naturally occurring and non-naturally occurring amino acids. Such modifications can include, for example, substitution or replacement of chemical groups and moieties on the amino acids, or by derivatization of the amino acids. Amino acid mimetics include, for example, organic structures that exhibit functionally similar properties to those of the reference amino acids, such as charge and charge spacing characteristics. For example, an organic structure that mimics arginine (Arg or R) will have a positively charged moiety positioned in a similar molecular space and with the same mobility as the ε-amino group of the side chain of the naturally occurring Arg amino acid. Mimetics also include constrained structures to maintain optimal spacing and charge interactions between amino acids or amino acid functional groups. Those skilled in the art know or can determine which structures constitute functionally equivalent amino acid analogs and amino acid mimetics.

[0148] As used herein, the term "antibody" encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (e.g., dAb, Fab, Fab', F(ab')2, Fv), single chains (scFv), synthetic variants thereof, naturally occurring variants, fusion proteins comprising an antibody portion having an antigen-binding fragment with the desired specificity, humanized antibodies, chimeric antibodies, and any other modified configuration of an immunoglobulin molecule comprising an antigen-binding site or fragment (epitope recognition site) with the desired specificity. Certain features and properties of antibodies (and antigen-binding fragments thereof) are described in more detail herein.

[0149] 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 that is 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.

[0150] As used herein, the term "antigen-binding fragment" refers to a polypeptide fragment containing at least one CDR of an immunoglobulin heavy and / or light chain that binds an antigen of interest. In this regard, an antigen-binding fragment of an antibody described herein may include a V or V region from an antibody that binds to a target molecule. H and V L In certain embodiments, the antigen-binding fragments of the present disclosure comprise one, two, three, four, five or all six CDRs of the sequence of an antibody disclosed herein.H and V L All 6 CDRs of the sequence.

[0151] 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, an antibody or antigen-binding fragment thereof binds a target molecule (e.g., an IL-11Ra polypeptide or an epitope or complex thereof) with a dissociation constant of about or ranging from about <10 -7 M to about 10 -8 M. In some embodiments, the antibody or antigen-binding fragment thereof binds a target molecule (e.g., an IL-11Ra polypeptide or an epitope or complex thereof) with a dissociation constant of about or ranging from about <10 -9 M to about <10 -10 M. In certain illustrative embodiments, the affinity (K D or EC 50 ) of an antibody or antigen-binding fragment thereof for a target molecule (the target to which it specifically binds) is about, at least about, or less than about 0.01 nM, 0.05 nM, 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 26 nM, 27 nM, 28 nM, 29 nM, 30 nM, 40 nM, or 50 nM.

[0152] A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates with a specific cell, substance, or specific epitope more frequently, more rapidly, for a longer duration, and / or with a higher affinity than a molecule, such as a polypeptide or antibody, to react or associate with a specific cell, substance, or epitope to an alternative cell, substance, or epitope. An antibody "specifically binds" or "preferentially binds" to a target molecule or epitope if it binds with higher affinity, higher avidity, more readily, and / or for a longer duration than it binds to other substances or epitopes, e.g., if the superiority reaches a statistically significant amount. Typically, one member of a pair of molecules exhibiting specific binding has an area on its surface or has a cavity that specifically binds to and is therefore complementary to a specific spatial and / or polar organization of the other member of the pair. Thus, the members of a pair of molecules have the property of specifically binding to each other. For example, an antibody that specifically or preferentially binds to a particular epitope is an antibody that binds to a particular epitope with greater affinity, with greater avidity, more readily, and / or for a longer duration than it binds to other epitopes. It should also be understood from reading this definition that, for example, an antibody (or portion or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. The term also applies to situations where, for example, an antibody is specific for a particular epitope carried by multiple antigens, in which case a particular binding member carrying an antigen binding fragment or domain will be able to bind to the various antigens carrying the epitope; for example, it may be cross-reactive to multiple different forms of a target antigen from multiple species that share a common epitope.

[0153] Immunological binding generally refers to non-covalent interactions between immunoglobulin molecules and antigens for which the immunoglobulin is specific, such as those occurring due to, for example but not limited to, 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 can be measured in terms of the dissociation constant (K) of the interaction. D ) aspect, where the smaller K D Indicates greater affinity. The immunological binding properties of a selected polypeptide can be quantified using methods well known in the art. One such method requires measuring the rates of formation and dissociation of the antigen binding site / antigen complex, where those rates depend on the concentration of the complex partners, the affinity of the interaction, and on geometric parameters that affect the rates equally in both directions. Thus, the "association rate constant" (Kon) and the "dissociation rate constant" (Koff) can be determined by calculating the concentration and actual rates of association and dissociation. The ratio of Koff / Kon allows for the elimination of all parameters unrelated to affinity and is therefore equal to the dissociation constant K. DAs used herein, the term "affinity" encompasses the equilibrium constant for the reversible binding of two agents and is expressed as K D or EC 50 The affinity of a binding protein for 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). Alternatively, as used herein, the term "avidity" refers to the resistance of a complex of two or more agents to dissociation upon dilution. In some embodiments, affinity is expressed as a half maximal effective concentration (EC 50 ) indicates that the half-maximal effective concentration is the concentration of an agent (eg, an anti-IL-11Rα antibody) as disclosed herein that induces a response halfway between baseline and maximum after a specified exposure time. EC 50 Often used as a measure of an antibody's potency.

[0154] Antibodies can be prepared by any of a variety of techniques known to those of ordinary skill in the art. See, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. Monoclonal antibodies specific for the polypeptide of interest can be prepared, for example, using the techniques of Kohler and Milstein, Eur. J. Immunol. 6:511-519 and modifications thereof. Also included are methods of expressing human antibodies using transgenic animals such as mice. See, for example, 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. Specific examples include of Platform (see, eg, US Patent No. 6,596,541).

[0155] Antibodies can also be produced or identified by using phage display libraries or yeast display libraries (see, for example, 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 variable region genes and seven light chain variable region genes. The combination of these genes produces 49 frameworks in the master library. By superimposing highly variable gene cassettes (CDR=complementarity determining regions) on these frameworks, a large human antibody repertoire can be replicated. Also included are human libraries designed with fragments of human donor origin encoding light chain variable regions, heavy chain CDR-3, synthetic DNA encoding the diversity in heavy chain CDR-1, and synthetic DNA encoding the diversity in heavy chain CDR-2. Other libraries suitable for use will be clear to those skilled in the art.

[0156] In certain embodiments, antibodies and Fab thereof as described herein comprise heavy chain and light chain CDR groups inserted respectively between heavy chain and light chain framework region (FR) groups, and the FR groups provide support to CDR and limit the spatial relationship of CDR relative to each other. As used herein, the term "CDR group" refers to three hypervariable regions in heavy chain or light chain V district. Starting from the N-terminal of heavy chain or light chain, these districts are respectively expressed as "CDR1", "CDR2" and "CDR3". Therefore, the antigen binding site comprises six CDRs, which include the CDR groups from each of the heavy chain and light chain V districts. The polypeptide comprising a single CDR (e.g., CDR1, CDR2 or CDR3) is referred to as a "molecular recognition unit" in this article. Crystallographic analysis of multiple antigen-antibody complexes has shown that the amino acid residues of CDR form extensive contacts with the antigen of combination, wherein the most extensive antigen contact is the antigen contact with heavy chain CDR3. Therefore, the molecular recognition unit is primarily responsible for the specificity of the antigen binding site.

[0157] As used herein, the term "FR group" refers to the four flanking amino acid sequences of the CDRs in the CDR group that frame the heavy or light chain V region. Some FR residues may contact the bound antigen; however, the FR is primarily responsible for folding the V region into an antigen binding site, particularly the FR residues directly adjacent to the CDRs. Within the FRs, certain amino acid residues and certain structural features are very highly conserved. In this regard, most V region sequences contain an internal disulfide loop consisting of approximately 90 amino acid residues. When the V region folds into the binding site, the CDRs are displayed as protruding loop motifs that form the antigen binding surface. It is generally recognized that there are conserved structural regions of FRs that convert the folded shape of the CDR loops into certain "canonical" structures - regardless of the precise CDR amino acid sequence. Further, it is known that certain FR residues participate in non-covalent interdomain contacts that stabilize the interaction between the antibody heavy and light chains.

[0158] 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 ed., US Department of Health and Human Services 1987, and updates thereto.

[0159] Also included are "monoclonal" antibodies, which refer to a homogeneous antibody population, wherein the monoclonal antibody comprises amino acids (naturally occurring and non-naturally occurring) that participate in the selective binding of an epitope. The term "monoclonal antibody" encompasses not only complete monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chains (scFv), variants thereof, fusion proteins including antigen-binding portions, humanized monoclonal antibodies, chimeric monoclonal antibodies, and immunoglobulin molecules comprising antigen-binding fragments (epitope recognition sites) with the desired specificity and capable of binding to an epitope. Any other modified configuration is not intended to limit the source of the antibody or the manner in which it is formed (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals). The term encompasses all immunoglobulins and the fragments described above under the definition of "antibody," etc.

[0160] The Fv fragment for use according to some embodiments can be produced by preferential proteolytic cleavage of IgM, and can be produced by preferential proteolytic cleavage of IgG or IgA immunoglobulin molecules in rare cases. However, more commonly, recombinant techniques as known in the art are used to obtain the Fv fragment. Fv fragments comprise non-covalent VH::VL heterodimers comprising an antigen binding site that retains many 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, Fv is stabilized by other means, such as by incorporation of at least one disulfide bond ( and Pluckthun, J. Mol. Biol. 305, 989-1010, 2001).

[0161] In certain embodiments, single-chain Fv (scFV) antibodies are contemplated. For example, kappa bodies (111 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 regarding selection of antibodies with desired specificity.

[0162] Single-chain Fv (scFv) polypeptides are covalently linked VH::VL heterodimers expressed according to a gene fusion comprising VH and VL encoding genes connected by a peptide-encoded linker. Huston et al., (PNAS USA. 85(16):5879-5883, 1988). Various methods have been described for identifying the chemical structure 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 the 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.

[0163] In certain embodiments, the antibodies or antigen-binding fragments described herein take the form of "bifunctional antibodies". Bifunctional antibodies are multimers of polypeptides, each polypeptide comprising a first domain and a second domain, wherein the first domain comprises a binding region for an immunoglobulin light chain, and the second domain comprises a binding region for an immunoglobulin heavy chain, wherein the two domains are connected (e.g., by a peptide linker) but cannot associate with each other to form an antigen binding site: the antigen binding site is formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94 / 13804). The dAb fragment of an antibody consists of a VH domain (Ward et al., Nature 341:544-546, 1989). Bifunctional antibodies and other multivalent or multispecific fragments can be constructed, for example, by gene fusion (see WO94 / 13804; and Holliger et al., Proceedings of the National Academy of Sciences of the United States of America 90:6444-6448, 1993).

[0164] Also included are minibodies comprising an scFv linked to a CH3 domain (see Hu et al., Cancer Res. 56:3055-3061, 1996). See also Ward et al., Nature 341:544-546, 1989; Heinze et al., Science 242:423-426, 1988; Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988); PCT / US92 / 09965; WO94 / 13804; and Reiter et al., Nature Biotechnology 14:1239-1245, 1996).

[0165] In case of bispecific antibodies, these can be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger and Winter, Current Opinion Biotechnol. 4:446-449, 1993), e.g., chemically or from hybrid hybridomas, or can be any of the bispecific antibody fragments mentioned above.

[0166] In contrast to bispecific whole antibodies, bispecific diabodies can also be particularly useful, as they can be readily constructed and expressed in E. coli. Phage display (WO94 / 13804) can be used to easily select diabodies (and many other polypeptides, such as antibody fragments) with the appropriate binding specificity from libraries. If one arm of the diabody is to remain constant, e.g., specific for antigen X, a library can be generated in which the other arm is varied and antibodies with the appropriate specificity are selected. Bispecific whole antibodies can be generated by a variety of methods (Brinkman and Kontermann, mAbs 9:182-212, 2017), including knobs-into-holes engineering (Ridgeway et al., Protein Eng. 9:616-621, 1996).

[0167] In certain embodiments, the antibodies or antigen-binding fragments described herein take the form of . is an IgG4 antibody with the hinge region removed (see GenMab Utrecht, The Netherlands; see also, e.g., US20090226421). This antibody technology results in a stable smaller antibody format with a longer therapeutic window than currently small antibody formats would expect. IgG4 antibodies are considered inert and therefore do not interact with the immune system. The intact human IgG4 antibody can be modified by eliminating the hinge region of the antibody to obtain a half molecule fragment with different stability properties compared to the corresponding intact IgG4 (GenMab Utrecht). The bisected IgG4 molecule leaves only one region available to bind a cognate antigen (e.g., a disease target) and , and therefore binds only one site on a target cell monovalently.

[0168] In certain embodiments, the antibodies or antigen-binding fragments described herein take the form of a nanobody. Nanobodies are encoded by a single gene and are produced efficiently in almost all prokaryotic and eukaryotic hosts, e.g., E. coli (see, e.g., U.S. Patent No. 6,765,087), molds (e.g., Aspergillus or Trichoderma), and yeasts (e.g., Saccharomyces, Kluyvermyces, Hansenula, or Pichia) (see, e.g., U.S. Patent No. 6,838,254). The production process is scalable, and thousands of kilograms of nanobodies have been produced. Nanobodies can be formulated as long shelf-life ready-to-use solutions. The Nanoclone method (see WO 06 / 079372) is a proprietary method for the production of nanobodies against a desired target based on automated high-throughput selection of B cells.

[0169] In some embodiments, the antibodies or antigen-binding fragments described herein take the form of an aptamer (see, e.g., Ellington et al., Nature 346, 818-22, 1990; Heinze 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 have been engineered to bind to a variety of molecular targets such as small molecules, proteins, nucleic acids, and even cells, tissues, and organisms through repeated rounds of in vitro selection or equivalent methods like SELEX (Systematic Evolution of Ligands by Exponential Enrichment). See, e.g., U.S. Patent Nos. 6,376,190 and 6,387,620, which are incorporated by reference.

[0170] Peptide aptamers are generally included in a variable peptide loop connected to a protein scaffold at both ends, and the protein scaffold is a dual structural constraint that generally increases the binding affinity of the peptide aptamer to a level comparable to that of the antibody (e.g., in the nanomolar range). In certain embodiments, the variable loop length can be composed of about 10-20 amino acids (including all integers therebetween), and the scaffold can include any protein with good solubility and compatibility. Some exemplary embodiments use bacterial protein-thioredoxin-A as a scaffold protein, and the variable loop is inserted into the reduction active site (-Cys-Gly-Pro-Cys-loop in the wild-type protein), wherein two cysteine ​​side chains can form a disulfide bridge. For example, a method for identifying peptide aptamers is described in U.S. Application No. 2003 / 0108532, which is incorporated by reference. Peptide aptamer selection can be performed using different systems known in the art (including yeast two-hybrid system).

[0171] In some embodiments, the antibodies or antigen-binding fragments described herein are in the form of avimers. Avimer refers to a multimeric binding protein or peptide engineered using in vitro exon shuffling and phage display. Multiple binding domains are connected, thereby producing greater affinity and specificity than 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. Application Nos. 2004 / 0175756, 2005 / 0048512, 2005 / 0053973, 2005 / 0089932, and 2005 / 0221384, which are incorporated by reference.

[0172] (a) In some embodiments, the antibodies or antigen-binding fragments described herein take the form of adnectins. Adnectins refer to a class of targeted biologics derived from human fibronectin, an abundant extracellular protein that naturally associates with other proteins. See, for example, U.S. Application Nos. 2007 / 0082365; 2008 / 0139791; and 2008 / 0220049, incorporated by reference. Adnectins typically consist of a native fibronectin backbone and multiple targeting domains derived from specific portions of human fibronectin. Targeting domains can be engineered to enable the adnectin to specifically recognize an IL-11Rα polypeptide or an epitope thereof.

[0173] In some embodiments, the antibodies or antigen-binding fragments described herein take the form of anticalin. Anticalin refers to a class of antibody mimics typically synthesized from human lipocalin, a family of binding proteins with hypervariable loop regions supported by a structurally rigid framework. See, for example, U.S. Application No. 2006 / 0058510. Anticalin is typically about 20 kDa in size. Anticalin 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 a connected α-helix. In certain aspects, conformational biases that enable specific binding are generated in one or more hypervariable loop regions. See, for example, Skerra, FEBS J., 275:2677-83, 2008, incorporated by reference.

[0174] 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 can offer advantages over antibodies for target binding in drug discovery and development. Among other uses, DARPins are well suited for in vivo imaging or delivery of toxins or other therapeutic payloads because they have favorable molecular properties, including small size and high stability. The low-cost bacterial production and rapid production of many target-specific DARPins make the DARPin approach useful for drug discovery. In addition, DARPins can be easily produced in multispecific formats, making it possible to target effector DARPins to specific organs or to target multiple receptors with a single molecule composed of several DARPins. See, for example, Stumpp et al., Curr Opin Drug Discov Devel., 10:153-159, 2007; U.S. Application No. 2009 / 0082274; and PCT / EP2001 / 10454, which are incorporated by reference.

[0175] Heavy chain dimers are also included, such as antibodies from camelids and sharks. Camelid and shark antibodies consist of homodimeric pairs of two chains (both without light chains) with V-like and C-like domains. H The VH domain of IgG heavy chain dimers is called the VHH domain. Shark Ig-NARs consist of a homodimer composed of one variable domain (called the V-NAR domain) and five C-like constant domains (C-NAR domains).

