Anti-il-11r alpha antibodies for treating thyroid eye disease

Abstract

Provided are methods of treating thyroid eye disease (TED) by administering an antibody or and antigen binding fragment thereof that binds to human interleukin-11 receptor subunit α (IL-11Rα).

Description

ANTI-IL-llRa ANTIBODIES FOR TREATING THYROID EYE DISEASECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 437,607, filed on January 6, 2023, and to U.S. Provisional Patent Application No. 63 / 444,492, filed on February 9, 2023, and to U.S. Provisional Patent Application No. 63 / 466,112, filed on May 12, 2023, and to U.S. Provisional Patent Application No. 63 / 529,910, filed on July 31, 2023, and to U.S. Provisional Patent Application No. 63 / 537,030, filed on September 7, 2023, and to U.S. Provisional Patent Application No. 63 / 592,899, filed on October 24, 2023, and to U.S. Provisional Patent Application No. 63 / 595,626, filed on November 2, 2023, and to U.S. Provisional Patent Application No. 63 / 608,744, filed on December 11, 2023, the content of which are incorporated by reference herein in their entirety.BACKGROUND

[0001] Interleukin- 11 (IL-11) is a member of the IL-6 family, and plays a prominent role in chronic inflammation, autoimmunity, cancer, and other diseases. It also plays a critical role in pathological wound healing.

[0002] 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, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos) (see, for example, 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 treating TED. Provided herein are compositions and methods that address this need.SUMMARY

[0003] Embodiments of the present disclosure include methods of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human interleukin-11 receptor subunit a (IL-1 IRa) (see,for example, PCT / US2022 / 075680, which is incorporated by reference in its entirety). In particular embodiments, the anti-IL-1 IRa antibody or antigen binding fragment thereof antagonizes or inhibits the binding and / or signaling activity between IL-1 IRa and IL-11. In another aspect, the present disclosure provides an antibody which binds to IL- 1 IRa and interferes with the binding of IL-11 to IL-1 IRa.

[0004] In some embodiments, the patient has one or more clinical signs of TED. In some embodiments, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0005] In certain embodiments, the patient has a Clinical Activity Score (CAS) of 3 or more, or 4 or more, 5 or more, or 6 or more, wherein the CAS comprises one point for each of: spontaneous orbital pain, gaze-evoked orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and caruncle, and plica semilunaris inflammation. In some embodiments, the patient has a VISA (vision, inflammation, strabismus, appearance / exposure) score of 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more. In some embodiments, the patient has abnormal thyroid function, optionally hyperthyroidism. In some embodiments, the patient has autoantibody stimulation of thyroid stimulating hormone receptor (TSHR). In some embodiments, the patient has increased levels of thyroid-stimulating immunoglobulin (TSI). In some embodiments, the patient has Graves’ disease.

[0006] 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 being female, being of middle age, being a smoker, and undergoing or having undergone treatment with radioactive iodine. In some embodiments, the patient has increased levels of IL-1 IRa and / or IL-11 in blood or tissue around the eye, for example, in orbital fibroblasts. In some embodiments, the patient has increased levels of circulatory IL-11.

[0007] Certain embodiments comprise the steps of:(a) determining if the patient has TED; and(b) administering the pharmaceutical composition to the patient if the patient hasTED.

[0008] In some embodiments, (a) comprises measuring one or more clinical signs of TED, optionally selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0009] Certain embodiments comprise the steps of:(a) determining the CAS of the patient; and(b) administering the pharmaceutical composition to the patient if the CAS is 3 or more, or 4 or more, 5 or more, or 6 or more.

[0010] Certain embodiments comprise the steps of:(a) determining the VISA score of the patient; and(b) administering the pharmaceutical composition to the patient if the VISA score is 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more.

[0011] Certain embodiments comprise the steps of:(a) determining thyroid function in the patient; and(b) administering the pharmaceutical composition to the patient if the patient has abnormal thyroid function, optionally hyperthyroidism.

[0012] Certain embodiments comprise the steps of:(a) determining levels of thyroid-stimulating immunoglobulin (TSI) in the patient; and(b) administering the pharmaceutical composition to the patient if the levels of TSI in the patient are increased relative to a control or reference standard.

[0013] Certain embodiments comprise the steps of:(a) determining levels of IL-1 IRa and / or IL-11 in blood or tissue around the patient’s eye, for example, in orbital fibroblasts; and(b) administering the pharmaceutical composition to the patient if the levels of IL- 1 IRa and / or IL-11 in the blood or tissue around the patient’s eye (for example, in orbital fibroblasts) are increased relative to a control or reference standard.

[0014] Certain embodiments comprise the steps of:(a) determining levels of circulatory IL-11 in the patient; and(b) administering the pharmaceutical composition to the patient if the levels of circulatory IL-11 are increased relative to a control or reference standard.

[0015] In some embodiments, the patient is treatment-naive to a TED therapy, including a patient with chronic TED.