[0176] In camelids, the diversity of the antibody repertoire is determined by the complementarity determining regions (CDRs) 1, 2, and 3 in the VH or VHH regions. The 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 is in contrast to the CDR3 regions of antibodies from many other species. For example, the average length of the CDR3 of mouse VH is 9 amino acids. Libraries composed of camelid-derived antibody variable regions that maintain the in vivo diversity of camelid variable regions can be generated, for example, by the methods disclosed in U.S. patent application serial number 20050037421, published on February 17, 2005.

[0177] In certain embodiments, antibody or its antigen binding fragment is humanized.These embodiments relate to chimeric molecules prepared using recombinant technology, and the chimeric molecule has an antigen binding site derived from an immunoglobulin from a non-human species, and the remaining immunoglobulin structure of the molecule is based on the structure and / or sequence of human immunoglobulin.Antigen binding site can include a complete variable domain fused to a constant domain or a CDR (complete or partial) only transplanted to an appropriate framework region in a variable domain. The epitope binding site can be wild type or can be modified by one or more amino acid substitutions. This eliminates the constant region as an immunogen in human individuals, but there is still the possibility of an immune response to exogenous variable regions (LoBuglio et al., Proceedings of the National Academy of Sciences of the United States of America 86:4220-4224, 1989; Queen et al., Proceedings of the National Academy of Sciences of the United States of America 86:10029-10033, 1988; Riechmann et al., Nature 332:323-327, 1988). Illustrative methods for humanizing antibodies include those described in US Patent No. 7,462,697.

[0178] Another approach focuses not only on providing humanized constant regions, but also on modifying the variable regions to reshape them into human form as much as possible. It is known that the variable regions of both heavy and light chains contain three complementary determining regions (CDRs) flanked by four framework regions (FRs), which vary in response to the epitope in question and determine the binding capacity. The four FR regions are relatively conserved in a given species and presumably provide a scaffold for the CDRs. When preparing non-human antibodies for a specific epitope, the variable regions can be "reshaped" or "humanized" by transplanting CDRs derived from non-human antibodies onto FRs present in the human antibody to be modified. The application of this method to various antibodies has been reported in the following literature: Sato et al., Cancer Research 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 Hybridoma 2:124-134, 1991; Gorman et al., PNAS 88:4181-4185, 1991; Tempest et al., Bio / Technology 9:266-271, 1991; Co et al., PNAS 88:2869-2873, 1991; Carter et al., PNAS 89:4285-4289, 1992; and Co et al., J Immunol. 148:1149-1154, 1992. In some embodiments, the humanized antibody retains all CDR sequences (e.g., a humanized mouse antibody containing all six CDRs from a mouse antibody). In some embodiments, only some CDR sequences are transplanted from non-human antibodies (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 with respect to the original antibody, and the one or more CDRs are also referred to as "derived from" one or more CDRs from the original antibody.

[0179] In certain embodiments, antibody is " chimeric " antibody. In this respect, chimeric antibody comprises the antigen binding fragment that the heterologous Fc part of antibody and different antibodies is operably connected or otherwise fused. In certain embodiments, Fc domain or heterologous Fc domain are derived from people. In certain embodiments, Fc domain or heterologous Fc domain are derived from mouse. In other embodiments, heterologous Fc domain can be from the different Ig classifications derived from parent antibody, comprise IgA (comprising subclass IgA1 and IgA2), IgD, IgE, IgG (comprising subclass IgG1, IgG2, IgG3 and IgG4) and IgM. In other embodiments, heterologous Fc domain can comprise CH2 and CH3 domain from one or more in different Ig classifications. As described above for humanized antibodies, the antigen-binding fragment of a chimeric antibody can include only one or more of the CDRs of an antibody described herein (e.g., 1, 2, 3, 4, 5, or 6 CDRs of an antibody described herein), or can include the entire variable domain (VL, VH, or both).

[0180] The term "binding" refers to the direct association between two molecules due to, for example, covalent, electrostatic, hydrophobic and ionic and / or hydrogen bonding interactions (including interactions such as salt bridges and water bridges).

[0181] "Coding sequence" refers to any nucleic acid sequence that contributes to the coding of a 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 coding of a polypeptide product of a gene.

[0182] 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.

[0183] “Consisting of is meant to include and be limited to whatever follows the phrase “consisting of.” Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that other elements may not be present. “Consisting essentially of” is meant to include any elements listed after the phrase, and be limited to other elements that do not interfere with or facilitate the activity or behavior specified for the listed elements in this disclosure. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, but other elements are optional and may or may not be present, depending on whether they materially affect the activity or behavior of the listed elements.

[0184] In the context of antibodies, the term "effector function" or "ADCC effector function" refers to the ability of the antibody to connect to other arms of the immune system (including, for example, activation of the classical complement pathway, or connection through Fc receptors). The complement-dependent pathway is primarily driven by the interaction of C1q with the C1 complex of aggregated antibody Fc domains. 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), which bind to the Fc region of IgG that is bound to the target cell. Fc receptors (FcRs) are key immunomodulatory receptors that associate antibody-mediated (humoral) immune responses with cellular effector functions. Receptors for all classes of immunoglobulins have been identified, including FcγRs (IgG), FcεRI (IgE), FcαRI (IgA), FcμRs (IgM), and FcδRs (IgD). At least three classes of human IgG receptors are found on leukocytes: CD64 (FcγRI), CD32 (FcγRIIa, FcγRIIb, and FcγRIIc), and CD16 (FcγRIIIa and FcγRIIIb). FcγRI is classified as a high-affinity receptor (nanomolar range K D ), while FcγRII and FcγRIII have low to moderate affinities (micromolar range K D When Fc binding occurs, signaling pathways are triggered, leading to the secretion of various substances that mediate the destruction of target cells, such as lytic enzymes, perforins, granzymes, and tumor necrosis factor. The level of ADCC effector function varies among human IgG subtypes. While this depends on the allotype and specific FcvR, in simple terms, ADCC effector function is "high" for human IgG1 and IgG3, and "low" for IgG2 and IgG4.

[0185] The term "endotoxin-free" or "substantially endotoxin-free" generally refers to compositions, solvents, and / or blood vessels that contain, at most, trace amounts (e.g., amounts that have no clinically adverse physiological effects on a subject) of endotoxins and preferably contain no detectable amounts of endotoxins. Endotoxins are toxins associated with certain microorganisms, such as bacteria (typically gram-negative bacteria), but can be found in gram-positive bacteria such as Listeria monocytogenes. The most common endotoxins are lipopolysaccharides (LPS) or lipooligosaccharides (LOS), which are found in the outer membranes of various gram-negative bacteria and represent the central pathogenic characteristics of these bacteria in terms of their ability to cause disease. Small amounts of endotoxins in humans may cause fever, decreased blood pressure, inflammation, and coagulation activation, as well as other adverse physiological effects.

[0186] Therefore, in pharmaceutical production, it is usually desirable to remove most or all traces of endotoxin from pharmaceuticals and / or pharmaceutical containers, because even a small amount may also produce adverse effects on the human body. A pyrogen oven can be used for this purpose, because decomposing most endotoxins usually requires a temperature exceeding 300°C. For example, based on primary packaging materials such as syringes or bottles, a combination of a glass temperature of 250°C and a hold time of 30 minutes is usually enough to achieve a 3-log reduction in endotoxin levels. Other methods of removing endotoxins are envisioned, including chromatography and filtration as described herein and as known in the art.

[0187] Endotoxins can be detected using conventional techniques known in the art. For example, the Limulus Amoebocyte Lysate assay using horseshoe crab blood is a very sensitive assay for detecting the presence of endotoxins. In this test, very low levels of LPS can cause detectable coagulation of the horseshoe crab lysate, as a powerful enzyme cascade amplifies this reaction. Endotoxins can also be quantified by enzyme-linked immunosorbent assay (ELISA). In order to be substantially free of endotoxins, 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 about 1-10 EU.

[0188] The term "epitope" includes any determinant capable of specifically binding to an immunoglobulin or T cell receptor, preferably a polypeptide determinant. An epitope comprises a region of an antigen that is bound to an antibody. In certain embodiments, an epitope determinant comprises a chemically active surface group of a molecule, such as an amino acid, a sugar side chain, a phosphoryl group, or a sulfonyl group, and in certain embodiments may have a specific three-dimensional structural characteristic and / or a specific charge characteristic. With respect to the primary structure of an antigen (e.g., an IL-11Rα polypeptide), an epitope may be continuous or non-continuous. In specific embodiments, an epitope comprises 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 continuous amino acids (i.e., linear epitopes) or non-continuous amino acids (i.e., conformational epitopes) of a reference sequence as described herein (see, e.g., Table B1) or a target molecule, consisting of, or essentially consisting of.

[0189] An "epitope" comprises a portion of an antigen or other macromolecule capable of forming a binding interaction that interacts with the variable region binding pocket of a binding protein. This binding interaction can be manifested as intermolecular contact with one or more amino acid residues of a CDR. Antigen binding can involve a CDR3 or a CDR3 pair. An epitope can be a linear peptide sequence (i.e., "continuous") or can be composed of discontinuous amino acid sequences (i.e., "conformational" or "discontinuous"). A binding protein can recognize one or more amino acid sequences; thus, an epitope can be defined by more than one distinct amino acid sequence. The epitope recognized by a binding protein 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 substantially not recognized in an unmodified polypeptide, but is recognized by a binding protein of a denatured or proteolytically hydrolyzed polypeptide. Amino acid sequences that are not exposed or only partially exposed in the unmodified polypeptide structure are potential cryptic epitopes. If the epitope is not exposed or only partially exposed, it is likely buried in the interior of the polypeptide.Candidate cryptic epitopes can be identified, for example, by examining the three-dimensional structure of the unmodified polypeptide.

[0190] The term "half-maximal effective concentration" or "EC 50 ” refers to the concentration of an agent (e.g., an antibody) as described herein that induces a response between baseline and maximum after some specified exposure time; thus, the EC of a graded dose-response curve is 50 It 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 the maximum effect is observed. “EC 90 ” can be based on “EC 50 " and Hill slope, or can be determined directly from the data using routine knowledge in the art. In some embodiments, the EC of an agent (e.g., an antibody) 50 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 EC of the agent 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. 50 The value was about 1 nM or less.

[0191] "Immune response" means any immunological response derived from the immune system, including responses from cells and organs, innate and acquired 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 subpopulations thereof. Cellular responses include, for example, effector functions, cytokine release, phagocytosis, efferocytosis, translocation, transport, proliferation, differentiation, activation, inhibition, cell-cell interactions, apoptosis, and the like. Organism responses include, for example, IgG, IgM, IgA, IgE responses, and their corresponding effector functions.

[0192] The "half-life" of an agent such as an antibody can refer to the time it takes for the agent to lose half of its pharmacological, physiological or other activity when administered to the serum or tissue 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 an agent to decrease to half of the initial amount administered to the serum or tissue of an organism, relative to such amount or concentration when administered to the serum or tissue of an organism, or relative to any other defined time point. Half-life can be measured in serum and / or any one or more selected tissues.

[0193] The terms "modulate" and "alter" include "increasing," "enhancing," or "stimulating," as well as "reducing," "reducing," or "inhibiting," typically by a statistically significant or physiologically significant amount or degree relative to a control. An "increased," "stimulated," or "enhanced" amount is typically a "statistically significant" amount and may include an increase of 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 or more times (e.g., 500 times, 1000 times) (including all integers and ranges therebetween, e.g., 1.5, 1.6, 1.7, 1.8, etc.) relative to the amount produced by a non-composition (e.g., no agent) or a control composition. An amount that is "reduced" or "decreased" or "inhibited" 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) relative to the amount produced in the absence of the composition (e.g., in the absence of the agent) or in the control composition. Examples of comparisons and "statistically significant" amounts are described herein.

[0194] The terms "polypeptide," "protein," and "peptide" are used interchangeably and mean a polymer of amino acids that is not limited to any particular length. The term "enzyme" encompasses polypeptide or protein catalysts. The term encompasses modifications such as myristoylation, sulfation, glycosylation, phosphorylation, and the addition or deletion of signal sequences. The term "polypeptide" or "protein" means one or more amino acid chains, wherein each chain comprises amino acids covalently linked by peptide bonds, and wherein the polypeptide or protein may comprise multiple chains having the sequence of a natural protein (i.e., a protein produced by a naturally occurring cell, specifically a non-recombinant cell, or a genetically engineered cell or a recombinant cell) linked together non-covalently and / or covalently by peptide bonds, and includes molecules having the amino acid sequence of a natural protein or molecules having deletions, additions, and / or substitutions of one or more amino acids of the natural sequence. In certain embodiments, a polypeptide is a "recombinant" polypeptide produced by a recombinant cell that includes one or more recombinant DNA molecules that are typically made from a heterologous polynucleotide sequence or combination of polynucleotide sequences that cannot otherwise be found in the cell.

[0195] As used herein, the term "isolated" polypeptide or protein means that the subject protein: (1) is free of at least some other proteins with which the subject protein is normally found in nature; (2) is substantially free of other proteins from the same source, e.g., from the same species; (3) is expressed by cells from a different species; (4) has been separated by at least about 50% from polynucleotides, lipids, carbohydrates, or other materials with which the subject protein is naturally associated; (5) is not associated (by covalent or non-covalent interactions) with protein moieties with which the "isolated protein" is associated in nature; (6) is operably associated (by covalent or non-covalent interactions) with polypeptides with which the subject protein 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, or may be of synthetic origin, or any combination thereof. In certain embodiments, an isolated protein is substantially free of proteins or polypeptides or other contaminants found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research, or otherwise).

[0196] In certain embodiments, the "purity" of any given agent (e.g., an antibody) in a composition can be defined. For example, certain compositions can include an agent that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure, including all decimals and ranges therebetween, on a protein or weight-weight basis, as measured, for example, but in no way limited to, by high performance liquid chromatography (HPLC), a well-known form of column chromatography commonly used in biochemistry and analytical chemistry to separate, identify, and quantify compounds.

[0197] 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 sequences described by name and sequences described in the tables and sequence listing.

[0198] Certain embodiments comprise biologically active "variants" and "fragments" of the polypeptides (e.g., antibodies) described herein, and polynucleotides encoding the same. A "variant" contains one or more substitutions, additions, deletions, and / or insertions relative to a reference polypeptide or polynucleotide (see, e.g., Tables and Sequence Listings). A variant polypeptide or polynucleotide comprises an amino acid or nucleotide sequence having 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 described herein, and substantially retains the activity of the reference sequence. Also included are sequences consisting 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 or sequences that differ from a reference sequence by additions, deletions, insertions or substitutions of said amino acids or nucleotides and that substantially retain the activity of said reference sequence. In certain embodiments, additions or deletions comprise C-terminal and / or N-terminal additions and / or deletions.

[0199] As used herein, the term "sequence identity" or, for example, including "a sequence that is at least 50% identical to..." refers to the extent to which sequences are identical on a nucleotide-by-nucleotide basis or on an amino acid-by-amino acid basis within a comparison window. Thus, "percentage of sequence identity" can be calculated by comparing two optimally aligned sequences within a comparison window, determining the number of positions at which the same nucleic acid base (e.g., A, T, C, G, I) or the same amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) occurs in the two sequences to produce the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to produce the percentage of sequence identity. The best alignment for comparing sequences over a comparison window can be by computerized implementation of the algorithm (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package 7.0 version of the Genetics Computer Group, 575 Science Drive Madison, Wis., USA), or by testing the best alignment (i.e., resulting in the highest percentage homology within the comparison window) produced by any of the various selected methods. Reference can also be made to the BLAST program family, for example, disclosed by Altschul et al., Nucleic Acids Research, 25:3389,1997.

[0200] The term "solubility" refers to that the agent (e.g., antibody) provided herein is dissolved in a liquid solvent and forms a homogeneous solution. Solubility is typically expressed as concentration, or solute mass / unit volume solvent (grams of solute / kilogram of solvent, g / dL (100mL), mg / ml, etc.), molar concentration, mass molarity, molar fraction or other similar concentration descriptions. The maximum equilibrium amount of the solute that a unit amount of solvent can dissolve is the solubility of the solute in the solvent under the specified conditions comprising temperature, pressure, pH and solvent properties. In certain embodiments, at physiological pH or other pH, for example, 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) solubility is measured. In certain embodiments, solubility is measured in water or physiological buffers such as PBS or NaCl (with or without NaPO 4 ). In specific 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 NaPO4). 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°C, 21°C, 22°C, 23°C, 24°C, 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.

[0201] A "subject" or "a subject in need thereof" or "patient" or "a patient in need thereof" includes mammalian subjects such as human subjects.

[0202] "Substantially" or "essentially" means almost completely or entirely, for example, 95%, 96%, 97%, 98%, 99% or more of some given amount.

[0203] "Statistically significant" means that the result is unlikely to have occurred by chance. Statistical significance can be determined by any method known in the art. Common measures of significance include the p-value, which is the frequency or probability that the observed event would occur if the null hypothesis were true. If the p-value obtained is less than the significance level, the null hypothesis is rejected. In simple cases, the significance level is defined as a p-value of 0.05 or less.

[0204] A "therapeutic response" refers to an improvement in symptoms (whether or not sustained) upon administration of one or more therapeutic agents.

[0205] As used herein, the terms "therapeutically effective amount," "therapeutic dose," "prophylactically effective amount," or "diagnostically effective amount" are the amount of an agent (eg, anti-IL-11Rα antibody) required to elicit a desired biological response upon administration.

[0206] As used herein, "treatment" of a subject (e.g., a mammal, such as a human) or cell is any type of intervention used to attempt to alter the natural course of a disease or condition. Treatment includes, but is not limited to, the administration of a pharmaceutical composition and can be performed prophylactically or after the initiation of a pathological event or after contact with a pathogen. Also included are "preventive" treatments, which may be intended to reduce the rate of progression of the disease or condition being treated, delay the onset of the disease or condition, or reduce the severity of its onset. "Treatment" or "prevention" does not necessarily mean complete eradication, cure, or prevention of a disease or condition or its associated symptoms.

[0207] The term "wild-type" refers to a gene or gene product (eg, polypeptide) that is most commonly observed in a population, and is therefore arbitrarily designated as the "normal" or "wild-type" form of the gene.

[0208] Unless explicitly stated otherwise, each embodiment in this description applies mutatis mutandis to all other embodiments.

[0209] Methods of treatment, antibodies and pharmaceutical compositions

[0210] Embodiments of the present disclosure relate to methods 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). Thyroid eye disease is the most common inflammatory orbital disease and is associated with autoimmune thyroid dysfunction. It is a progressive condition with symptoms and signs that can cause significant facial disfigurement and visual disability, but rarely leads to blindness.

[0211] In some cases, TED is characterized by orbital inflammation caused by fibroblast activation (see, e.g., Li et al., Curr Opin Ophthalmol. 29(6): 528-534, 2018). Studies have 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, cascading to adipogenesis and fibroblast hyaluronic acid synthesis in the orbit (ibid.). Increased orbital adipose tissue and glycosaminoglycan sequestration within the EOM cause soft tissue volume expansion, leading to increased congestion and pressure in the orbit associated with the pathogenic signs of TED.

[0212] Women have a higher incidence of TED, but 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). Studies have shown that TED patients do not have a specific genetic predisposition and that the disease is more likely to be caused by environmental influences and epigenetic changes (see, e.g., Yin et al., Thyroid. 22(7):730-6, 2012). TED has many risk factors, including female sex, middle-aged age, and smoking, which not only increase the development of TED but also reduce the efficacy of treatment (see, e.g., Wang et al., Ther Clin Risk Manag. 15:1305-1318, 2019). Treatment with radioactive iodine is another exemplary risk factor for TED (see, eg, Sikder and Weinberg, Ophthalmologica. 224(4): 199-203, 2010).

[0213] 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 prominent, then after excluding confounding causes, the diagnosis is made by the presence of thyroid dysfunction or accommodation abnormalities, proptosis, optic nerve dysfunction, or extraocular muscle (EOM) involvement. If eyelid retraction is absent, the diagnosis is made by proptosis, optic nerve dysfunction, or EOM involvement in the presence of thyroid dysfunction or accommodation abnormalities. In many cases, TED is associated with Grave's disease.

[0214] 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). The wide-eyed appearance leads to chronic eye exposure, particularly during sleep. Initially, this may be associated with foreign body sensation, dryness, and tearing. Over time, severe corneal lesions may develop, which increase the risk of corneal scarring, ulcers, perforations, and endophthalmitis (see, e.g., Douglas, Eye (Lond). 33(2):183-190, 2019). Protrusion or exophthalmos is the second most common clinical sign of TED, primarily caused by EOM and / or fat expansion, and may also increase the risk of exposure. In some patients with TED, a bunion or inability to completely close the eyelids is also observed (see, e.g., Smith and Hegedus, supra). A temporal elevation of the upper eyelid contour or temporal flare is often observed. EOM dysfunction is found in many patients and often results in diplopia if eye misalignment ensues (see, e.g., Smith and Hegedus, supra). The inferior and medial rectus muscles are most commonly affected, inducing hypotropia (downward deviation), esotropia (inward deviation), and / or potentially restricting eye movements if the muscles become fibrotic. Many patients experience a dull, compressive pain in the eye. Eyelid edema and erythema, conjunctival injection, and chemosis (conjunctival edema) are also observed. There may also be a fibroinflammatory reaction in the orbital tissue and activated Thy1 + and Thy1 -The relative proportion of OF can determine whether excessive extracellular matrix accumulation or adipogenesis predominates in TED (see, e.g., Shan et al., Journal of Neuro-Ophthalmology. 34(2): 177-185, 2014). Color vision impairment (color vision loss) or loss of visual acuity secondary to compressive optic neuropathy has been observed in rare cases but signifies serious disease. TED can be unilateral or highly asymmetric. Thus, in some cases, the one or more clinical signs are selected from: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema), as well as other signs described herein and known in the art.

[0215] The Clinical Activity Score (CAS) system uses history and external examination results to assess TED activity. In some cases, patients are scored at their initial visit, with one point for each of the following symptoms: spontaneous orbital pain, gaze-induced orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and inflammation of the caruncle or plica semilunaris (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 three or higher at the initial assessment is considered active disease. In some cases, at follow-up, patients are given an additional point for each of the following criteria: an increase in proptosis of ≥2 mm, a decrease in mobility of either eye of ≥5°, or a decrease in visual acuity of ≥1 Snellen line (see, e.g., supra). A score of four or higher indicates active disease. Thus, in certain embodiments, a patient in need thereof has a Clinical Activity Score (CAS) of 3 or higher, or 4 or higher, 5 or higher, or 6 or higher.

[0216] 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 section excludes optic neuropathy by assessing visual acuity, color vision defects, pupillary response, and optic nerve appearance. The inflammation section modifies the above CAS criteria by excluding caruncle / plica semilunar inflammation (including inflammation of the plica semilunar in the case of chemosis) and grading chemosis and lid edema on a scale of 0-2. Retrobulbar pain is graded as 0 = no pain, 1 = pain with movement, and 2 = pain at rest. Conjunctival and eyelid congestion are graded as present or absent, and the score of the worst-scoring eyelid is recorded (range 0-8). The strabismus section tracks the progression of EOM dysfunction and diplopia. The appearance / exposure section assesses symptomatic proptosis, lid retraction, and dry eye. In some embodiments, the patient in need thereof has a VISA score of 4 or higher, 5 or higher, 6 or higher, 7 or higher, or 8 or higher.

[0217] In certain embodiments, the patient in need has abnormal thyroid function, such as hyperthyroidism. In some cases, the patient has autoantibody stimulation of the thyroid stimulating hormone receptor (TSHR). Thyrotropin (TSI) is a TSHR antibody that is directly related to 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. Therefore, in some embodiments, the patient in need has an increased level of TSI, e.g., relative to a control or reference level. In some embodiments, the patient suffers from Grave's disease.

[0218] In some embodiments, the patient has one or more risk factors associated with TED. Examples of one or more risk factors include female sex, middle-aged age (e.g., 40 to 60 years or older), smoking, and currently undergoing or having undergone radioactive iodine treatment. In certain embodiments, the patient in need thereof has increased IL-11Rα and / or IL-11 levels in the blood or tissue surrounding the eye (e.g., orbital blood, orbital tissue, such as orbital fibroblasts), for example relative to healthy controls or reference levels. In some embodiments, the patient in need thereof has increased circulating IL-11 levels.

[0219] Certain embodiments include one or more steps of diagnosing a patient for TED prior to administering a pharmaceutical composition as described herein. For example, certain embodiments include the steps of: (a) determining whether the patient has TED; and (b) administering the pharmaceutical composition to the patient if the patient has TED. The one or more steps of determining whether the patient has TED can utilize any one or more diagnostic procedures described herein and known in the art. For example, in some cases, step (a) comprises measuring one or more clinical signs of TED, including: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

[0220] Specific embodiments include (a) determining the patient's CAS; and (b) administering a pharmaceutical composition to the patient if the CAS is 3 or higher, or 4 or higher, 5 or higher, or 6 or higher. Further embodiments include the following steps: (a) determining the patient's VISA score; and (b) administering a pharmaceutical composition to the patient if the VISA score is 4 or higher, 5 or higher, 6 or higher, 7 or higher, or 8 or higher. Some embodiments include the following steps: (a) determining the patient's thyroid function; and (b) administering a pharmaceutical composition to the patient if the patient has abnormal thyroid function, such as hyperthyroidism. Certain embodiments include the following steps: (a) determining the patient's TSI level; and (c) administering a pharmaceutical composition to the patient if the patient's TSI level is increased relative to a control or reference standard. Some embodiments include the following steps: (a) determining the level of IL-11Rα and / or IL-11 in the patient's blood or tissue surrounding the eye (e.g., orbital blood, orbital tissue, such as orbital fibroblasts) (e.g., protein expression, mRNA expression); 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 tissue surrounding the eye is increased relative to a control or reference standard. Certain embodiments include the following steps: (a) determining the patient's circulating IL-11 level; and (b) administering a pharmaceutical composition to the patient if the circulating IL-11 level is increased relative to a control or reference standard. The antibodies and antigen-binding fragments thereof disclosed herein can be used to determine the protein expression level of IL-11Rα in the patient's blood or tissue.

[0221] The methods provided herein can be combined with any one or more diagnostic procedures to achieve diagnosis of TED prior to treatment with a pharmaceutical composition comprising an anti-IL-11Rα antibody or antigen-binding fragment thereof.

[0222] 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), a surgical sample, or other biopsy sample obtained from a patient, including a blood or tissue sample from around the eye of a patient (e.g., an orbital blood or orbital tissue sample, such as an orbital fibroblast). Certain embodiments of step (a) include performing a thyroid function test on the blood or other biological sample, for example by measuring the levels of TSH, T4, and / or T3 and determining whether the patient has abnormal thyroid function, 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., a bioassay in which cyclic adenosine monophosphate (cAMP) production by thyrotropin (TSH)-responsive cells following exposure to the patient’s serum is compared to cyclic adenosine monophosphate (cAMP) production obtained in the same cells following exposure to normal control serum (see Preissner et al., Clin Chem. 49(8): 1402-1404, 2003) to determine whether the patient has increased TSI levels relative to a reference or control. Certain embodiments include performing a bioassay on a blood or other biological sample obtained from the patient (e.g., a circulating blood, orbital blood, or orbital tissue sample, such as an orbital fibroblast) to determine whether the patient has increased IL-11 Ra and / or IL-11 (e.g., circulating IL-11) levels relative to a reference or control. Examples of a “reference” include a value, amount, sequence, or other characteristic obtained from a database, a value, amount, sequence, or other characteristic obtained from one or more control tissues (e.g., healthy tissues from one or more controls, such as one or more control subjects, e.g., a control population of healthy subjects).

[0223] In some embodiments, the patient has not been treated with a TED therapy. A “treatment-naive” patient has not previously undergone a prior TED therapy, such as a therapy described herein. In some embodiments, the patient has chronic TED.

[0224] In some embodiments, the patient is undergoing or has previously undergone TED therapy and is intolerant, relapsed, and / or refractory to the (previous) TED therapy. "Relapse" refers to the return of a past condition or disease state, such as after a period of treatment-related rest or disease inactivity. In some embodiments, recurrent TED patients are identified by an initial response to the previous TED therapy as measured by a decrease in proptosis, followed by a recovery of proptosis after a period of time despite continued treatment with the same TED therapy. In some embodiments, the reduction in proptosis is greater than about 2 mm. In some embodiments, the recovery of proptosis is an increase in proptosis back to a pre-treatment baseline measurement. In some embodiments, the recovery of proptosis is an increase in proptosis compared to the maximum response to the previous TED therapy. In some embodiments, recurrent TED patients are identified by an initial response to TED therapy as measured by a decrease in CAS score, followed by a reversal after a period of time despite continued treatment with the same TED therapy. Patients who are "refractory" to previous TED therapy have not significantly responded to, previously failed to respond, or have become non-responsive (e.g., by selection) to the previous TED therapy. In some embodiments, refractory patients are identified by insufficient improvement in proptosis. In some embodiments, insufficient improvement in proptosis is less than about 2 mm. In some embodiments, refractory patients are identified by minimal or no change in CAS score. An "intolerant" patient is one who has an adverse event (AE) profile that requires interruption of prior TED therapy or that justifies such interruption. In some embodiments, intolerant, recurrent and / or refractory patients have active TED. In some cases, the patient's TED is progressing. In certain embodiments, the progression of TED in a patient in an intolerant / recurrent / refractory disease state is more aggressive than before TED therapy. In some embodiments, TED progression is indicated by worsening of one or more clinical signs of TED, an increase in CAS score and / or an increase in VISA score compared to the clinical signs, CAS score and / or VISA score before TED therapy. In certain such and related embodiments, the efficacy of the antibodies claimed herein and / or their different mechanisms of action relative to prior (now inadequately responsive) TED therapies can provide clinical advantages in treating progressive disease states, including more aggressive progressive disease states.

[0225] In some embodiments, the (prior) TED therapy 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 tetoquitumumab, ganituzumab, darotuzumab, cixitumumab, and phentoquitumumab therapy. In some embodiments, the FcRn inhibitory therapy is selected from bartolimumab (IMVT-1401), egalimod, nicallimumab, onorimab, and lorixizumab therapy. In a specific embodiment, IL-6 inhibitor therapy is selected from clalizumab, elcitumomab, levitra monoclonal antibody, olozumab, sarrelizumab, sirucilumab and tocilizumab therapy. In certain embodiments, steroid therapy is selected from methylprednisolone (optionally, IV methylprednisolone sodium succinate), prednisolone (optionally, oral prednisolone) and prednisone (optionally, oral prednisone) therapy. In certain embodiments, CD20 inhibitor therapy is selected from isobetamin, obinutuzumab, octuzumab, ofalimumab, rituximab and utoximab therapy. In certain embodiments, TNF-α inhibitor therapy is selected from adalimumab, certolizumab pegol, etanercept, golimumab and infliximab.

[0226] In some embodiments, the patient is undergoing or has previously undergone tadalafil therapy and is intolerant, relapsed, and / or refractory to the (previous) tadalafil therapy. "Relapse" refers to the recurrence of a past condition or disease state, for example, after a treatment-related rest or disease inactivity period. In some embodiments, recurrent TED patients are identified by measuring an initial response to the previous tadalafil therapy by a reduction in the degree of proptosis, followed by a recovery of the degree of proptosis after a period of time despite continued treatment with the same tadalafil therapy. In some embodiments, the reduction in the degree of proptosis is greater than about 2 mm. In some embodiments, the recovery of the degree of proptosis is an increase in the degree of proptosis back to the pre-treatment baseline measurement. In some embodiments, the recovery of the degree of proptosis is an increase in the degree of proptosis compared to the maximum response to the previous tadalafil therapy. In some embodiments, the initial response to tadalafil therapy is measured by a reduction in the CAS score, followed by a reversal after a period of time despite continued treatment with the same tadalafil therapy. Patients who are "refractory" to prior tazobactam therapy have not had a significant response to, have previously failed to respond to, or have become unresponsive (e.g., by selection) to prior tazobactam therapy. In some embodiments, refractory patients are identified by insufficient improvement in proptosis. In some embodiments, insufficient improvement in proptosis is less than about 2 mm. In some embodiments, refractory patients are identified by minimal or no change in CAS score. In some embodiments, intolerant, recurrent, and / or refractory patients have active TED. In some cases, the patient's TED is developing. In certain embodiments, the progression of TED in a patient in an intolerant / recurrent / refractory disease state is more aggressive in the patient than before tazobactam therapy. In some embodiments, TED progression is indicated by worsening of one or more clinical signs of TED, an increase in CAS score, and / or an increase in VISA score compared to clinical signs, CAS score, and / or VISA score before tazobactam therapy. In certain such and related embodiments, the efficacy of the antibodies claimed herein and / or their different mechanisms of action relative to prior (now inadequately responsive) tuximab therapy can provide clinical advantages in treating progressive disease states, including more aggressive progressive disease states. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for one half-life of tuximab from the last dose of tuximab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for two half-lives of tuximab from the last dose of tuximab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for three half-lives of tuximab from the last dose of tuximab.In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 4 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 5 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 6 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 7 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 8 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 9 half-lives of Titumumab from the last dose of Titumumab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for 10 half-lives of tiuximab from the last dose of tiuximab. In some embodiments, the anti-IL-11Rα antibodies or antigen-binding fragments thereof of the present disclosure are administered for more than 10 half-lives of tiuximab from the last dose of tiuximab.

[0227] Certain embodiments include combination therapies, including wherein the method comprises administering a pharmaceutical composition comprising an anti-IL-11Rα antibody or antigen-binding fragment thereof as described herein in combination with at least one other TED therapy.

[0228] In some embodiments, the at least one other TED therapy is administered prior to administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the at least one other TED therapy is administered concurrently with administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, administration of the at least one other TED therapy and administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure are performed sequentially. In some embodiments, the at least one other TED therapy is administered in the same composition as the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the at least one other TED therapy is administered in a separate composition from the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure.

[0229] In some embodiments, the at least one other 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 + ORT 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 teitutumumab, ganitutumumab, darotuzumab, citrullumab, and phentocin therapy. In some embodiments, the FcRn inhibitory therapy is selected from bartolimumab (IMVT-1401), agamod, nicallimumab, onorizumab, and lorixizumab therapy. In some embodiments, the IL-6 inhibitor therapy is selected from clatuzumab, elcitumomab, levitra, olotumumab, sarrellumab, siltuximab, sirukumab, and tocilizumab therapy. In certain embodiments, the steroid therapy is selected from methylprednisolone (optionally, IV methylprednisolone sodium succinate), prednisolone (optionally, oral prednisolone), and prednisone (optionally, oral prednisone) therapy. In some embodiments, the CD20 inhibitor therapy is selected from isobetamin, obinutuzumab, octomel, ofavumab, rituximab, and utoximab therapy. In some embodiments, the TNF-α inhibitor therapy is selected from adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.