[0016] In some embodiments, the patient is undergoing or has previously undergone a TED therapy and is intolerant, relapsed, and / or refractory to the (prior) TED therapy. In some embodiments, a relasped TED patient is identified by an initial response to a prior TED therapy measured by a reduction in proptosis, that is subsequently regressed after a period of time despite continued treatment with the same TED therapy. In some embodiments, the reduction in proptosis is greater than about 2mm. In some embodiments, the regression of proptosis is an increase in proptosis back to a pretreatment baseline measurement. In some embodiments, the regression of proptosis is an increase in proptosis from the maximal response to the prior TED therapy. In some embodiments, a relapsed TED patient is identified by an initial response to the TED therapy measured by a reduction in CAS score, that is then subsequently reversed after a period of time despite continued treatment with the same TED therapy. In some embodiments, a refractory patient is identified by a lack of improvement in proptosis. In some embodiments, the lack of improvement in proptosis is less than about 2mm. In some embodiments, a refractory patient is identified by little to no change in CAS score. In some embodiments, the intolerant, relapsed and / or refractory patient has active TED. In some instances, the TED is progressing in the patient. In certain embodiments, a patient in an intolerant / relapsed / refractory disease statehas TED that progresses more aggressively in the patient than prior to the TED therapy. In some embodiments, TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and / or an increased VISA score, relative to the clinical signs, CAS scores, and / or VISA scores from prior to the TED therapy. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanism of action relative to the prior (now refractory) TED therapy can provide clinical advantages in treating a progressing disease state, including a more aggressively progressing disease state.

[0017] In some embodiments, the (prior) TED therapy is selected from insulin-like growth factor-1 receptor (IGF- lR)-inhibitor therapy, FcRn-inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)-inhibitor therapy, including combinations thereof (e.g., steroid + ORT therapies). In certain embodiments, the IGF-lR-inhibitor therapy is a small molecule. In certain embodiments, the IGF-lR-inhibitor therapy is a IGF-1R antibody. In certain embodiments, the IGF-lR-inhibitor antibody is selected from teprotumumab, 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 particular embodiments, the IL-6 inhibitor 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-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0018] In some embodiments, the patient is undergoing or has previously undergone a teprotumumab therapy and is intolerant, relapsed, and / or refractory to the (prior) teprotumumab therapy. In some embodiments, a relasped TED patient is identified by an initial response to a prior teprotumumab therapy measured by a reduction in proptosis, that is subsequently regressed after a period of time despite continued treatment with the same teprotumumab therapy. In some embodiments, the reduction in proptosis is greater than about 2mm. In some embodiments, theregression of proptosis is an increase in proptosis back to a pretreatment baseline measurement. In some embodiments, the regression of proptosis is an increase in proptosis from the maximal response to the prior teprotumumab therapy. In some embodiments, a relapsed TED patient is identified by an initial response to the teprotumumab therapy measured by a reduction in CAS score, that is then subsequently reversed after a period of time despite continued treatment with the same teprotumumab therapy. In some embodiments, a refractory patient is identified by a lack of improvement in proptosis. In some embodiments, the lack of improvement in proptosis is less than about 2mm. In some embodiments, a refractory patient is identified by little to no change in CAS score. In some embodiments, the intolerant, relapsed and / or refractory patient has active TED. In some instances, the TED is progressing in the patient. In certain embodiments, a patient in an intolerant / relapsed / refractory disease state has TED that progresses more aggressively in the patient than prior to the teprotumumab therapy. In some embodiments, TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and / or an increased VISA score, relative to the clinical signs, CAS scores, and / or VISA scores from prior to the teprotumumab therapy. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanism of action relative to the prior (now refractory) teprotumumab therapy can provide clinical advantages in treating a progressing disease state, including a more aggressively progressing disease state. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 1 teprotumumab half life from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 2 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 3 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 4 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 5 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 6 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 7 teprotumumab half lives from the last doseof teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 8 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 9 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 10 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered greater than 10 teprotumumab half lives from the last dose of teprotumumab.

[0019] Certain embodiments include combination therapies, wherein the methods comprise administering the pharmaceutical composition (comprising an anti-IL-1 IRa antibody, or antigen-binding fragment thereof) in combination with at least one additional TED therapy.

[0020] In some embodiments, the at least one additional TED therapy is administered prior to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered simutaneously to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered sequentially to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered within the same composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered in a separate composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.

[0021] In some embodiments, the at least one additional TED therapy is selected from IGF- IR-inhibitor therapy, FcRn-inhibitor therapy, IL-6-inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)- inhibitor therapy. In certain embodiments, the IGF-lR-inhibitor therapy is an antibody therapy. In some embodimetns, the IGF-lR-inhibitor antibody therapy is selected from teprotumumab, 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 some embodiments, the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab,sirukumab, and tocilizumab therapy. In particular 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 ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy. In some embodiments, the TNF- a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0022] In some embodiments, the at least one additional TED therapy is an IGF-lR-inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody, e.g. teprotumumab, ganitumab, dalotuzumab, cixutumumab, or figitumumab therapy. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered simutaneously to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered prior to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered sequentially to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered within the same composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered in a separate composition as the anti- ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 2 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 3 times during the the treatment with the anti-ILl IRa antibodies or antigenbinding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 4 times during the the treatment with the anti- ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 5 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 6 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g.IGF-1R antibody) is administered about 1 to about 7 times during the the treatment with the anti- IL1 IRa antibodies or antigen-binding fragments of the disclosure.

[0023] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to a fibronectin domain III of human IL-1 IRa, or approximately residues 90-197 of SEQ ID NO: 260. In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to the second extracellular domain of IL- 1 IRa.