[0230] In some embodiments, the at least one other TED therapy is an IGF-1R inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody, such as teixumab, ganituzumab, darotolumab, cixitumumab, or phentolumab therapy. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered concurrently with the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered prior to the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the administration of the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) and the administration of the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure are performed sequentially. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) and the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure are administered in the same composition. In some embodiments, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered in a composition separate from the anti-IL11Rα antibody or antigen-binding fragment of the present disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g., 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., 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., 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, the IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered about 1 to about 5 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., IGF-1R antibody) is administered about 1 to about 6 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the disclosure. In some embodiments, IGF-1R inhibitor therapy (e.g., IGF-1R antibody) is administered about 1 to about 7 times during treatment with an anti-IL11Rα antibody or antigen-binding fragment of the disclosure.

[0231] 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 cause a clinically relevant reduction or improvement in symptoms of a specific disease indication known to a skilled clinician. Administration of the pharmaceutical composition to a patient can improve 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); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema). In specific embodiments, administration of the pharmaceutical composition to a patient can improve the patient's Clinical Activity Score (CAS), optionally by at least one, two, three, four, or five points, optionally to a CAS of 3 or less, 2 or less, or 1 or less. In some embodiments, administering a pharmaceutical composition to a patient can improve the patient's VISA score, optionally by at least one, two, three, four, or five points, optionally to a VISA score of 4 or less, 3 or less, 2 or less, or 1 or less. In some embodiments, administering a pharmaceutical composition to a patient can reduce the level of IL-11Rα and / or IL-11 in the blood or tissue surrounding the patient's eyes (e.g., orbital blood, orbital tissue, such as orbital fibroblasts). In specific embodiments, administering a pharmaceutical composition to a patient can reduce the patient's circulating IL-11 levels.

[0232] As described 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 is characterized by or includes a heavy chain variable region (V H ), wherein the VH comprises a complementarity determining region V H CDR1 sequence, V H CDR2 sequence and V H CDR3 sequence, and light chain variable region (V L ), wherein the VL includes a complementarity determining region V L CDR1 sequence, V L CDR2 sequence and V L CDR3 sequences. H 、V H CDR1, V H CDR2, V H CDR3, V L 、V L CDR1, VL CDR2 and V L CDR3 sequences are provided in Table A1 and Table A2 below.

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239] Thus, in certain embodiments, the antibody or antigen-binding fragment thereof comprises: V H A sequence comprising a complementarity determining region V selected from Table A1 H CDR1, V H CDR2 and V H CDR3 sequences and their variants that bind to IL-11Rα; and V L A sequence comprising a complementarity determining region V selected from Table A1 L CDR1, V L CDR2 and V L CDR3 sequences and their variants that bind to IL-11Rα. In a specific embodiment, the antibody comprises: V H Sequence comprising V H CDR1, V H CDR2 and V H CDR3 sequence; and V L Sequence comprising V L CDR1, V L CDR2 and V L CDR3 sequences, where all CDR sequences are from a single named antibody (e.g., mAb1) in Table A1.

[0240] In certain embodiments, the CDR sequences are as follows:

[0241] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 1-3, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V Lthe CDR3 sequences comprise SEQ ID NOs: 4-6, respectively;

[0242] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequences comprise SEQ ID NOs: 7-9, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequences comprise SEQ ID NOs: 10-12, respectively;

[0243] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequences comprise SEQ ID NOs: 13-15, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequences comprise SEQ ID NOs: 16-18, respectively;

[0244] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequences comprise SEQ ID NOs: 19-21, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequences comprise SEQ ID NOs: 22-24, respectively;

[0245] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequences comprise SEQ ID NOs: 25-27, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequences comprise SEQ ID NOs: 28-30, respectively;

[0246] the V H the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequences comprise SEQ ID NOs: 31-33, respectively, and the V L the CDR1 sequence, the V LCDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 34-36, respectively;

[0247] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 37-39, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 40-42, respectively;

[0248] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 43-45, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 46-48, respectively;

[0249] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 49-51, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 52-54, respectively;

[0250] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 55-57, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 58-60, respectively;

[0251] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 61-63, respectively, and the V LCDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 64-66, respectively;

[0252] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 67-69, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 70-72, respectively;

[0253] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 73-75, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 76-78, respectively;

[0254] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 79-81, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 82-84, respectively;

[0255] The V H CDR1 sequence, the V H CDR2 sequence and the V H The CDR3 sequences comprise SEQ ID NOs: 85-87, respectively, and the V L CDR1 sequence, the V L CDR2 sequence and the V L The CDR3 sequences comprise SEQ ID NOs: 88-90, respectively;

[0256] The V H CDR1 sequence, the V H CDR2 sequence and the V Hthe CDR1 sequence, the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 91-93, respectively, and the V L the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 94-96, respectively;

[0257] the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 97-99, respectively, and the V L the CDR2 sequence, and the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 100-102;

[0258] the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 103-105, respectively, and the V L the CDR2 sequence, and the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 106-108;

[0259] the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 109-111, respectively, and the V L the CDR2 sequence, and the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 112-114;

[0260] the CDR1 sequence, the V H the CDR2 sequence, and the V H the CDR2 sequence, and the V H the CDR3 sequence comprises SEQ ID NO: 115-117, respectively, and the V L the CDR2 sequence, and the V L the CDR2 sequence, and the V L the CDR3 sequence comprises SEQ ID NO: 118-120;

[0261] the CDR1 sequence, the V H the CDR2 sequence, and the VH the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 121-123, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 124-126, respectively;

[0262] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 127-129, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 130-132, respectively;

[0263] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 133-135, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 136-138, respectively;

[0264] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 139-141, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 142-144, respectively;

[0265] the V H the CDR1 sequence, the V H the CDR2 sequence and the V H the CDR3 sequence comprises SEQ ID NO: 145-147, respectively, and the V L the CDR1 sequence, the V L the CDR2 sequence and the V L the CDR3 sequence comprises SEQ ID NO: 148-150, respectively;

[0266] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequence comprise SEQ ID NOs: 151-153, respectively, and the V L CDR1 sequence, the V L CDR2 sequence, and the V L CDR3 sequence comprise SEQ ID NOs: 154-156, respectively;

[0267] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequence comprise SEQ ID NOs: 157-159, respectively, and the V L CDR1 sequence, the V L CDR2 sequence, and the V L CDR3 sequence comprise SEQ ID NOs: 160-162, respectively;

[0268] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequence comprise SEQ ID NOs: 163-165, respectively, and the V L CDR1 sequence, the V L CDR2 sequence, and the V L CDR3 sequence comprise SEQ ID NOs: 166-168, respectively;

[0269] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequence comprise SEQ ID NOs: 169-171, respectively, and the V L CDR1 sequence, the V L CDR2 sequence, and the V L CDR3 sequence comprise SEQ ID NOs: 172-174, respectively;

[0270] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequence comprise SEQ ID NOs: 175-177, respectively, and the V L CDR1 sequence, the V L CDR2 sequence, and the V Lthe CDR3 sequences comprise SEQ ID NOs: 178-180, respectively;

[0271] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or L CDR1 sequence, the V L CDR2 sequence, and the V L CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or

[0272] the V H CDR1 sequence, the V H CDR2 sequence, and the V H CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or L CDR1 sequence, the V L CDR2 sequence, and the V L CDR3 sequences comprise SEQ ID NOs: 184-186, respectively; or

[0273] also comprise minor variants of the foregoing CDRs. Exemplary variants bind IL-11Ra and have 1, 2, or 3 total alterations in any one or more individual CDRs, e.g., any one or more of the V H CDR1 sequence, V H CDR2 sequence, V H CDR3 sequence, V L CDR1 sequence, V L CDR2 sequence, and / or V L CDR3 sequence. Exemplary "alterations" include amino acid substitutions, additions, and deletions.

[0274] Exemplary V H sequences, and V L sequences are provided in Table A2 below.

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] Accordingly, in certain embodiments, the antibody or antigen-binding fragment thereof binds to IL-11 Ra and comprises a V H sequences and corresponding V L sequences. In certain embodiments, the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to a sequence selected from Table A2, including, for example, where the V H has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in one or more framework regions. In some embodiments, the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to a sequence selected from Table A2, including, for example, where the V L has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in one or more framework regions. In specific embodiments, the V H comprises a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to a sequence selected from Table A2, and the V L comprises a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to a sequence selected from Table A2, and the V H regions are from the same single named antibody (e.g., mAbl). In specific embodiments, the V H comprises a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to a sequence selected from Table A2, and the V L comprises a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to a sequence selected from Table A2, and the V H and V L sequences, wherein the antibody comprises the CDRs of the single named antibody (e.g., mAbl) as set forth in Table A1.

[0282] In some embodiments, the V H and VL As follows:

[0283] The V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 193, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 194;

[0284] The V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 195, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 196;

[0285] The V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 197, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 198;

[0286] The V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 199, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 200;

[0287] The V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202;

[0288] The V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 203, and the V Lcomprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 204;

[0289] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 205, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 206;

[0290] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 207, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 208;

[0291] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 209, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 210;

[0292] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 211, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 212;

[0293] The V H comprising a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 213, and wherein said V L comprising a sequence at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 214;

[0294] The V Hcomprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 215, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 216;

[0295] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 217, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 218;

[0296] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 219, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 220;

[0297] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 221, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 222;

[0298] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 223, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 224;

[0299] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 225, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 226;

[0300] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 227, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 228;

[0301] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 229, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 230;

[0302] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 231, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 232;

[0303] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 233, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 234;

[0304] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 235, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 236;

[0305] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 237, and the V Lcomprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 238;

[0306] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 239, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 240;

[0307] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 241, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 242;

[0308] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 243, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 244;

[0309] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 245, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 246;

[0310] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 247, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 248;

[0311] the V Hcomprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 249, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 250;

[0312] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 251, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 252;

[0313] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 253, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 254; or

[0314] the V H comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 255, and the V L comprises a sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 256.

[0315] Also included are variants thereof that bind to IL-11Ra, e.g., a variant of any one or more of the foregoing V H and / or V L having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in one or more framework regions of the sequence. Exemplary “alterations” include amino acid substitutions, additions, and deletions.

[0316] As described above, the antibodies or antigen-binding fragments thereof described herein bind to IL-11Ra (e.g., membrane-bound IL-11Ra). In certain embodiments, the antibodies or antigen-binding fragments thereof bind to human IL-11Ra or a region or fragment thereof. The amino acid sequence of human IL-11Ra is provided below in Table B1.

[0317]

[0318] Accordingly, in certain embodiments, the antibody or antigen-binding fragment thereof binds to an IL-11Ra sequence (e.g., a human IL-11Ra sequence) in Table B1. In certain embodiments, the antibody or antigen-binding fragment thereof binds to mature IL-11Ra. In certain embodiments, the antibody or antigen-binding fragment thereof binds to soluble IL-11Ra. In certain embodiments, the antibody or antigen-binding fragment thereof binds to IL-11Ra membrane precursor.

[0319] In certain embodiments, the IL-11Ra antibody or antigen-binding fragment thereof binds to a conformational epitope on IL-11Ra.

[0320] In certain embodiments, the IL-11Ra antibody or antigen-binding fragment thereof binds to a linear epitope on IL-11Ra.

[0321] In particular embodiments, the antibody or antigen-binding fragment thereof binds to the first fibronectin type III domain in human IL-11Ra (also referred to herein as the second extracellular domain of IL-11Ra, which comprises residues 90-197 of SEQ ID NO: 260).

[0322] In certain embodiments, the IL-11Ra antibody or antigen-binding fragment thereof binds to an epitope spanning residues 115-134 in mature IL-11Ra. In certain embodiments, exemplary antibodies of the present disclosure that exhibit such binding comprise V H CDR1, V H CDR2, and V H CDR3 sequences of SEQ ID NO: 25-27, respectively, and V L CDR1, V L CDR2, and V L CDR3 sequences of SEQ ID NO: 25-27, respectively. In certain embodiments, exemplary antibodies of the present disclosure that exhibit such binding comprise the V H sequence of SEQ ID NO: 201 and the V L sequence of SEQ ID NO: 202.

[0323] In certain embodiments, the IL-11Ra antibody or antigen-binding fragment thereof binds to an epitope comprising the residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261). In certain embodiments, the IL-11Ra antibody or antigen-binding fragment thereof binds to an epitope comprising a subset of residues located within ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261). In certain embodiments, exemplary antibodies of the present disclosure that exhibit such binding comprise VH CDR1, V H CDR2, and V H CDR3 sequences, and V L CDR1, V L CDR2, and V L CDR3 sequences. In certain embodiments, exemplary antibodies of the present disclosure presenting such binding include V H sequences of SEQ ID NO: 201 and V L sequences of SEQ ID NO: 202.

[0324] In some embodiments, the antibody or antigen-binding fragment thereof binds to human IL-11 Ra 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 pM, 5 pM, 10 pM, 20 pM, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, 200 pM, 300 pM, 400 pM, or 500 pM, or optionally binds with an affinity ranging from about 1 pM to about 500 pM, about 1 pM to about 400 pM, about 1 pM to about 300 pM, about 1 pM to about 200 pM, about 1 pM to about 100 pM, about 1 pM to about 50 pM, about 1 pM to about 40 pM, about 1 pM to about 30 pM, about 1 pM to about 20 pM, about 1 pM to about 10 pM, about 1 pM to about 5 pM, about 5 pM to about 500 pM, about 5 pM to about 400 pM, about 5 pM to about 300 pM, about 5 pM to about 200 pM, about 5 pM to about 100 pM, about 5 pM to about 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 200 pM, about 10 pM to about 100 pM, about 10 pM to about 50 pM, about 10 pM to about 40 pM, about 10 pM to about 30 pM, about 10 pM to about 20 pM, or about 20 pM to about 500 pM, about 20 pM to about 400 pM, 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-11 Ra relative to the TS7 antibody and the 8E2 antibody (see, e.g., U.S. Patent Nos. 9,796,782; 9,340,618).

[0325] In some embodiments, the antibody or antigen-binding fragment thereof is an IL-11Ra antagonist. In some cases, the antibody or antigen-binding fragment thereof antagonizes the binding and / or signaling activity between IL-11Ra and its ligand, IL-11. In some embodiments, the antibody or antigen-binding fragment thereof antagonizes or reduces the binding and / or signaling activity between IL-11Ra and IL-11 by about or at least about 10% to 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), for example, in a cell-based assay. In some embodiments, the anti-IL-11Ra antibody or antigen-binding fragment thereof reduces IL-11-mediated STAT3 phosphorylation. In an exemplary assay, cells expressing IL-11Ra and gpl30 are cultured in the presence of IL-11, in the presence or absence of an IL-11Ra binding protein. The level of STAT3 phosphorylation is then assessed by Western blot 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 relative to the potency of 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 agonist activity relative to IL-11 signaling.

[0326] In some embodiments, the antibody or antigen-binding fragment thereof inhibits or otherwise reduces IL-11Ra dimerization or complex formation, e.g., with gpl30. In certain embodiments, the antibody or antigen-binding fragment thereof inhibits or otherwise reduces IL-11Ra dimerization or complex formation by about or at least about 10% to 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), for example, in a cell-based assay.

[0327] In some embodiments, an anti-IL-l lRa antibody or antigen-binding fragment thereof reduces proliferation of cells expressing IL-l lRa and gpl30 (e.g., cells that naturally express or are modified to express both proteins) (e.g., BaF3 cells, B9 cells, T10 cells) cultured in the presence of IL-11. Methods for assessing cell proliferation are known in the art and include, for example, MTT reduction and / or thymidine incorporation. Assays using B9 cells or T10 cells are described (see Dams-Kozlowska et al., BMC Biotechnology, 12:8, 2012; and Yokote et al., J AOAC, 83:1053-1057, 2000). For T10 cells, proliferation can be measured by colorimetric detection of the reduction of the tetrazolium compound 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5- tetrazolio]-l,3-thene (WST-1). IL-l lRa binding proteins that reduce proliferation to a level compared to that observed in the absence of the IL-l lRa binding protein are considered to reduce or otherwise decrease IL-11 signaling.

[0328] For illustrative purposes only, the binding interactions between IL-l lRa and an antibody or antigen-binding fragment thereof, or the binding / signaling between IL-l lRa and IL-11 described herein can be detected and quantified using various conventional methods, including Assays (e.g., with appropriately labeled soluble reagents bound to sensor chips) performed with cells expressing IL-11Ra on their surface (either naturally or recombinantly) for FACS analysis, immunoassays, fluorescent staining assays, ELISA assays, and microcalorimetry methods such as ITC (isothermal titration calorimetry). Similarly, functional properties of anti-IL-11Ra antibodies can be assessed using a variety of methods known to those of skill in the art: affinity / binding assays (e.g., surface plasmon resonance, competitive inhibition assays); cytotoxicity assays, cell viability assays, cell proliferation or differentiation assays, etc. Other assays can test the ability of the antibodies described herein to block normal IL-11Ra-mediated responses. The antibodies described herein can also be tested for in vitro and in vivo efficacy. Such assays can be performed using accepted protocols known to the skilled artisan (see, e.g., Current Protocols in Molecular Biology (Greene Publ. Assoc. Inc. and John Wiley & Sons, Inc., New York, NY); Current Protocols in Immunology (ed. John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober, John Wiley & Sons, Inc., New York, NY 2001) or commercially available kits.

[0329] In particular embodiments, the heavy chain constant region or Fc region of the antibody or antigen-binding fragment thereof comprises, consists of, or consists essentially of, an IgA (including sub-classes IgAl and IgA2), IgD, IgE, IgG (including sub-classes IgGl, IgG2, IgG3, and IgG4), or IgM heavy chain constant region or Fc domain, optionally a human Fc domain, or hybrids and / or variants thereof. In particular embodiments, the heavy chain constant region or Fc region comprises, consists of, or consists essentially of, a heavy chain constant region or Fc region from human IgGl or IgG4 (see, e.g., Allberse and Schuurman, Immunology. 105:9-19, 2002) or fragments or variants thereof. Table Fl below provides an exemplary heavy chain constant region sequence (CHl, hinge (underlined), CH2, and CH3 regions) from human IgG4.

[0330] Examples of variant IgG4 sequences that can be used include the S228P / S241P variant.

[0331]

[0332] Table F2 below provides an exemplary heavy chain sequence for mAb 5.

[0333]

[0334] In certain embodiments, the antibody or antigen-binding fragment thereof includes a variant or otherwise modified Fc region, including an Fc region having altered properties or biological activities relative to a wild-type Fc region. Examples of modified Fc regions include: Fc 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 modified or derivatized, e.g., by biotinylation (see, e.g., U.S. Application No. 2010 / 0209424), phosphorylation, sulfation, etc.; or any combination of the foregoing. Such modifications can be employed to alter (e.g., increase, decrease) the binding properties of the Fc region to one or more particular FcRs (e.g., FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, FcyRIIIb, FcRn), its pharmacokinetic properties (e.g., stability or half-life, bioavailability, tissue distribution, volume of distribution, concentration, rate constant for elimination, rate of elimination, area under the curve (AUC), clearance, C max max min max, fluctuation), its immunogenicity, its complement binding or activation, and / or CDC / ADCC / ADCP-related activities of the Fc region, and other properties described herein. Modified Fc regions of human and / or mouse origin are included.

[0335] ​​In certain embodiments, the antibody or antigen-binding fragment thereof includes a hybrid Fc region, e.g., an Fc region that includes 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 that include a derivatized or otherwise modified Fc region. In certain aspects, the Fc region is modified relative to a wild-type or naturally occurring Fc region by, e.g., phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, acetylation, amidation, etc. In certain embodiments, the Fc region includes a wild-type or native glycosylation pattern, or alternatively, it includes increased glycosylation relative to the native form, decreased glycosylation relative to the native form, or it is completely deglycosylated. As one example of a modified Fc glycoform, reduced glycosylation of an Fc region results in reduced binding to the Clq region of the first complement component Cl, reduced ADCC-related activity, and / or reduced CDC-related activity. Certain embodiments thus employ a deglycosylated or aglycosylated Fc region. See, e.g., WO 2005 / 047337 for production of exemplary aglycosylated Fc regions. Another example of an Fc region glycoform is produced by substitution of the Q295 position according to the numbering system of Kabat et al. with a cysteine residue (see, e.g., U.S. Application No. 2010 / 0080794). Certain embodiments include Fc regions in which about 80-100% of the glycoproteins in the Fc region include a mature core carbohydrate structure that lacks fucose (see, e.g., U.S. Application No. 2010 / 0255013). Some embodiments include Fc regions that are optimized by substitution or deletion to reduce the level of fucosylation, e.g., to increase affinity for FcyRI, FcyRIa, or FcyRIIIa and / or to improve phagocytosis by cells expressing FcyRIIa (see U.S. Application Nos. 2010 / 0249382 and 2007 / 0148170).

[0336] As another example of a modified Fc glycoform, the Fc region of an antibody or antigen-binding fragment thereof can include oligomannose glycoforms N-linked glycans, and optionally one or more of: increased ADCC effector activity, increased binding affinity for FcyRIIIA (and certain other FcRs), similar or increased binding specificity for targets of IL-11 R alpha polypeptides, similar or higher binding affinity for targets of IL-11 R alpha polypeptides, and / or similar or lower binding affinity for the mannose receptor relative to a corresponding Fc region containing complex N-linked glycans (see, e.g., U.S. Application No. 2007 / 0092521 and U.S. Patent No. 7,700,321). As another example, Fc region affinity for FcyRs has been enhanced using engineered glycoforms produced by expressing antibodies in engineered or variant cell lines (see, e.g., Umana et al., Nature Biotech. 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. Application No. 2007 / 0111281). Certain Fc region glycoforms include an increased proportion of N-glycoside-linked complex sugar chains that do not have a first position of fucose bound to the sixth position of N-acetylglucosamine at the reducing end of the sugar chain (see, e.g., U.S. Application No. 2010 / 0092997). Particular embodiments can include IgG Fc regions that are glycosylated with at least one galactose moiety linked to the corresponding terminal sialic acid moiety by an alpha-2,6 linkage, optionally wherein the Fc region has higher anti-inflammatory activity relative to a corresponding wild-type Fc region (see U.S. Application No. 2008 / 0206246). These and certain other methods of altered glycosylation greatly enhance the ability of Fc regions to selectively bind FcRs (such as FcyRIII) to mediate ADCC and alter other properties of Fc regions as described herein.

[0337] Certain variants, fragments, hybrids, or otherwise modified Fc regions of antibodies or antigen-binding fragments thereof can alter binding to one or more FcRs, and / or corresponding alterations in effector function, relative to the corresponding wild-type Fc sequence (e.g., same species, same Ig class, same Ig subclass). For example, such Fc regions can have increased binding to one or more of Fcy receptors, Fca receptors, Fcs receptors, and / or neonatal Fc receptors, relative to the corresponding wild-type Fc sequence. In other embodiments, variant Fc regions, fragment Fc regions, hybrid Fc regions, or modified Fc regions can have decreased binding to one or more of Fcy receptors, Fca receptors, Fcs receptors, and / or neonatal Fc receptors, relative to the corresponding wild-type Fc sequence. Specific FcRs are described elsewhere herein.

[0338] In some embodiments, the antibody comprises an Fc domain comprising one or more mutations to increase binding to one or more of Fcy receptors, Fca receptors, Fcs receptors, and / or neonatal Fc receptors, relative to the corresponding wild-type Fc sequence. In some embodiments, the antibody comprises an IgGl or IgG3 Fc domain comprising one or more mutations to increase binding to one or more of Fcy receptors, Fca receptors, Fcs 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 IgGl and IgG3, optionally comprising one or more mutations to increase effector function.

[0339] In some embodiments, the antibody comprises an Fc domain comprising one or more mutations to decrease binding to one or more of Fcy receptors, Fca receptors, Fcs receptors, and / or neonatal Fc receptors, relative to the corresponding wild-type Fc sequence. In some embodiments, the antibody comprises an IgGl or IgG3 Fc domain comprising one or more mutations to decrease binding to one or more of Fcy receptors, Fca receptors, Fcs 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 decrease effector function. In some embodiments, the antibody comprises an Fc domain selected from human IgG2 and IgG4, comprising one or more mutations to decrease effector function.

[0340] Specific examples of Fc variants with altered (e.g., increased, decreased) effector function / FcR binding can be found, for example, in U.S. Patent Nos. 5,624,821 and 7,425,619; U.S. Application Nos. 2009 / 0017023, 2009 / 0010921, and 2010 / 0203046; and WO 2000 / 42072 and WO 2004 / 016750. Certain examples include human Fc regions with one or more substitutions at positions 298, 333, and / or 334, e.g., S298A, E333A, and / or K334A (numbering based on the EU index of Kabat et al.), which have been shown to increase binding to the activating receptor FcyRIIIa and decrease binding to the inhibitory receptor FcyRIIb. These mutations can be combined to obtain double and triple mutant variants that further improve binding to FcRs. Certain embodiments include the S298A / E333A / K334A triple mutant, which has increased binding to FcyRIIIa, decreased binding to FcyRIIb, and increased 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 engineered Fc glycoforms with increased binding to FcRs, as disclosed in Umana et al., supra; and U.S. Patent No. 7,662,925. Some embodiments include Fc regions that include 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. Application Nos. 2009 / 0163699 and 20060173170).

[0341] The effector functions of certain variant Fc regions, fragment Fc regions, hybrid Fc regions, or modified Fc regions can be altered relative to the corresponding wild-type Fc sequence. For example, the complement fixation or activation of such an Fc region can be increased, the Clq binding affinity can be increased, the CDC-related activity can be increased, the ADCC-related activity can be increased, and / or the ADCP-related activity can be increased relative to the corresponding wild-type Fc sequence. In other embodiments, the complement fixation or activation of such an Fc region can be decreased, the Clq binding affinity can be decreased, the CDC-related activity can be decreased, the ADCC-related activity can be decreased, and / or the ADCP-related activity can be decreased relative to the corresponding wild-type Fc sequence. As just one illustrative example, the Fc region can include a deletion or substitution in a complement fixation site, such as a Clq binding site, and / or a deletion or substitution in an ADCC site. Examples of such deletions / substitutions are described in, e.g., 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, e.g., by employing the animal model described in Clynes et al., PNAS. 95:652-656, 1998.

[0342] The stability or half-life of certain variant Fc regions, hybrid Fc regions, or modified Fc regions can be altered relative to the corresponding wild-type Fc sequence. In certain embodiments, the half-life of such Fc regions can be increased relative to the corresponding wild-type Fc sequence. In other embodiments, the half-life of the variant Fc region, hybrid Fc region, or modified Fc region can be decreased relative 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 (e.g., radiolabeling, ELISA, or other methods). In vivo measurements of stability or half-life can be measured in one or more bodily 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 one example, modifications that alter the binding ability of an Fc region to FcRn can alter its in vivo half-life. Non-limiting examples of assays for measuring in vivo pharmacokinetic properties (e.g., in vivo mean elimination half-life) and Fc modifications that alter Fc binding to FcRn are described, for example, in U.S. Patent Nos. 7,217,797 and 7,732,570; and U.S. Application Nos. US 2010 / 0143254 and US 2010 / 0143254.

[0343] Other non-limiting examples of modifications that alter stability or half-life include substitutions / deletions at one or more amino acid residues selected from 251-256, 285-290, and 308-314 in the CH2 domain and 385-389 and 428-436 in the CH3 domain, according to the numbering system of Kabat et al. See U.S. Application No. 2003 / 0190311. Particular examples include substitution with leucine at position 251, substitution with tyrosine, tryptophan, or phenylalanine at position 252, substitution with threonine or serine at position 254, substitution with arginine at position 255, substitution with glutamine, arginine, serine, threonine, or glutamic acid at position 256, substitution with threonine at position 308, substitution with proline at position 309, substitution with serine at position 311, substitution with aspartic acid at position 312, substitution with leucine at position 314, substitution with arginine, aspartic acid, or serine at position 385, substitution with threonine or proline at position 386, substitution with arginine or proline at position 387, substitution with proline, asparagine, or serine at position 389, substitution with methionine or threonine at position 428, substitution with tyrosine or phenylalanine at position 434, substitution with histidine, arginine, lysine, or serine at position 433, and / or substitution with histidine, tyrosine, arginine, or threonine at position 436, including any combination thereof. Such modifications optionally increase the affinity of the Fc region for the FcRn and thereby increase the half-life relative to the corresponding wild-type Fc region.

[0344] The solubility of certain variant Fc regions, hybrid Fc regions, or modified Fc regions can be altered relative to the corresponding wild-type Fc sequence. In certain embodiments, the solubility of such Fc regions can be increased relative to the corresponding wild-type Fc sequence. In other embodiments, the solubility of the variant Fc region, hybrid Fc region, or modified Fc region can be decreased relative to the corresponding wild-type Fc sequence. Solubility can be measured in vitro, e.g., under physiological conditions, e.g., according to routine techniques in the art. Exemplary solubility measurements are described elsewhere herein.

[0345] A variant Fc region can also have one or more mutant hinge regions, e.g., as described in U.S. Application No. 2003 / 0118592. For example, one or more of the cysteines in the hinge region can be deleted or substituted with a different amino acid. The mutant hinge region can not include a cysteine residue, or it can include one, two, or three fewer cysteine residues than the corresponding wild-type hinge region. In some embodiments, an Fc region having a mutant hinge region of this type exhibits reduced dimerization ability relative to a wild-type Ig hinge region.

[0346] In particular embodiments, the antibody or antigen-binding fragment thereof has a biological half-life of 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 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 intermediate half-life, including all ranges therebetween, at about pH 7.4, at about physiological pH, at about 25°C or room temperature, and / or at about 37°C or human body temperature (e.g., in vivo, in serum, in a given tissue, in a given species, such as rat, mouse, monkey, or human).

[0347] In some embodiments, the antibody or antigen-binding fragment thereof has a Tm m about or at least about 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, or 75°C. In some embodiments, the antibody or antigen-binding fragment thereof has a Tm m about 65°C or higher, for example in PBS (phosphate buffered saline).

[0348] For in vivo use, certain embodiments include a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as described herein, and a pharmaceutically acceptable carrier. To prepare a therapeutic or pharmaceutical composition, an effective or desired amount of agent(s) is mixed with any of the pharmaceutical carriers known to those of skill in the art in order to suit the particular agent and / or mode of administration. The pharmaceutical carrier can be a liquid, semi-liquid, or solid. Solutions or suspensions used for parenteral, intradermal, intraocular, subcutaneous, direct instillation into the urinary bladder, or topical application can include, for example, sterile diluent such as water, saline solution (e.g., phosphate buffered saline; PBS), fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents (such as benzyl alcohol and methyl parabens), antioxidants (such as ascorbic acid and sodium bisulfite), and chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); buffers (such as acetate, citrate, and phosphate). If administered intravenously (e.g., by IV infusion), suitable carriers include normal saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents such as dextrose, polyethylene glycol, polypropylene glycol, and mixtures thereof.

[0349] Administration of the agents described herein, in pure form or in an appropriate therapeutic or pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for similar uses, for similar purposes. Therapeutic or pharmaceutical compositions can be prepared by combining a composition containing an agent 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. Additionally, other pharmaceutically active ingredients (including other small molecules as described elsewhere herein) and / or suitable excipients, such as salts, buffers and stabilizers, can be present in the composition, but need not be.

[0350] Administration can be by various routes, including oral, parenteral, nasal, intravenous, intraocular, intradermal, intramuscular, subcutaneous, instillation into the urinary bladder, or topical administration. The preferred mode of administration depends on the nature of the condition to be treated or prevented. Particular embodiments include administration by IV infusion.

[0351] The carrier can include, for example, a pharmaceutically or physiologically acceptable carrier, excipient, or stabilizer, which is nontoxic to the cells or mammal being exposed thereto at the dosages and concentrations employed. A nontoxic physiologically acceptable carrier is generally an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; 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; 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 nonionic surfactants such as polysorbate 20 (TWEEN 20), polyethylene glycol (PEG), and poloxamer (PLURONICS F68), and the like. TM TM

[0352] In some embodiments, one or more agents can be entrapped, for example, in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16thEdition, Oslo A., Ed., (1980). One or more particles or liposomes can further include other therapeutic or diagnostic agents.

[0353] ​​The precise dose 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 compositions in model systems known in the art and extrapolating therefrom. Controlled clinical trials can also be performed. Dosage can also vary with the severity of the condition to be alleviated. Pharmaceutical compositions are generally formulated and administered to exert a therapeutically useful effect while minimizing undesirable side effects. The compositions can be administered at one time, or can be divided into multiple smaller doses administered at intervals of time. The specific dose regimen for any particular subject can be adjusted over time according to the individual need.

[0354] Accordingly, typical routes of administering these and related therapeutic or pharmaceutical compositions 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 injections, intravenous, instillation into the bladder, intramuscular, intrasternal injection or infusion techniques. Therapeutic or pharmaceutical compositions according to certain embodiments of the present disclosure are formulated to permit the active ingredients contained therein to be bioavailable upon administration of the compositions to a subject or patient. Compositions to be administered to a subject or patient can take the form of one or more dosage units, where, for example, a tablet can be a single dosage unit, and a container of a pharmaceutical preparation in aerosol form described herein can hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent in light of this disclosure, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition, (Philadelphia College of Pharmacy and Science, 2000). Compositions to be administered will generally contain a therapeutically effective amount of a pharmaceutical agent described herein for treatment of a disease or condition of interest.

[0355] Therapeutic or pharmaceutical compositions can be in the form of a solid or a liquid. In some embodiments, the carrier is particulate, such that the compositions are, for example, in tablet or powder form. The carrier can be a liquid, wherein the composition is, for example, an oral oil, an injectable liquid, or an aerosol, which can be useful, for example, in inhalable administration. When oral administration is intended to be used, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension, and gel forms are included within the forms considered herein as solid or liquid. Certain embodiments include sterile injectable solutions.

[0356] As a solid composition for oral administration, a pharmaceutical composition can be formulated into a powder, granule, gel, compressed tablet, pill, capsule, chewing gum, wafer, etc. Such solid compositions will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following can be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent. When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0357] A therapeutic or pharmaceutical composition can be in liquid form, e.g., elixir, syrup, solution, gel, emulsion, or suspension. As two examples, a liquid can be for oral administration or for delivery by injection. When intended for oral administration, preferred compositions include one or more of a sweetening agent, preservatives, dye / colorant, and flavoring agent, in addition to the compound of the present application. In compositions intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can be included.