[0024] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to an epitope that spans residues 115-134 in IL-1 IRa. In certain embodiments, an exemplary antibody of the disclosure that exhibits such binding comprises the VHCDR1, VHCDR2, and VHCDR3 sequences of SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences of SEQ ID NOs: 28-30, respectively. In certain embodiments, an exemplary antibody of the disclosure that exhibits such binding comprises the VHsequence of SEQ ID NO: 201, and the VLsequence of SEQ ID NOs: 202.

[0025] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to an epitope comprising the residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261), or binds residues located within said sequence. In some embodiments, the IL- 1 IRa antibody, or antigen binding fragment thereof, binds to an epitope comprising the residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261), and addtionally comprises cross-links at positions S138, S147, K151, S162 and T165.

[0026] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, comprises: a heavy chain variable region (VH) that comprises complementary determining region VHCDR1, VHCDR2, and VHCDR3 sequences selected from Table Al and variants thereof which specifically bind to IL-1 IRa; and a light chain variable region (VL) that comprises complementary determining region VLCDR1, VLCDR2, and VLCDR3 sequences selected from Table Al and variants thereof which specifically bind to IL- 1 IRa.

[0027] In specific embodiments:the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 1-3, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 4-6, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 7-9, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 10- 12, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 13-15, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 16- 18, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 19-21, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 22- 24, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 28- 30, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 31-33, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 34- 36, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 34-39, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 40- 42, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 43-45, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 46- 48, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 49-51, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 52- 54, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 55-57, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 58- 60, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 61-63, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 64- 66, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 67-69, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 70- 72, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 73-75, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 76- 78, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 79-81, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 82- 84, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 85-87, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 88- 90, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 91-93, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 94- 96, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 97-99, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 100- 102, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 103-105, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 106- 108, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 109-111, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 112- 114, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 115-117, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 118- 120, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 121-123, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 124- 126, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 127-129, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 130- 132, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 133-135, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 136- 138, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 139-141, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 142- 144, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 145-147, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 148- 150, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 151-153, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 154- 156, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 157-159, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 160- 162, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 163-165, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 166- 168, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 169-171, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 172- 174, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 175-177, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 178- 180, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 181-183, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 184- 186, respectively; or the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 187-189, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 190- 192, respectively.

[0028] In certain embodiments, the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, optionally wherein the VHhas 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in the framework regions. In certain embodiments, the VL comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, optionally wherein the VLhas 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in the framework regions.

[0029] In particular embodiments: the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and the VL comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and the VL comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 256.In certain embodiments, the antibody, or antigen binding fragment thereof, has one or more of the following characteristics: has a binding affinity for human IL-1 IRa of less than about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 30 pM, and optionally has increased binding affinity for human IL-1 IRa relative to that of the TS7 and 8E2 antibodies; antagonizes the binding and / or signaling activity between IL-1 IRa and IL-11, and optionally has increased potency as an IL-11 signaling antagonist relative to that of the TS7 and 8E2 antibodies; reduces IL-1 lRa / gpl30 dimerization or complex formation, optionally in a cell-based assay; and / or has reduced N-linked glycosylation in VLCDR3, optionally relative to the TS7 and 8E2 antibodies.

[0030] In some embodiments, the IL- 1 IRa antibody, or antigen binding fragment thereof, comprises an IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, 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 antigen binding fragment thereof, comprises an IgG Fc domain with high effector function in humans, optionally an IgGl or IgG3 Fc domain. In some embodiments, the antibody, or antigen binding fragment thereof, comprises an IgG Fc domain with low effector function in humans, optionally an IgG2 or IgG4Fc domain. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a human IgGl or IgG4 Fc domain, optionally selected from Table Fl.

[0031] In certain embodiments, the IL-1 IRa 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 that comprises a human IgG4 Fc domain with an S228P mutation (EU numbering).

[0032] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, is selected from an Fv fragment, a single chain Fv (scFv) polypeptide, an adnectin, an anticalin, an aptamer, an avimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.

[0033] In certain embodiments, the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the antibody or antigen binding fragment, and is substantially aggregate- and endotoxin-free. In some embodiments, the composition has reduced or undetectable heterogeneity of N-linked glycosylation (optionally relative to the TS7 and 8E2 antibodies), optionally in the VLCDR3 sequence. In specific embodiments, the pharmaceutical composition is a sterile, injectable solution, optionally suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.

[0034] In certain embodiments, administering the pharmaceutical composition to the patient improves one or more clinical signs of TED. In some embodiments, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0035] In certain embodiments, administering the pharmaceutical composition to the patient improves the Clinical Activity Score (CAS) of the patient, 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 the pharmaceutical composition to the patient improves the VISAscore of the patient, optionally by at least one, two, three, four, or five points, optionally to a VISA or 4 or less, 3 or less, 2 or less, or 1 or less. In specific embodiments, administering the pharmaceutical composition to the patient reduces levels of IL-1 IRa or IL-11 in the blood or tissue around the patient’s eye.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIGS. 1A-1C show cell surface expression on fibroblasts from orbital tissue of a TED patient compared to that of a healthy (non-TED) patient. FIG. 1A shows CD90 expression, FIG. IB shows CD45 expression, and FIG. 1C shows IL- 1 IRa expression using the mAb5 antibody. Healthy control (dashed line); TED (black line); unstained / secondary Ab alone (light gray line).

[0037] FIG. 2 shows hyaluronan release by orbital fibroblasts that were preincubated with media alone (no antibody control) or mAb5 (10 pg / mL) for 1 hour and then stimulated with human recombinant IL-11 (1.1, 3.3 or 10 ng / mL) for an additional 96 hours. Data are expressed as the fold change relative to vehicle control for n=4 independent experiments using n=3 TED donors with 2 biological replicates per treatment. ** denotes p<0.01 compared the mAb5 treated cells as compared using a One-way ANOVA with Dunnet’s post-hoc multiple comparisons test.

[0038] FIG. 3 shows cell proliferation by orbital fibroblasts that were preincubated with media alone (no antibody control) or mAb5 (10 pg / mL) for 1 hour and then stimulated with human recombinant IL-11 (1.1, 3.3 or 10 ng / mL) for an additional 96 hours. Data are expressed as the fold change relative to vehicle control for n=4 independent experiments using n=3 TED donors with 2 biological replicates per treatment. ** denotes p<0.0001 compared the mAb5 treated cells as compared using a One-way ANOVA with Dunnet’s post-hoc multiple comparisons test.

[0039] FIGS. 4A-4C show the dose-dependent effects of IL-11, with mAb5 (10 ng / mL, hatched) and without mAb5 (solid), on hyaluronan release from orbital fibroblasts from patient sample #2 (FIG. 4A, no prior TED therapy), patient sample #1 (FIG. 4B, prior teprotumumab therapy), and patent sample #3 (FIG. 4C, prior corticosteroid therapy).

[0040] FIGS. 5A-5C show the effects of mAb5 at 3. 10, 30 and lOOpg / mL on IL-11(lOng / mL) induced HA release from orbital fibroblasts from patient samples #2, #4, and #5(FIG. 5A; no prior TED therapy), patient sample # 1 (FIG. 5B, prior teprotumumab therapy), and patient sample #3 (FIG. 5C, prior corticosteroid therapy).

[0041] FIGS. 6A-6C show the comparative inhibitory effects of mAb5 teprotumumab and isotype control (all at lOpg / mL) on HA release induced by lOng / mL IL-11 from orbital fibroblasts from TED patients; FIG. 6A shows the effects on naive patient samples (no prior TED therapy, n=4), FIG. 6B shows the effects on patient sample with prior teprotumumab therapy (n=l), and FIG. 6C shows the effects on patient sample with prior corticosteroid therapy (n=2).

[0042] FIGS. 7A-7C show the comparative effects of mAb5 teprotumumab (and isotype control antibodies (all at lOpg / mL) on proliferation of orbital fibroblasts induced by lOng / mL IL- 11 from TED patients; FIG. 7A shows the effects on naive patient samples (no prior TED therapy, n=4), FIG. 7B shows the effects on patient sample with prior teprotumumab therapy (n=l), and 7C shows the effects on patient samples with prior corticosteroid therapy (n=2).

[0043] FIGS. 8A-8B show that mAb5 has a binding affinity for human IL-1 IRa of about 37 pm (FIG. 8A), and the 340 antibody has significantly weaker (~35-fold) binding affinity for human IL-1 IRa of about 1.3 nM (FIG. 8B).

[0044] FIGS. 9A-9C show that mAb5 (FIG. 9 A) and mAb29 (FIG. 9B) have strong functional potency as measured by pSTAT3 inhibition; in contrast, the 340 antibody (FIG. 9C) shows no functional activity in this assay.

[0045] FIG. 10 shows the combination effect of mAb5 and teprotumumab on HA release after stimulation with IL-11 + IGF-1 in orbital fibroblasts. Data was obtained from n>8 donors from 2 separate studies. #### p<0.0001 vs Veh., *** p<0.001; ****p<0.0001 vs IGF-1 + IL-11, p<0.05 vs. teprotumumab + mAb5 combo by one way ANOVA w / Dunnett’s post-test. IGF-1 (lOOng / mL), IL-11 (lOng / mL), mAb5 (lOpg / mL), and teprotumumab (10 pg / mL).

[0046] FIGS. 11A-11B show dose response curves for mAb5 as measured by its effects on pSTAT3 (FIG. 11 A) and HA release (FIG. 11B) in orbital fibroblasts from TED patients.

[0047] FIG. 12A shows procollagen I release (ng / mL) by orbital fibroblasts from n=6 TED donors that were stimulated with TGFP (5 ng / mL) for 96 hr. FIG. 12B shows inhibition ofTGFP-stimulated procollagen I release by orbital fibroblasts from n=6 TED donors that were preincubated with mAb5 (3 pg / mL) or teprotumumab (10 pg / mL) for 1 hour and then stimulated with human recombinant TGFP (5 ng / mL) for an additional 96 hr. ### p<0.001 vs Veh; ** p<0.01 vs TGFP control by one-way ANOVA with Dunnett’s post-hoc multiple comparison test.

[0048] FIG. 13 shows mAb5’s ability to reduce multiple cytokines in orbital fibroblasts after stimulation with IL-11 + IGF-1. Cytokine release by human orbital fibroblasts that were preincubated with mAb5 (3 pg / mL) or teprotumumab (10 pg / mL) for 1 hr before stimulation with either human recombinant the combination of IL- 11 + IGF-1 (100 ng / mL) for an additional 96 hr. Cell supernatants were measures by multiplex analysis at Eve Technologies (Calgary, CAN) and data are shown as individual replicates from n=6 TED patients for each treatment.