[0358] A liquid therapeutic or pharmaceutical composition, whether it be solution, suspension or other like form, can include one or more of the following adjuvants: sterile diluent such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0359] Liquid therapeutic or pharmaceutical compositions intended for administration by parenteral, intraocular, or oral routes are typically formulated in dosage units to provide an appropriate dose of the agent. Usually, this amount will be at least 0.01% of the agent of interest in the composition. When intended for oral administration, this amount can range from 0.1% to about 70% of the weight of the composition. Certain oral therapeutic or pharmaceutical compositions contain from about 4% to about 75% of the agent of interest. In certain embodiments, the therapeutic or pharmaceutical compositions and formulations are prepared so that a parenteral dosage unit contains from 0.01% to 10% by weight of the agent of interest prior to dilution.

[0360] Therapeutic or pharmaceutical compositions can be intended for topical administration, in which case the carrier will conveniently comprise a solution, emulsion, ointment or gel base. For example, the base can comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents can be present in a therapeutic or pharmaceutical composition for topical administration. If intended for transdermal administration, the composition can include a transdermal patch or iontophoresis device.

[0361] Therapeutic or pharmaceutical compositions can be intended for rectal administration in the form of suppositories to melt in the rectum and release the medicament. Compositions for rectal administration can contain an oleaginous base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycols.

[0362] Therapeutic or pharmaceutical compositions can include various materials, which modify the physical form of the solid or liquid dosage unit. For example, the composition can include a material that forms a coating shell around the active ingredients. The materials that form the coating shell are typically inert and can be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients can be encased in a gelatin capsule. The therapeutic or pharmaceutical compositions in solid or liquid form can include components that are

[0363] Therapeutic or pharmaceutical compositions can consist essentially of dosage units that can be administered as an aerosol. The term aerosol is used to describe a variety of systems ranging from those of colloidal nature to systems consisting of a pressurized package. Delivery can be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols can be delivered in single phase, bi-phasic, or tri-phasic systems to deliver the active ingredients. Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together can form a kit. One of ordinary skill in the art without needing to make additional experiments in order to determine the preferred aerosol.

[0364] The compositions described herein can be prepared with carriers that protect the agent from rapid elimination from the body, such as timed-release formulations or coatings. Such carriers include controlled-release formulations, such as, 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 of ordinary skill in the art.

[0365] Pharmaceutical compositions can be prepared by methods well known in the pharmaceutical field. For example, therapeutic compositions or pharmaceutical compositions intended for administration by injection may include one or more salts, buffers and / or stabilizers and, together with sterile distilled water, form a solution. Surfactants may be added to promote the formation of a uniform solution or suspension. Surfactants are compounds that non-covalently interact with a medicament to promote the dissolution or uniform suspension of the medicament in an aqueous delivery system.

[0366] The therapeutic composition or pharmaceutical composition can be administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the specific 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 rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. In some cases, the therapeutically effective daily dose (for a 70 kg mammal) is about 0.001 mg / kg (i.e., about 0.07 mg) to about 100 mg / kg (i.e., about 7.0 g); preferably, the therapeutically effective dose (for a 70 kg mammal) is about 0.01 mg / kg (i.e., about 0.7 mg) to about 50 mg / kg (i.e., about 3.5 g); more preferably, the therapeutically effective dose (for a 70 kg mammal) is about 1 mg / kg (i.e., about 70 mg) to about 25 mg / kg (i.e., about 1.75 g). In some embodiments, the therapeutically effective dose is administered on a weekly, biweekly, or monthly basis. In specific embodiments, a therapeutically effective dose is administered weekly, biweekly, or monthly, for example, 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.

[0367] Also provided are antibodies, antigen-binding fragments thereof, or pharmaceutical compositions of the present disclosure for use as medicaments. The antibodies, fragments thereof, or pharmaceutical compositions of the present disclosure can be used in any of the therapeutic methods disclosed herein. In specific embodiments, the antibodies, fragments thereof, or pharmaceutical compositions of the present disclosure can be used in methods for treating TED, ameliorating symptoms of TED, and / or reducing the progression of TED.

[0368] The methods and compositions provided herein can be combined with other treatment modalities for treating TED. Examples include supportive care (e.g., improving thyroid function, smoking cessation, selenium supplementation), corticosteroids, radiotherapy, and surgical management, e.g., eyelid retraction repair, strabismus surgery, and orbital decompression.

[0369] Also included are patient care kits comprising (a) an antibody or antigen-binding fragment thereof that binds to IL-11Ra 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.

[0370] The kits herein can also comprise one or more additional therapeutic agents or other components suitable or desired for the indication being treated or for the diagnostic application desired. The kits herein can also comprise one or more syringes or other components needed or desired to facilitate the intended mode of delivery (e.g., a holder, an implantable reservoir, etc.).

[0371] In some embodiments, the patient care kits contain separate containers, partitions, or compartments for the compositions and the informational material. For example, the compositions can be contained in a bottle, vial, or syringe, and the informational material can be contained in association with the container, e.g., in the form of a label affixed to the bottle, vial, or syringe. In some embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the compositions are contained in a bottle, vial, or syringe with the informational material affixed to the bottle, vial, or syringe in the form of a label. In some embodiments, the kit contains a plurality (e.g., a pack) of separate containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of the antibody, and optionally at least one additional therapeutic agent. For example, the kit contains a plurality of syringes, ampules, foil packets, or blister packs, each of which contains a single unit dosage of the antibody, and optionally at least one additional therapeutic agent. The containers of the kit can be air-tight, water-tight (e.g., impermeable to moisture changes or evaporation), and / or light-tight.

[0372] The patient care kits optionally contain a device suitable for administering the compositions, e.g., a syringe, inhaler, dropper (e.g., eye dropper), swab (e.g., cotton or wooden swab), or any such delivery device. In some embodiments, the device is an implantable device that dispenses metered doses of the agent. Also included are methods of providing a kit, e.g., by combining the components described herein.

[0373] 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 skilled in the art, based on the teachings of this disclosure, that certain changes and modifications may be made thereto 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 skilled in the art will readily recognize various non-critical parameters that may be changed or modified to produce substantially similar results.

[0374] Examples

[0375] Non-limiting exemplary embodiments of the present disclosure are provided herein.

[0376] Example I-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 α (IL-11Rα).

[0377] Embodiment I-2. The method of embodiment I-1, wherein the patient has one or more clinical signs of TED.

[0378] Example 1-3. The method of Example 1-2, wherein the one or more clinical signs are selected from: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

[0379] Embodiment 1-4. The method of any one of embodiments 1-1 to 1-3, wherein the patient has a Clinical Activity Score (CAS) of 3 or higher, or 4 or higher, 5 or higher, or 6 or higher, wherein the CAS includes one point for each of spontaneous orbital pain, gaze-evoked orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and caruncle and inflammation of the plica semilunaris.

[0380] Embodiment I-5. The method of any one of embodiments I-1 to I-4, wherein the patient has a VISA (Vision, Inflammation, Strabismus, Appearance / Exposure) score of 4 or higher, 5 or higher, 6 or higher, 7 or higher, or 8 or higher.

[0381] Embodiment I-6. The method according to any one of embodiments I-1 to I-5, wherein the patient has abnormal thyroid function, optionally hyperthyroidism.

[0382] Example I-7. The method of any one of Examples I-l to I-6, wherein the patient has autoantibodies to the thyroid-stimulating hormone receptor (TSHR) stimulation.

[0383] Example I-8. The method of any one of Examples I-l to I-7, wherein the patient has increased levels of thyroid-stimulating immunoglobulins (TSI).

[0384] Example I-9. The method of any one of Examples I-l to I-8, wherein the patient has Grave’s disease.

[0385] Example I-10. The method of any one of Examples I-l to I-9, wherein the patient has one or more risk factors associated with TED.

[0386] Example I-11. The method of Example I-10, wherein the one or more risk factors are selected from the group consisting of being female, being middle-aged, smoking, and being currently undergoing or having undergone radioactive iodine treatment.

[0387] Example I-12. The method of any one of Examples I-l to I-l l, wherein the patient has increased levels of IL-l lRa and / or IL-l 1 in blood or tissue around the eye, optionally in orbital fibroblasts, and / or wherein the patient has increased levels of circulating IL-l 1.

[0388] Example I-13. The method of any one of Examples I-l to I-12, comprising:

[0389] a. determining whether the patient has TED; and

[0390] b. administering the pharmaceutical composition to the patient if the patient has TED.

[0391] Example I-14. The method of Example I-13, wherein (a) comprises measuring one or more clinical signs of TED, optionally selected from the group consisting of: upper eyelid retraction (unilateral or bilateral); exophthalmos (proptosis); bunny eyes (inability of the eyelids to fully close); 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 (conjunctival edema).

[0392] Example I-15. The method of Example I-13 or I-14, comprising:

[0393] a. determining the CAS of the patient; and

[0394] b. administering the pharmaceutical composition to the patient if the CAS is 3 or greater, or 4 or greater, 5 or greater, or 6 or greater.

[0395] Example I-16. The method of any one of Examples I-13 to I-15, comprising:

[0396] a. determining a VISA score of the patient; and

[0397] b. 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.

[0398] Example I-17. The method of any one of Examples I-13 to I-16, comprising:

[0399] a. determining thyroid function of the patient; and

[0400] b. administering the pharmaceutical composition to the patient if the patient has abnormal thyroid function, optionally hyperthyroidism.

[0401] Example I-18. The method of any one of Examples I-13 to I-17, comprising:

[0402] a. determining thyroid stimulating immunoglobulin (TSI) levels of the patient; and

[0403] b. administering the pharmaceutical composition to the patient if the patient has elevated TSI levels relative to a control or reference standard.

[0404] Example I-19. The method of any one of Examples I-1 to I-18, comprising:

[0405] a. determining levels of IL-11Ra and / or IL-11 in blood or tissue surrounding the eye, optionally orbital fibroblasts, of the patient; and

[0406] b. administering the pharmaceutical composition to the patient if the patient has elevated levels of IL-11Ra and / or IL-11 in blood or tissue surrounding the eye, optionally in orbital fibroblasts, relative to a control or reference standard.

[0407] Example I-20. The method of any one of Examples I-1 to I-19, wherein the patient has not been treated with a TED therapy, optionally the patient has chronic TED.

[0408] Embodiment I-21. The method of any one of embodiments I-1 to I-19, wherein the patient is undergoing or has previously undergone a TED therapy and is relapsing / refractory / intolerant to the TED therapy, optionally a patient with active TED.

[0409] Embodiment I-22. The method of embodiment I-21, wherein the patient’s TED is progressing, optionally indicated by worsening of one or more clinical signs of TED, an increase in CAS score, and / or an increase in VISA score compared to clinical signs or scores prior to the TED therapy, optionally wherein the progression of TED in the patient is more aggressive than prior to the TED therapy.

[0410] Embodiment I-23. The method of any one of embodiments I-20 to I-22, wherein the TED therapy is selected from the group consisting of 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-alpha (TNF-a) inhibitor therapy.

[0411] Embodiment I-24. The method of embodiment I-23, wherein the IGF-1R inhibitor therapy is selected from the group consisting of teprotumumab, ganitumab, darotumumab, cixutumumab, and fingolimod therapy.

[0412] Embodiment I-25. The method of embodiment I-23, wherein the FcRn inhibitory therapy is selected from the group consisting of batoclimab (IMVT-1401), efgartigimod, nicatimomab, ondermab, and rolichumab therapy.

[0413] Embodiment I-26. The method of embodiment I-23, wherein the IL-6 inhibitor therapy is selected from the group consisting of clazakizumab, ameilumab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.

[0414] Embodiment I-27. The method of embodiment I-23, wherein the steroid therapy is selected from the group consisting of methylprednisolone (optionally, IV methylprednisolone sodium succinate), prednisolone (optionally, oral prednisolone), and prednisone (optionally, oral prednisone) therapy.

[0415] Embodiment I-28. The method of embodiment I-23, wherein the CD20 inhibitor therapy is selected from the group consisting of ibatumomab tiuxetan, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0416] Example I-29. The method of Example I-23, wherein the TNF-a inhibitor therapy is selected from the group consisting of adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0417] Example I-30. The method of any one of Examples I-1 to I-29, comprising administering the pharmaceutical composition in combination with at least one other TED therapy.

[0418] Example I-31. The method of Example I-30, wherein the at least one other TED therapy is selected from the group consisting of IGF-1R inhibitor therapy, FcRn inhibitor therapy, IL-6 inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20 inhibitor therapy, and tumor necrosis factor-alpha (TNF-a) inhibitor therapy.

[0419] Example I-32. The method of Example I-31, wherein the IGF-1R inhibitor therapy is selected from the group consisting of tiragolumab, ganitumab, daratumumab, cixutumumab, and figitumumab therapy.

[0420] Example I-33. The method of Example I-32, wherein the IGF-1R inhibitor therapy is administered 1 to 7 times simultaneously or sequentially with administration of the pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or antigen-binding fragment thereof that binds to human IL-11Ra.

[0421] Example I-34. The method of Example I-31, wherein the FcRn inhibitory therapy is selected from the group consisting of batoclimab (IMVT-1401), efgartigimod, nicatimomab, ondermab, and rosilixatimab therapy.

[0422] Example I-35. The method of Example I-31, wherein the IL-6 inhibitor therapy is selected from the group consisting of clazakizumab, anakinra, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.

[0423] Example I-36. The method of Example I-31, wherein the steroid therapy is selected from the group consisting of methylprednisolone (optionally, IV methylprednisolone sodium succinate), prednisolone (optionally, oral prednisolone), and prednisone (optionally, oral prednisone) therapy.

[0424] Example I-37. The method of Example I-31, wherein the CD20 inhibitor therapy is selected from the group consisting of ibatumomab tiuxetan, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0425] Embodiment 1-38. The method of embodiment 1-31, wherein the TNF-α inhibitor therapy is selected from adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.

[0426] Embodiment 1-39. The method of any one of embodiments 1-1 to 1-38, wherein the antibody or antigen-binding fragment thereof binds to fibronectin domain III of human IL-11Rα or approximately residues 90-197 of SEQ ID NO: 260.

[0427] 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.

[0428] Embodiment 1-41. The method of embodiment 1-39, wherein the antibody or antigen-binding fragment thereof recognizes an epitope comprising the amino acid sequence of SEQ ID NO: 261.

[0429] Embodiment 1-42. The method of embodiment 1-41, wherein the epitope comprises residues S116, S125, K129, S140, and T143 of SEQ ID NO: 260.

[0430] Embodiment 1-43. The method of any one of embodiments 1-1 to 1-42, wherein the antibody or antigen-binding fragment thereof comprises:

[0431] a. Heavy chain variable region (V H ), which comprises a complementarity determining region V selected from Table A1 H CDR1, V H CDR2 and V H CDR3 amino acid sequences and variants thereof that specifically bind to IL-11Rα; and

[0432] b. Light chain variable region (V L ), which comprises a complementarity determining region V selected from Table A1 L CDR1, V L CDR2 and V L CDR3 amino acid sequences and their variants that specifically bind to IL-11Rα.