[0049] FIGS. 14A-14D shows mAb5’s ability to inhibit IL-6 and MCP-1 / CCL2 release more effectively than Teprotumumab. IL-6 (FIGS. 14 A and B) and MCP-1 (FIGS. 14 C and D) release by human orbital fibroblasts that were preincubated with mAb5 (3 pg / mL) or teprotumumab (10 pg / mL) for 1 hr before stimulation with either human recombinant IL-11 (10 ng / mL; FIGS. 14 A and C) or the combination of IL-11 + IGF-1 (100 ng / mL; FIGS. 14 B and D) for an additional 96 hr. Data represent the mean ± SEM of n=6 TED patients as compared by One-way ANOVA with Dunnett’s post-test. ###,p< 0.001; #### p<0.0001 vs Veh. **** p<0.05; ** p<0.01; **** p<0.0001 versus Isotype control only by one-way ANOVA with Dunnett’s post-hoc multiple comparison test

[0050] FIG. 15 shows a panel of commercially available antibodies to IL-11 and IL- 1 IRa that were compared to mAb5 for their ability to inhibit HA production from TED donor orbital fibroblasts stimulated with IL-11 and IGF-1. Antibodies to IL-11 are shown in dark grey bars and antibodies to IL- 1 IRa in black bars.

[0051] FIG. 16 shows a partial sequence of IL-1 IRa with the epitope of mAb5 shown. Epitope mapping of mAb5 was carried using two mass spectrometry methods. The epitope identified by HDX-MS is shown in bold text spanning mature IL- 1 IRa residues 115-134. Crosslinks identified by XL-MS are indicated at positions S138, S 147, KI 51, SI 62 and T165 indicating these residues are at, or close to, the mAb5 epitope.

[0052] FIGS. 17A-17B demonstrates that anti-IL-1 IRa mAb5 is effective at inhibition of IL11 and hyper IL-11 signaling. Inhibition of STAT3 phosphorylation was tested using a luciferase reporter assay. FIG. 17A shows inhibition of IL- 11 signaling induced by addition of IL-11. Solid line, circular symbols is data with mAb5, dashed line, triangular symbols is anti-IL- 11 mAb. FIG. 17B shows inhibition of STAT3 phosphorylation induced by hyper IL-11. Symbols and lines for each antibody as in FIG. 17A. mAb5 effectively inhibits signaling in both assays, whereas anti-IL-11 mAb is only effective in inhibition of IL- 11 induced signaling, not from hyper IL-11 (soluble receptor IL-11 complex).

[0053] FIG. 18 shows the ability of mAb5 to reduce M22 stimulated HA production in TED orbital fibroblasts. HA release by human orbital fibroblasts that were preincubated with mAb5 (1 or 10 pg / mL) or teprotumumab (10 pg / mL) for 1 h before stimulation with the TSHR agonist antibody M22. Three donors were used and data is presented as mean HA level (ng / mL). The window of stimulation by M22 is indicated by dotted and dashed lines.DETAILED DESCRIPTION

[0054] The present disclosure relates to methods of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human interleukin- 11 receptor subunit a (IL- 1 IRa). In some embodiments, the antibody, or antigen binding fragment thereof, binds to the fibronectin domain III of human IL- 1 IRa or the second extracellular domain of IL- 1 IRa, and antagonizes the binding and / or signaling activity between IL-1 IRa and IL-11. Exemplary antibodies, and antigen binding fragments thereof, are described herein.

[0055] The practice of the present disclosure will employ, unless indicated specifically to the contrary, 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 explained fully 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 el al. , Short Protocols in Molecular Biology, 3rded., Wiley & Sons, 1995; Sambrook and Russell, Molecular Cloning: A Laboratory Manual (3rd Edition, 2001); Maniatis et al. Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A Practical Approach, vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed.,1984); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., 1985); Transcription and Translation (B. Hames & S. Higgins, eds., 1984); Animal Cell Culture (R. Freshney, ed., 1986);Perbal, A Practical Guide to Molecular Cloning (1984) and other like references.Definitions

[0056] As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the content clearly dictates otherwise.

[0057] By “about” is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0058] The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody, and additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. An antigen may have one or more epitopes. As used herein, the term “antigen” includes substances that are capable, under appropriate conditions, of inducing an immune response to the substance and of reacting with the products of the immune response. For example, an antigen can be recognized by antibodies (humoral immune response) or sensitized T-lymphocytes (T helper or cell- mediated immune response), or both. Antigens can be soluble substances, such as toxins and foreign proteins, or particulates, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (epitopes) combines with the antibody or a specific receptor on a lymphocyte. More broadly, the term “antigen” includes any substance to which an antibody binds, or for which antibodies are desired, regardless of whether the substance is immunogenic. For such antigens, antibodies can be identified by recombinant methods, independently of any immune response.

[0059] An “antagonist” refers to an agent (e.g., antibody) that interferes with or otherwise reduces the physiological action of another agent or molecule. In some instances, the antagonist specifically binds to the other agent or molecule. Included are full and partial antagonists.

[0060] An “agonist” refers to an agent (e.g., antibody) that increases or enhances the physiological action of another agent or molecule. In some instances, the agonist specifically binds to the other agent or molecule. Included are full and partial agonists.

[0061] As used herein, the term “amino acid” is intended to mean both naturally occurring and non-naturally occurring amino acids as well as amino acid analogs and mimetics. Naturally- occurring amino acids include the 20 (L)-amino acids utilized during protein biosynthesis as well as others such as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, homocysteine, citrulline and ornithine, for example. Non-naturally occurring amino acids include, for example, (D)-amino acids, norleucine, norvaline, p-fluorophenylalanine, ethionine and the like, which are known to a person skilled in the art. Amino acid analogs include modified forms of naturally and non-naturally occurring amino acids. Such modifications can include, for example, substitution or replacement of chemical groups and moieties on the amino acid or by derivatization of the amino acid. Amino acid mimetics include, for example, organic structures which exhibit functionally similar properties such as charge and charge spacing characteristic of the reference amino acid. For example, an organic structure which mimics arginine (Arg or R) would have a positive charge moiety located in similar molecular space and having the same degree of mobility as the e-amino group of the side chain of the naturally occurring Arg amino acid. Mimetics also include constrained structures so as to maintain optimal spacing and charge interactions of the amino acid or of the amino acid functional groups. Those skilled in the art know or can determine what structures constitute functionally equivalent amino acid analogs and amino acid mimetics.

[0062] As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as dAb, Fab, Fab’, F(ab’)2, Fv), single chain (scFv), synthetic variants thereof, naturally occurring variants, fusion proteins comprising an antibody portion with an antigen binding fragment of the required specificity, humanized antibodies, chimeric antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site or fragment (epitope recognition site) of the required specificity. Certain features and characteristics of antibodies (and antigen binding fragments thereof) are described in greater detail herein.

[0063] An antibody or antigen binding fragment can be of essentially any type. As is well known in the art, an antibody is an immunoglobulin molecule capable of specific binding to atarget, such as an immune checkpoint molecule, through at least one epitope recognition site, located in the variable region of the immunoglobulin molecule.

[0064] The term “antigen binding fragment” as used herein refers to a polypeptide fragment that contains at least one CDR of an immunoglobulin heavy and / or light chain that binds to the antigen of interest. In this regard, an antigen binding fragment of the herein described antibodies may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a VHand VLsequence from antibodies that bind to a target molecule. In a particular embodiment, an antigen binding fragment of the present disclosure comprises all 6 CDRs of the VHand VLsequences of an antibody disclosed herein.

[0065] The binding properties of antibodies and antigen binding fragments thereof can be quantified using methods well known in the art (see Davies et al., Annual Rev. Biochem. 59:439-473, 1990). In some embodiments, an antibody or antigen binding fragment thereof specifically binds to a target molecule, for example, an IL-1 IRa polypeptide or an epitope or complex thereof, with an equilibrium dissociation constant that is about or ranges from about <10’7M to about 10'8M. In some embodiments, the equilibrium dissociation constant is about or ranges from about <10-9M to about <10'10M. In certain illustrative embodiments, an antibody or antigen binding fragment thereof has an affinity (KDor EC50) for a target molecule (to which it specifically binds) of about, at least about, or 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, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, or 50 nM.

[0066] A molecule such as a polypeptide or antibody is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular cell, substance, or particular epitope than it does with alternative cells or substances, or epitopes. An antibody “specifically binds” or “preferentially binds” to a target molecule or epitope if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances or epitopes, for example, by a statistically significant amount. Typically one member of the pair of molecules that exhibit specific binding has an area on its surface, or a cavity, which specifically binds to and is therefore complementary to a particular spatial and / or polar organization of the other member of the pair of molecules. Thus, the members of the pair have the property of binding specifically to each other. For instance, an antibody that specifically or preferentially binds to a specific epitope is an antibody that binds that specific epitope with greater affinity, avidity, morereadily, and / or with greater duration than it binds to other epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. The term is also applicable where, for example, an antibody is specific for a particular epitope which is carried by a number of antigens, in which case the specific binding member carrying the 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 a number of different forms of a target antigen from multiple species that share a common epitope

[0067] Immunological binding generally refers to the non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific, for example by way of illustration and not limitation, as a result of electrostatic, ionic, hydrophilic and / or hydrophobic attractions or repulsion, steric forces, hydrogen bonding, van der Waals forces, and other interactions. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (KD) of the interaction, wherein a smaller KDrepresents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen binding site / antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and on geometric parameters that equally influence the rate in both directions. Thus, both the “on rate constant” (Kon) and the “off rate constant” (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. The ratio of Koff / Kon enables cancellation of all parameters not related to affinity, and is thus equal to the dissociation constant KD. As used herein, the term “affinity” includes the equilibrium constant for the reversible binding of two agents and is expressed as KDor EC50. Affinity of a binding protein to a ligand such as affinity of an antibody for an epitope can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (fM). As used herein, the term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution. In some embodiments, affinity is expressed in the terms of the half maximal effective concentration (EC50), which refers to the concentration of an agent, such as an anti-IL-1 IRa antibody, as disclosed herein, which induces a response halfway between the baseline andmaximum after a specified exposure time. The EC50is commonly used as a measure of an antibody’s potency.