[0433] Embodiment 1-44. The method of embodiment 1-43, wherein:

[0434] The V H CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 1-3, respectively, and the VL CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 4-6, respectively;

[0435] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 7-9, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 10-12, respectively;

[0436] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 13-15, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 16-18, respectively;

[0437] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 19-21, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 22-24, respectively;

[0438] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 25-27, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 28-30, respectively;

[0439] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 31-33, respectively, and the V L CDR1, V LCDR2 and V L CDR3 amino acid sequences comprise SEQ ID NOs: 34-36, respectively;

[0440] the V H CDR1, V H CDR2 and V H CDR3 amino acid sequences comprise SEQ ID NOs: 34-39, respectively, and the V L CDR1, V L CDR2 and V L CDR3 amino acid sequences comprise SEQ ID NOs: 40-42, respectively;

[0441] the V H CDR1, V H CDR2 and V H CDR3 amino acid sequences comprise SEQ ID NOs: 43-45, respectively, and the V L CDR1, V L CDR2 and V L CDR3 amino acid sequences comprise SEQ ID NOs: 46-48, respectively;

[0442] the V H CDR1, V H CDR2 and V H CDR3 amino acid sequences comprise SEQ ID NOs: 49-51, respectively, and the V L CDR1, V L CDR2 and V L CDR3 amino acid sequences comprise SEQ ID NOs: 52-54, respectively;

[0443] the V H CDR1, V H CDR2 and V H CDR3 amino acid sequences comprise SEQ ID NOs: 55-57, respectively, and the V L CDR1, V L CDR2 and V L CDR3 amino acid sequences comprise SEQ ID NOs: 58-60, respectively;

[0444] the V H CDR1, V H CDR2 and V H CDR3 amino acid sequences comprise SEQ ID NOs: 61-63, respectively, and the V L CDR1, V L CDR2 and V Lthe CDR3 amino acid sequences comprise SEQ ID NOs: 64-66, respectively;

[0445] the V H CDR1, V H CDR2, and V H the CDR3 amino acid sequences comprise SEQ ID NOs: 67-69, respectively, and the V L CDR1, V L CDR2, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 70-72, respectively;

[0446] the V H CDR1, V H CDR2, and V H the CDR3 amino acid sequences comprise SEQ ID NOs: 73-75, respectively, and the V L CDR1, V L CDR2, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 76-78, respectively;

[0447] the V H CDR1, V H CDR2, and V H the CDR3 amino acid sequences comprise SEQ ID NOs: 79-81, respectively, and the V L CDR1, V L CDR2, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 82-84, respectively;

[0448] the V H CDR1, V H CDR2, and V H the CDR3 amino acid sequences comprise SEQ ID NOs: 85-87, respectively, and the V L CDR1, V L CDR2, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 88-90, respectively;

[0449] the V H CDR1, V H CDR2, and V H the CDR3 amino acid sequences comprise SEQ ID NOs: 91-93, respectively, and the V L CDR1, V L CDR2, and V L the CDR3 amino acid sequences comprise SEQ ID NOs: 94-96, respectively;

[0450] The V H CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 97-99, respectively, and the V L CDR1, V L CDR2 and V L The CDR3 amino acid sequences comprise SEQ ID NOs: 100-102, respectively;

[0451] The V H CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 103-105, respectively, and the V L CDR1, V L CDR2 and V L The CDR3 amino acid sequences comprise SEQ ID NOs: 106-108, respectively;

[0452] The V H CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 109-111, respectively, and the V L CDR1, V L CDR2 and V L The CDR3 amino acid sequences comprise SEQ ID NOs: 112-114, respectively;

[0453] The V H CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 115-117, respectively, and the V L CDR1, V L CDR2 and V L The CDR3 amino acid sequences comprise SEQ ID NOs: 118-120, respectively;

[0454] The V H CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 121-123, respectively, and the V L CDR1, V L CDR2 and V L The CDR3 amino acid sequences comprise SEQ ID NOs: 124-126, respectively;

[0455] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 127-129, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 130-132, respectively;

[0456] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 133-135, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 136-138, respectively;

[0457] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 139-141, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 142-144, respectively;

[0458] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 145-147, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 148-150, respectively;

[0459] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 151-153, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 154-156, respectively;

[0460] The V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 157-159, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 160-162, respectively;

[0461] The V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 163-165, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 166-168, respectively;

[0462] The V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 169-171, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 172-174, respectively;

[0463] The V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 175-177, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 178-180, respectively;

[0464] The V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 181-183, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 184-186, respectively; or

[0465] The VH CDR1, V H CDR2 and V H The CDR3 amino acid sequences comprise SEQ ID NOs: 187-189, respectively, and the V L CDR1, V L CDR2 and V L The CDR3 amino acid sequences comprise SEQ ID NOs: 190-192, respectively.

[0466] Embodiment I-45. The method according to embodiment I-43 or I-44, wherein V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to an amino acid sequence selected from Table A2, optionally wherein V H There are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 alterations in the framework regions.

[0467] Embodiment I-46. The method according to embodiment I-43 or I-45, wherein V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to an amino acid sequence selected from Table A2, optionally wherein V L There are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 alterations in the framework regions.

[0468] Embodiment 1-47. The method of any one of Embodiments 1-43 to 1-46, wherein:

[0469] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 193, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 194;

[0470] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 195, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 196;

[0471] The V Hcomprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 197, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 198;

[0472] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 199, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 200;

[0473] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202;

[0474] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 203, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204;

[0475] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 206;

[0476] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 207, and the V Lcomprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 208; and the V

[0477] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 209; and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 210;

[0478] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 211; and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 212;

[0479] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 213; and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 214;

[0480] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 215; and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 216;

[0481] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 217; and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 218;

[0482] the V Hcomprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 219, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 220;

[0483] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 221, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 222;

[0484] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 223, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 224;

[0485] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 225, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 226;

[0486] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 227, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 228;

[0487] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 229, and wherein said V Lcomprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 230;

[0488] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 231, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 232;

[0489] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 233, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 234;

[0490] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 235, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 236;

[0491] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 237, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 238;

[0492] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 239, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 240;

[0493] The V Hcomprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 241, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 242;

[0494] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 243, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 244;

[0495] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 245, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 246;

[0496] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 247, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 248;

[0497] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 249, and the V L comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 250;

[0498] the V H comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 251, and the V Lcomprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 252;

[0499] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 253, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 254; or

[0500] The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 255, and wherein said V L Comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO:256.

[0501] Embodiment 1-48. The method of any one of embodiments 1-1 to 1-47, wherein the antibody or antigen-binding fragment thereof has one or more of the following characteristics:

[0502] a. increased binding affinity for human IL-11Rα compared to the 340 antibody, and increased functional efficacy compared to the 340 antibody, optionally as measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells;

[0503] b. having 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 having an increased binding affinity for human IL-11Rα compared to the TS7 and 8E2 antibodies;

[0504] c. antagonizing the binding and / or signaling activity between IL-11Rα and IL-11, and optionally increasing the potency of an IL-11 signaling antagonist compared to the TS7 and 8E2 antibodies;

[0505] d. reducing IL-11Rα / gp130 dimerization or complex formation, optionally in a cell-based assay; and / or

[0506] e. In V L N-linked glycosylation in CDR3 is reduced, optionally relative to the TS7 and 8E2 antibodies.

[0507] 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 sub-classes IgAl and IgA2), IgD, IgE, IgG (including sub-classes IgGl, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or hybrids and / or variants thereof.

[0508] Embodiment I-50. The method of embodiment I-49, wherein the antibody or antigen-binding fragment thereof comprises an IgG Fc domain having high effector function in humans, optionally an IgGl or IgG3 Fc domain.

[0509] Embodiment I-51. The method of embodiment I-49, wherein the antibody or antigen-binding fragment thereof comprises an IgG Fc domain having low effector function in humans, optionally an IgG2 or IgG4 Fc domain.

[0510] Embodiment I-52. The method of embodiment I-49, wherein the antibody or antigen-binding fragment thereof comprises a human IgGl or IgG4 Fc domain, optionally selected from Table Fl.

[0511] 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.

[0512] 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 having an S228P mutation (EU numbering).

[0513] 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 the group consisting of an Fv fragment, a single-chain Fv (scFv) polypeptide, a fibronectin, an anticalin, an aptamer, a high-affinity multimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.

[0514] 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% by protein relative to the at least one antibody or antigen-binding fragment, and is substantially free of aggregates and endotoxins.

[0515] Example I-57. The method of any one of embodiments I-1 to I-56, wherein the composition has reduced or undetectable N-linked glycosylation heterogeneity (optionally relative to the TS7 and 8E2 antibodies), optionally in the V L CDR3 sequence.

[0516] Example I-58. The method of any one of embodiments I-1 to I-57, wherein the pharmaceutical composition is a sterile injectable solution, optionally suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.

[0517] Example I-59. The method of any one of embodiments I-1 to I-58, wherein administration of the pharmaceutical composition to the patient improves one or more clinical signs of TED.

[0518] Example I-60. The method of embodiment I-59, wherein the one or more clinical signs are selected from the group consisting of: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); a bunny eye (inability of the eyelids to fully close); 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 bulbar conjunctival edema (chemosis).

[0519] Example I-61. The method of embodiment I-59 or I-60, wherein administration of the pharmaceutical composition to the patient improves the patient’s Clinical Activity Score (CAS), optionally by at least one, two, three, four, or five points, optionally to a CAS of 3 or less, 2 or less, or 1 or less.

[0520] Example I-62. The method of any one of embodiments I-59 to I-61, wherein administration of the pharmaceutical composition to the patient improves the patient’s VISA score, optionally by at least one, two, three, four, or five points, optionally to a VISA of 4 or less, 3 or less, 2 or less, or 1 or less.

[0521] Example I-63. The method of any one of embodiments I-1 to I-62, wherein administration of the pharmaceutical composition to the patient reduces IL-11Ra and / or IL-11 levels in blood or tissue around the patient’s eye, optionally in orbital fibroblasts.

[0522] Example I-64. The method of any one of embodiments I-1 to I-63, wherein administration of the pharmaceutical composition to the patient reduces circulating IL-11 levels in the patient.

[0523] Example

[0524] Example 1: Elevated IL-11 Ra expression in TED-derived fibroblasts

[0525] Flow cytometry was performed to compare IL-11 Ra expression on primary fibroblasts derived from orbital tissue of thyroid eye disease (TED) patients to primary fibroblasts derived from orbital tissue of non-TED individuals. IL-11 R levels on the cell surface were detected using antibody mAb5. As shown in Figures 1A-1C high levels of IL-11 Ra expression were detected on fibroblasts from diseased tissue relative to fibroblasts from normal tissue Figure 1C ). This result demonstrates that inhibitory anti-IL-11 Ra antibodies have therapeutic utility in treating TED, for example by inhibiting IL-11 Ra activity in tissues surrounding the eye of a TED patient.

[0526] Example 2: Anti-IL-11 Ra antibodies block IL-11 stimulated HA release and cell proliferation in orbital cells of TED patients

[0527] To assess the role of IL-11 in thyroid eye disease, fibroblasts were isolated from orbital tissue of thyroid eye disease (TED) patients and then stimulated with recombinant human IL-11 in culture in the presence and absence of IL-11 Ra blocking antibody mAb5. The effects of these treatments on hyaluronic acid (HA) release and cell proliferation, two events associated with TED pathogenesis, were measured.

[0528] Materials and Methods

[0529] Cell separation Orbital fat / connective tissue was isolated from TED patients during orbital decompression surgery. Donor information is provided in Table E1 below.

[0530]

[0531] Following isolation, the tissue was minced into 1-2 mm pieces, placed in a 6-well culture dish containing 3 mL of growth media (high glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 20% fetal bovine serum and 1% penicillin / streptomycin; both from Gibco Laboratories, New York, USA), and incubated at 37°C and 5% C02. The media 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.

[0532] Cell proliferation and HA releaseFollowing isolation, orbital fibroblasts (passage <5) were plated in growth medium at a density of 10,000 cells / well on black clear-bottom 96-well plates (Corning Costar, Cat# 3603) and maintained at 37°C and 5% C02 in a humidified incubator overnight. The next day, the medium was changed to 100 pL of starvation medium (high glucose Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 1% fetal bovine serum and 1% penicillin / streptomycin; both from Gibco Laboratories, New York, USA) for 24 hours to synchronize the cells. The next day, the medium was changed to fresh serum-starved medium and cells were pre-incubated with medium alone (vehicle, no antibody control), mAb5 (at indicated concentrations), RSV-002 (ichorbio, ICH5128, 10 ng / mL) and / or isotype control (10 ng / mL) for 1 hour, and then re-stimulated with human recombinant IL-11 (1.1, 3.3 or 10 ng / mL) for 96 hours. Following the 96-hour stimulation period, an aliquot of the medium was removed and frozen at -80°C for analysis of HA release. To measure cell proliferation, 10 pL of WST-1 cell proliferation reagent (Sigma-Aldrich, Cat# 11644807001) was added to each well and, following a 2-hour incubation, cell proliferation was assessed by measuring OD 450 with a Spectramax iD5 plate reader (Molecular Devices, San Jose, CA.). HA release was measured using a Duoset ELISA (R&D Systems, Cat# DY3614) according to the manufacturer’s recommendations.

[0533] Results

[0534] As shown in Figure 2 , recombinant IL-11 stimulated a dose-dependent increase in HA release from orbital fibroblasts (grey bar columns) and this was inhibited by mAb5 (hatched bar columns) at all IL-11 doses. Similarly, as shown in Figure 3 , recombinant IL-11 stimulated fibroblast proliferation at all doses and these effects were blocked by the addition of mAb5.

[0535] Figures 4A-4C IL-11 was shown to stimulate HA release from patient sample #2 Figure 4A (with no prior TED therapy), patient sample #1 Figure 4B (with prior RSV-002 therapy) and proprietary sample #3 Figure 4CDose-dependent effects of mAb5 on hyaluronan release from orbital fibroblasts of patients with TED (no prior TED therapy), patients with prior therapy with Figures 5A-5C Effects of mAb5 on IL-11 (10 ng / mL)-induced HA release from orbital fibroblasts of patients #2, #4, and #5 Figure 5A (no prior TED therapy), patient #1 Figure 5B (prior therapy with Teprotumumab), and patient #3 Figure 5C (prior therapy with corticosteroids).

[0536] Figures 6A-6C Comparative inhibitory effects of mAb5, Teprotumumab, and isotype control (all at 10 μg / mL) on 10 ng / mL IL-11 -induced HA release from orbital fibroblasts of patients with TED; Figure 6A Effects on untreated patient samples (no prior TED therapy, n=4), Figure 6B Effects on patient samples previously treated with Teprotumumab (n=1), and Figure 6C Effects on patient samples previously treated with corticosteroids (n=2). Figures 7A-7C Comparative effects of mAb5, Teprotumumab, and isotype control antibodies (all at 10 μg / mL) on proliferation of orbital fibroblasts of patients with TED induced by 10 ng / mL IL-11; Figure 7A Effects on untreated patient samples (no prior TED therapy, n=4), Figure 7B Effects on patient samples previously treated with Teprotumumab (n=1), and Figure 7C Effects on patient samples previously treated with corticosteroids (n=2).

[0537] Activation of the IGF-1 receptor (IGF-1R) is a disease driver in TED and is the target of the currently approved TED therapy, tepizolumab (TEPEZZA, an anti-IGF-1R mAb) (Lee and Kahaly, Best Pract Res Clin Endocrinol Metab. 37(2):101620, 2023). Based on our data showing crosstalk between the IL-11 and IGF-1 pathways, experiments were performed to measure the effects of mAb5, tepizolumab (ichorbio, ICH5128), and the combination (mAb5 / tepizolumab) on HA 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+IGF-1, and HA release was measured in response to treatment with mAb5 in combination with increasing concentrations (1, 3, and 10 μg / mL) of tepizolumab. As Figure 10 As shown in , the combination of mAb5 and increasing doses of tiuximab (solid grey bars) increased the inhibition of HA release in a dose-dependent manner compared to mAb5 or tiuximab alone (black bars and cross-hatched bars). These data suggest that treating patients with the anti-IL11Rα antibodies described herein in addition to the standard of care drug tiuximab may have increased therapeutic benefit relative to treatment with either agent alone.

[0538] Increased HA production is a key pathology in TED and causes orbital tissue edema and proptosis (bulging eyes). In preclinical studies, the ability of titumomab to inhibit HA release from orbital fibroblasts is a key translational readout and is associated with clinical efficacy in TED. Typical IL-11 signaling causes phosphorylation of STAT3 (pSTAT3), and IL-11 stimulation of orbital fibroblasts promotes HA release. For this reason, the dose-dependent effects of mAb 5 on IL-11-stimulated pSTAT3 and HA release were examined in orbital fibroblasts to determine the IC50 and IC90 for inhibition of IL-11R. Figures 11A-11B mAb5 was shown to inhibit pSTAT3 ( Figure 11A ), with IC50 and IC90 values ​​of 0.007 and 0.06 μg / mL, respectively, and blocked HA release ( Figure 11B ), with IC50 and IC90 values ​​of 0.05 and 0.48 μg / mL, respectively. These data demonstrate the efficacy of the anti-IL-11Rα antibodies described herein on IL-11 pathway activation in orbital fibroblasts and their efficacy in reducing clinically relevant endpoints in TED (e.g., HA release).

[0539] One cause of TED that is not effectively addressed by current standard-of-care therapy (teprotumumab) is excessive extracellular matrix accumulation in orbital tissues. Based on the role of IL-11 in this extraocular fibro-inflammatory response and the fact that TGFp, a potent profibrotic growth factor, can stimulate substantial IL-11 release, the effect of mAb5 on TGFp-stimulated procollagen I production was investigated and compared to that of teprotumumab. Figures 12A-12B TGFp stimulation was shown to increase procollagen I release by more than 3-fold Figure 12A ), and this increase was significantly inhibited by the addition of mAb5 Figure 12B ).

[0540] Overall, these results indicate that the anti-IL11Ra antibodies described herein can robustly inhibit HA release and proliferation of orbital fibroblasts from TED patients, including those who have undergone prior TED therapy (teprotumumab therapy, corticosteroid therapy) and can therefore be expected to have a more aggressive disease profile. These results also support a role for IL-11 and the IL-11Ra antibodies described herein in mediating excessive extracellular matrix accumulation in orbital tissues.

[0541] This demonstrates the clinical utility of IL-11Ra-based therapy with a different mechanism of action compared to prior or other TED therapies, such as teprotumumab and corticosteroid therapy. It also demonstrates the beneficial effects of combination therapy of teprotumumab with the anti-IL-11Ra antibodies described herein.

[0542] Example 3: Comparative affinity and potency

[0543] Experiments were performed to assess the comparative binding affinity and / or potency of mAb5 and mAb29 relative to an anti-ILRa monoclonal antibody having the HC of SEQ ID NO: 58 and the kappa LC of SEQ ID NO: 59 as described in U.S. Application No. 2020 / 0270340 (“340 antibody”). The binding affinity was measured by Bio-Layer Interferometry (BLI) and the potency by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells. As shown in Figures 8A-8B mAb5 has a binding affinity for human IL-11Ra of about 37 pm Figure 8A ), and the 340 antibody has a substantially weaker (about 35-fold) binding affinity for human IL-11Ra of about 1.3 nM Figure 8B As shown in Figures 9A-9C mAb5 Figure 9A ) and mAb29 Figure 9B) showed strong functional potency, as measured by pSTAT3 inhibition; in contrast, the 340 antibody ( Figure 9C ) showed no functional activity in this assay.

[0544] Example 4: Blocking IL-11Ra inhibits inflammatory cytokine production in orbital fibroblasts derived from TED patients

[0545] Infiltration of immune cells is a key pathogenic feature of TED and is an area of ongoing therapeutic drug development. Specifically, upregulation of cytokines including TNFa, IL-6, IL-8, and MCP-1 / CCL2 is thought to promote activation of immune cells, including T cells, B cells, and orbital fibroblasts, leading to orbital tissue expansion and remodeling (Fallah 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)). After stimulating patient-derived orbital fibroblasts for 96 hours with IL-11 and IGF-1, we compared the inhibitory effects of mAb5 to the approved TED therapeutic, teprotumumab, on a broad panel of cytokines. We then stimulated orbital fibroblasts with IL-11 or a combination of IL-11 and IGF-1 to assess the degree of inhibition of IL-6 and MCP-1 / CCL2 release by mAb5 and teprotumumab, both of which are upregulated in TED and are thought to play a role in the pathogenesis of TED (Fallah et al., Front Endocrinol (Lausanne). 12:654473 (2021)).

[0546] For the cytokine panel study, orbital fibroblasts were stimulated with a combination of IL-11 + IGF-1 for 96 hours, and a panel of 96 cytokines was measured by multiplex analysis for response to inhibition by mAb5 or teprotumumab ( Figure 13 ). Under similar treatment conditions, we then used ELISA to measure the specific effects of mAb5 and teprotumumab on IL-6 and MCP-1 / CCL2 release after stimulation with IL-11 alone or a combination of IL-11 + IGF-1 (Figure 14).

[0547] As a single agent, IL-11 stimulated IL-6 and MCP-1 / CCL2 release ( Figure 14A and 14C), but stimulation with the combination of IL-11 + IGF-1 did not significantly increase IL-6 and MCP-1 / CCL2 release. Notably, mAb5 inhibited IL-6 and MCP-1 / CCL2 release under all treatment conditions, while tildacerfont had no effect (Figure 14). The ability of IL-11 to stimulate IL-6 and MCP-1 / CCL2 to the same extent as combination treatment, coupled with the insufficient inhibition by tildacerfont, demonstrates that IL-11 is the primary driver of IL-6 and MCP-1 / CCL2 release by orbital fibroblasts under these treatment conditions. These data also suggest that IL-11 acts upstream of IL-6 as an inflammatory mediator in TED, which has significant clinical implications given the current efforts to therapeutically target the IL-6 pathway in TED. In summary, these data provide evidence of the pathological role of IL-11 in driving inflammation-mediated orbital tissue remodeling in TED.

[0548] Example 5: Comparison of mAb5 to commercially available antibodies against IL-11 and IL-11R

[0549] A panel of commercially available antibodies against IL-11 and IL-11R were tested for their ability to block HA production in TED patient-derived orbital fibroblasts compared to mAb5. The antibodies tested are displayed in Table E2 below.

[0550]

[0551] These antibodies were directly compared to mAb5 using the assay conditions as described in Example 2, using TED orbital fibroblasts stimulated with IL-11 and IGF-1. Cells from 12 different tissue donors were used for all antibodies except MM09, which used 6 donors, and results are displayed as the average fold over the vehicle condition. Figure 15 The results displayed in Table E3 clearly demonstrate that mAb5 is more effective than commercially available antibodies against IL-11 or IL-11R.

[0552] Example 6: Epitope mapping of mAb5

[0553] 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 was performed using methods developed by CovalX AG (Pimenova et al., J. Mass Spectrometry 43:185 (2008)). Briefly, human IL-11Ra was bound to mAb5 and cross-linked with a heterobifunctional linker. The resulting complex was digested with 5 different proteases (trypsin, chymotrypsin, ASP-N, elastase, and thermolysin), and the resulting peptides were analyzed by high resolution mass spectrometry for cross-linking or non-cross-linking. In addition, for HDX mapping, IL-11Ra was labeled with deuterium before and after complexing with mAb5, allowing determination of sites of differential deuterium labeling by mass spectrometry.

[0554] The results demonstrate 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), which spans residues 115-134 in mature IL-11Ra (SEQ ID NO: 260). Mapping by XL-MS localized the epitope to amino acid residues in IL-11Ra that overlap and extend the epitope. Cross-linking was identified at positions S116, S125, K129, S140, and T143, as shown in Figure 16 These results confirm that mAb5 binds to the second extracellular domain of IL-11R.

[0555] Example 7: Blocking IL-11 signaling with anti-IL-11Ra antibodies can effectively inhibit cis and trans IL-11 signaling

[0556] IL-11 has been reported to be able to signal in both the conventional (cis) manner, by binding to IL-11Ra and forming a complex with the co-receptor gpl30 on the same cell, and in the trans manner, where soluble IL-11Ra forms a complex with IL11 and signals to a cell bearing gpl30, which can or can not bear IL-11Ra (Lokau et al., BBA Mol. Cell Res. 1864. 2105-2117 (2017)). Thus, complete blockade of IL-11 signaling can require inhibition of both cis and trans signaling. To compare the ability of mAbs against IL-11 and IL-11R to achieve this, we tested inhibition of IL-11 signaling in a cell-based pSTAT3 reporter assay, where pSTAT3 stimulation is by IL-11 Figure 17A ) or by soluble IL-11R / IL-11 complex Figure 17BA soluble complex of IL-11R and IL-11 was obtained using a fusion protein of IL-11 and soluble IL-11R, called hyperIL-11 (Dams-Kozlowska et al., BMC Biotechnol. 12:8 (2012)).

[0557] STAT3 reporter gene (Luc)-HEK293 cell line, catalog number (Cat. No.) 79800-P, was purchased from BPS Bioscience and transfected with recombinant IL-11Rα. Cells were selected for the expression of IL-11Rα and stable clones were isolated for further experiments. Cells were grown, passaged, and assayed according to the BPS Bioscience protocol. Cells were added to 96-well microtiter plates at 25,000 cells / well and incubated at 37°C, 5% CO2 in humidified air for 30-45 minutes. A series of dilutions of mAb were added in duplicate columns or rows, and the plate was returned to the incubator and kept for another 1 hour at 37°C, followed by addition of 40ng / mL IL-11 or hyper IL-11 to each well to initiate signal transduction cascade and luciferase production. The plates were incubated at 37°C for 18-24 hours and luciferase was detected using the One-Step Luciferase Assay System (BPS Bioscience, Cat. No. 60690-1) according to the manufacturer's instructions.

[0558] The results shown in Figure 17 demonstrate that when pSTAT3 signaling is initiated by IL-11, mAb5 (anti-IL-11R) and anti-IL-11 mAb both have roughly equivalent potency (IC50 of mAb5 is 5.6 nM, IC50 of anti-IL-11 is 4.2 nM). However, when stimulated with hyper IL-11, mAb against IL-11 is ineffective, while the potency of mAb5 remains unchanged (IC50 is 5.4 nM). This data confirms that mAb5 effectively blocks both cis- and trans-IL-11 signaling.

[0559] Example 8: mAb5 inhibits HA production stimulated by autoantibodies against TSHR

[0560] Agonistic autoantibodies against the TSHR are considered an important driver of TED (Lee and Kahaly, Best Pract Res Clin Endocrinol Metab. 37(2): 101620 (2023)). M22 is a monoclonal agonistic autoantibody that is widely used experimentally to represent patient-derived autoantibodies (Krieger et al., J. Clin. Endocrinol. Metab. 101, 2340-2347 (2016)). In addition to the addition of PDGF to the culture medium to enhance cell levels of TSHR as described, TED patient-derived orbital fibroblasts were cultured and tested as described in Example 2 (van Steensel et al., J. Clin. Endocrinol. Metab. 97, E944-E953 (2012)). M22 induced HA production in orbital fibroblasts from three donors. This was effectively inhibited by mAb5 and the positive control antibody, retorlixumab Figure 18 ) In this study, mAb5 appeared to be more potent and effective than retorlixumab.

[0561] Example 9: Additional experiments to be performed

[0562] In addition, experiments will be performed to determine the effect of using anti-IL-11Ra antibodies on HA, IL-11 and IL-6 secretion by activated orbital fibroblasts and whether the effect is comparable, synergistic or additive to IGF1R blockade.

[0563] TED patient-derived orbital fibroblasts will be stimulated with anti-thyrotropin receptor (TSHR) monoclonal antibodies alone, whose sequence corresponds to M22 from KronusBio, or in combination with IL-11, in the presence and absence of anti-IL-11Ra antibodies, retorlixumab or both, to determine the effect on HA IL-11 and IL-6. Supernatants will be collected after 4 days for measurement of HA, IL-11 and IL-6 by ELISA and IL-11R levels on orbital fibroblasts by immunoblotting or staining.

[0564] Experiments will also be performed to evaluate the effects of TGFp at 0.03, 0.3, 3 ng / mL (and other doses) on orbital fibroblasts and the ability of anti-IL11R antibodies to block these effects. Proliferation / myofibroblast formation of orbital fibroblasts, SMA, collagen, fibronectin and IL-11R will also be evaluated at 24-96 hours after treatment or 48-72 hours after treatment. In addition, supernatants will be collected at different time points in the 48-72 hour time point and inflammatory cytokines will be measured by ELISA, including: IL-6, IL-8, procollagen, HA and IL-11.

[0565] IL-11 concentrations in serum / plasma from TED patients were compared to healthy individuals. Differences in IL-11 and IL-11R expression in the eye tissue of TED patients were compared to normal eye tissue, particularly observing fibroblasts, myoblasts, and other appropriate cell types.

Claims

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

3. The method of claim 2, wherein the one or more clinical signs are selected from the group consisting of: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

4. The method according to any one of claims 1 to 3, wherein the patient has a Clinical Activity Score (CAS) of 3 or higher, or 4 or higher, 5 or higher, or 6 or higher, wherein the CAS includes one point for each of the following: spontaneous orbital pain, gaze-evoked orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and caruncle and plica semilunaris inflammation.

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

6. The method according to any one of claims 1 to 5, wherein the patient has abnormal thyroid function, 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 increased thyroid stimulating immunoglobulin (TSI) levels.

9. The method of any one of claims 1 to 8, wherein the patient suffers from 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. The method of claim 10, wherein the one or more risk factors are selected from the group consisting of female sex, middle-aged age, smoking, and current or past radioactive iodine treatment.

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

13. The method according to any one of claims 1 to 12, comprising: a. Determine whether the patient has TED; and b. If the patient suffers from TED, administering the pharmaceutical composition to the patient.

14. The method of claim 13, wherein (a) comprises measuring one or more clinical signs of TED, optionally selected from: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

15. The method according to claim 13 or 14, comprising: a. Determine the patient's CAS; and b. If the CAS is 3 or higher, or 4 or higher, 5 or higher, or 6 or higher, administering the pharmaceutical composition to the patient.

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

17. The method according to any one of claims 13 to 16, comprising: a. Determine the patient's thyroid function; and b. If the patient has abnormal thyroid function, optionally hyperthyroidism, administering the pharmaceutical composition to the patient.

18. The method according to any one of claims 13 to 17, comprising: a. Determine the patient's thyroid stimulating immunoglobulin (TSI) level; and b. administering the pharmaceutical composition to the patient if the patient's TSI level is elevated relative to a control or reference standard.

19. The method according to any one of claims 1 to 18, comprising: a. determining the level of IL-11Rα and / or IL-11 in the blood or tissue surrounding the patient's eye, optionally in orbital fibroblasts; and b. administering the pharmaceutical composition to the patient if the level of IL-11Rα and / or IL-11 in the patient's blood or tissue surrounding the eye (optionally, in orbital fibroblasts) is elevated relative to a control or reference standard.

20. The method according to any one of claims 1 to 19, wherein the patient is not receiving TED therapy treatment, optionally a patient suffering from chronic TED.

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

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

23. The method of any one of claims 20 to 22, wherein the TED therapy 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.

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

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

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

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

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

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

30. The method of any one of claims 1 to 29, comprising administering the pharmaceutical composition in combination with at least one other TED therapy.

31. The method of claim 30, wherein the at least one other 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.

32. The method of claim 31, wherein the IGF-1R inhibitor therapy is selected from the group consisting of teitutumumab, ganitutumumab, darotoxinumab, cixitumumab, and phentocinumab therapy.

33. The method of claim 32, wherein the IGF-1R inhibitor therapy is administered 1 to 7 times simultaneously or sequentially with 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. The method of claim 31, wherein the FcRn inhibitory therapy is selected from the group consisting of batolizumab (IMVT-1401), igatimod, nipocalimab, onorimab, and lorixizumab therapy.

35. The method of claim 31, wherein the IL-6 inhibitor therapy is selected from the group consisting of clatuzumab, ecitumomab, lenvilimab, olomurumab, sareluzumab, siltuximab, sirukumab, and tocilizumab therapy.

36. 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) therapy.

37. The method of claim 31, wherein the CD20 inhibitor therapy is selected from the group consisting of isbetumomab, obinutuzumab, ocrelizumab, ofavumab, rituximab, and utuuximab therapy.

38. The method of claim 31, wherein the TNF-α inhibitor therapy is selected from adalimumab, certolizumab pegol, 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 approximately residues 90-197 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. 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. The method of claim 41, wherein the epitope comprises residues S116, S125, K129, S140, and T143 of SEQ ID NO:

260.

43. The method of any one of claims 1 to 42, wherein the antibody or antigen-binding fragment thereof comprises: a. Heavy chain variable region (V H ), which comprises a complementarity determining region V selected from Table A1 H CDR1, V H CDR2 and V H CDR3 amino acid sequences and variants thereof that specifically bind to IL-11Rα; and b. Light chain variable region (V L ), which comprises a complementarity determining region V selected from Table A1 L CDR1, V L CDR2 and V L CDR3 amino acid sequences and their variants that specifically bind to IL-11Rα.

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

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

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

47. A method according to any one of claims 43 to 46, wherein: a. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 193, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 194; b. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 195, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 196; c. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 197, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 198; d. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 199, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 200; e. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 201, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 202; f. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 203, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 204; g. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 205, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 206; h. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 207, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 208; i. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 209, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 210; j. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 211, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 212; k. V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 213, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 214; 1. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 215, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 216; m.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 217, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 218; n.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 219, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 220; o. Said V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 221, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 222; p.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 223, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 224; q. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 225, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 226; r. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 227, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 228; s.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 229, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 230; t.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 231, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 232; u.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 233, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 234; v.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 235, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 236; w.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 237, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 238; x.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 239, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 240; y. Said V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 241, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 242; z.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 243, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 244; dd.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 245, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 246; ee.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 247, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 248; ff. The V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 249, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 250; gg.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 251, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 252; hh.V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 253, and wherein said V L comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 254; or ii. V H comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 255, and wherein said V L Comprising 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 method of any one of claims 1 to 47, wherein the antibody or antigen-binding fragment thereof has one or more of the following characteristics: a. increased binding affinity for human IL-11Rα compared to the 340 antibody, and increased functional efficacy compared to the 340 antibody, optionally as measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells; b. the isolated antibody or antigen-binding fragment thereof has a binding affinity for human IL-11Rα of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM or 30 pM, and optionally has an increased binding affinity for human IL-11Rα relative to the binding affinity of the TS7 antibody and the 8E2 antibody; c. the isolated antibody or antigen-binding fragment thereof antagonizes the binding and / or signaling activity between IL-11Rα and IL-11, and optionally the isolated antibody or antigen-binding fragment thereof has increased potency as an IL-11 signaling antagonist relative to the potency of the TS7 antibody and the 8E2 antibody; d. the isolated antibody or antigen-binding fragment thereof reduces IL-11Rα / gp130 dimerization or complex formation, optionally in a cell-based assay; and / or e. Optionally, the isolated antibody or antigen-binding fragment thereof has a V L N-linked glycosylation in CDR3 is reduced.

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 a hybrid and / or variant thereof.

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

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

52. The method of claim 49, wherein the antibody or antigen-binding fragment thereof comprises a human IgG1 or IgG4 Fc domain, optionally 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. The method of any one of claims 1 to 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 having an S228P mutation (EU numbering).

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

56. The method of any one of claims 1 to 55, wherein the composition is at least about 80%, 85%, 90%, 95%, 98% or 99% pure on a protein basis relative to at least one of the antibodies or antigen-binding fragments and is substantially free of aggregates and endotoxins.

57. The method of any one of claims 1 to 56, wherein the composition has reduced or undetectable N-linked glycosylation heterogeneity (optionally relative to TS7 and 8E2 antibodies), optionally in V L There is reduced or no detectable N-linked glycosylation heterogeneity in the CDR3 sequence.

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

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

60. The method of claim 59, wherein the one or more clinical signs are selected from the group consisting of: upper eyelid retraction (unilateral or bilateral); proptosis (exophthalmos); lagophthalmos (inability to fully close the eyelids); extraocular muscle (EOM) dysfunction, optionally with hypotropia (downward deviation) and / or esotropia (inward deviation); eyelid edema; eyelid erythema; conjunctival injection; excessive extracellular matrix accumulation in orbital tissue; and chemosis (conjunctival edema).

61. The method of claim 59 or 60, wherein administration of the pharmaceutical composition to the patient improves the patient's Clinical Activity Score (CAS), optionally by at least one, two, three, four, or five points, optionally to a CAS of 3 or less, 2 or less, or 1 or less.

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

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

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

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