[0068] Antibodies can be prepared by any of a variety of techniques known to those of ordinary skill in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. Monoclonal antibodies specific for a polypeptide of interest can be prepared, for example, using the technique of Kohler and Milstein, Eur. J. Immunol. 6:511-519, and improvements thereto. Also included are methods that utilize transgenic animals such as mice to express human antibodies. See, e.g., Neuberger et al., Nature Biotechnology 14:826, 1996; Lonberg et al., Handbook of Experimental Pharmacology 113:49-101, 1994; and Lonberg et al., Internal Review of Immunology 13:65-93, 1995. Particular examples include the VELOCIMMUNE® platform by REGENEREX® (see, e.g., U.S. Patent No. 6,596,541).

[0069] Antibodies can also be generated or identified by the use of phage display or yeast display libraries (see, e.g., U.S. Patent No. 7,244,592; Chao et al., Nature Protocols. 1 :755-768, 2006). Non-limiting examples of available libraries include cloned or synthetic libraries, such as the Human Combinatorial Antibody Library (HuCAL), in which the structural diversity of the human antibody repertoire is represented by seven heavy chain and seven light chain variable region genes. The combination of these genes gives rise to 49 frameworks in the master library. By superimposing highly variable genetic cassettes (CDRs = complementarity determining regions) on these frameworks, the vast human antibody repertoire can be reproduced. Also included are human libraries designed with human-donor-sourced fragments encoding a lightchain variable region, a heavy-chain CDR-3, synthetic DNA encoding diversity in heavy-chain CDR-1, and synthetic DNA encoding diversity in heavy-chain CDR-2. Other libraries suitable for use will be apparent to persons skilled in the art.

[0070] In certain embodiments, antibodies and antigen binding fragments thereof as described herein include a heavy chain and a light chain CDR set, respectively interposed between a heavy chain and a light chain framework region (FR) set which provide support to the CDRs and define the spatial relationship of the CDRs relative to each other. As used herein, the term “CDR set” refers to the three hypervariable regions of a heavy or light chain V region. Proceeding from the N-terminus of a heavy or light chain, these regions are denoted as “CDR1,” “CDR2,” and “CDR3” respectively. An antigen binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. A polypeptide comprising a singleCDR, (e.g., a CDR1, CDR2 or CDR3) is referred to herein as a “molecular recognition unit.” Crystallographic analysis of a number of antigen-antibody complexes has demonstrated that the amino acid residues of CDRs form extensive contact with bound antigen, wherein the most extensive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units are primarily responsible for the specificity of an antigen binding site.

[0071] As used herein, the term “FR set” refers to the four flanking amino acid sequences which frame the CDRs of a CDR set of a heavy or light chain V region. Some FR residues may contact bound antigen; however, FRs are primarily responsible for folding the V region into the antigen binding site, particularly the FR residues directly adjacent to the CDRs. Within FRs, certain amino residues and certain structural features are very highly conserved. In this regard, most V region sequences contain an internal disulfide loop of around 90 amino acid residues. When the V regions fold into a binding-site, the CDRs are displayed as projecting loop motifs which form an antigen binding surface. It is generally recognized that there are conserved structural regions of FRs which influence the folded shape of the CDR loops into certain “canonical” structures — regardless of the precise CDR amino acid sequence. Further, certain FR residues are known to participate in non-covalent interdomain contacts which stabilize the interaction of the antibody heavy and light chains.

[0072] The structures and locations of immunoglobulin variable domains may be determined by reference to Kabat, E. A. et al., Sequences of Proteins of Immunological Interest. 4th Edition. US Department of Health and Human Services. 1987, and updates thereof.

[0073] Also include are “monoclonal” antibodies, which refer to a homogeneous antibody population wherein the monoclonal antibody is comprised of amino acids (naturally occurring and non-naturally occurring) that are involved in the selective binding of an epitope. The term “monoclonal antibody” encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab’, F(ab’)2, Fv), single chain (scFv), variants thereof, fusion proteins comprising an antigen binding portion, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding fragment (epitope recognition site) of the required specificity and the ability to bind to an epitope. It is not intended to be limited as regards the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals). The term includeswhole immunoglobulins as well as the fragments etc. described above under the definition of “antibody.”

[0074] The proteolytic enzyme papain preferentially cleaves IgG molecules to yield several fragments, two of which (the F(ab) fragments) each comprise a covalent heterodimer that includes an intact antigen binding site. The enzyme pepsin is able to cleave IgG molecules to provide several fragments, including the F(ab’)2 fragment which comprises both antigen binding sites. An Fv fragment for use according to certain embodiments can be produced by preferential proteolytic cleavage of an IgM, and on rare occasions of an IgG or IgA immunoglobulin molecule. Fv fragments are, however, more commonly derived using recombinant techniques known in the art. The Fv fragment includes a non-covalent VH::VL heterodimer including an antigen binding site which retains much of the antigen recognition and binding capabilities of the 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, Fvs are stabilized by other means, for example, incorporation of at least one disulfide bond (Worn & Pluckthun, J. Mol. Biol. 305, 989-1010, 2001)

[0075] In certain embodiments, single chain Fv (scFV) antibodies are contemplated. For example, Kappa bodies (Ill et al., Prot. Eng. 10:949-57, 1997); minibodies (Martin et al., EMBO J 13:5305-9, 1994); diabodies (Holliger et al., PNAS 90: 6444-8, 1993); or Janusins (Traunecker et al., EMBO J 10: 3655-59, 1991; and Traunecker et al., Int. J. Cancer Suppl. 7:51-52, 1992), may be prepared using standard molecular biology techniques following the teachings of the present application with regard to selecting antibodies having the desired specificity.

[0076] A single chain Fv (scFv) polypeptide is a covalently linked VH::VL heterodimer which is expressed from a gene fusion including VH- and VL-encoding genes linked by a peptide- encoding linker. Huston et al. (PNAS USA. 85(16):5879-5883, 1988). A number of methods have been described to discern chemical structures for converting the naturally aggregated — but chemically separated — light and heavy polypeptide chains from an antibody V region into an scFv molecule which will fold into a three dimensional structure substantially similar to the structure of an antigen binding site. See, e.g., U.S. Pat. Nos. 5,091,513 and 5,132,405, to Huston et al.; and U.S. Pat. No. 4,946,778, to Ladner et al.

[0077] In certain embodiments, the antibodies or antigen binding fragments described herein are in the form of a “diabody.” Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising a binding region of an immunoglobulin light chain and a second domain comprising a binding region of an immunoglobulin heavy chain, the two domains being linked (e.g., by a peptide linker) but unable to associate with each other to form an antigen binding site: antigen binding sites are 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). A dAb fragment of an antibody consists of a VH domain (Ward et al., Nature 341 :544-546, 1989). Diabodies and other multivalent or multispecific fragments can be constructed, for example, by gene fusion (see WO94 / 13804; and Holliger et al., PNAS USA. 90:6444-6448, 1993)).

[0078] Minibodies comprising a scFv joined to a CH3 domain are also included (see Hu et al., Cancer Res. 56:3055-3061, 1996). See also Ward et al., Nature. 341 :544-546, 1989; Bird et al., Science. 242:423-426, 1988; Huston et al., PNAS USA. 85:5879-5883, 1988);PCT / US92 / 09965; WO94 / 13804; and Reiter et al., Nature Biotech. 14: 1239-1245, 1996.

[0079] Where bispecific antibodies are to be used, these may 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., prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above.

[0080] Bispecific diabodies, as opposed to bispecific whole antibodies, may also be particularly useful because they can be readily constructed and expressed in E. coli. Diabodies (and many other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94 / 13804) from libraries. If one arm of the diabody is to be kept constant, for instance, with a specificity directed against antigen X, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected. Bispecific whole antibodies may be made by a number of methods (Brinkman & Kontermann, mAbs 9: 182-212, 2017) including knobs-into-holes engineering (Ridgeway et al., Protein Eng. 9:616-621, 1996).

[0081] In certain embodiments, the antibodies or antigen binding fragments described herein are in the form of a UniBody®. A UniBody® is an IgG4 antibody with the hinge regionremoved (see GenMab Utrecht, The Netherlands; see also, e.g., US20090226421). This antibody technology creates a stable, smaller antibody format with an anticipated longer therapeutic window than current small antibody formats. IgG4 antibodies are considered inert and thus do not interact with the immune system. Fully human IgG4 antibodies may be modified by eliminating the hinge region of the antibody to obtain half-molecule fragments having distinct stability properties relative to the corresponding intact IgG4 (GenMab, Utrecht). Halving the IgG4 molecule leaves only one area on the UniBody® that can bind to cognate antigens (e.g., disease targets) and the UniBody® therefore binds univalently to only one site on target cells.

[0082] In certain embodiments, the antibodies and antigen binding fragments described herein are in the form of a nanobody. Nanobodies are encoded by single genes and are efficiently produced in almost all prokaryotic and eukaryotic hosts, for example, E. coli (see U.S. Pat. No. 6,765,087), molds (for example Aspergillus or Trichoderma) and yeast (for example Saccharomyces, Kluyveromyces, Hansenula or Pichia (see U.S. Pat. No. 6,838,254). The production process is scalable and multi-kilogram quantities of nanobodies have been produced. Nanobodies may be formulated as a ready -to-use solution having a long shelf life. The Nanoclone method (see WO 06 / 079372) is a proprietary method for generating Nanobodies against a desired target, based on automated high-throughput selection of B-cells.

[0083] In some embodiments, the antibodies or antigen binding fragments described herein are in the form of an aptamer (see, e.g., Ellington et al., Nature. 346, 818-22, 1990; and Tuerk et al., Science. 249, 505-10, 1990, incorporated by reference). Examples of aptamers included nucleic acid aptamers (e.g., DNA aptamers, RNA aptamers) and peptide aptamers. Nucleic acid aptamers refer generally to nucleic acid species that have been engineered through repeated rounds of in vitro selection or equivalent method, such as SELEX (systematic evolution of ligands by exponential enrichment), to bind to various molecular targets such as small molecules, proteins, nucleic acids, and even cells, tissues and organisms. See, e.g., U.S. Patent Nos. 6,376,190; and 6,387,620, incorporated by reference.

[0084] Peptide aptamers typically include a variable peptide loop attached at both ends to a protein scaffold, a double structural constraint that typically increases the binding affinity of the peptide aptamer to levels comparable to that of an antibody’s (e.g., in the nanomolar range). In certain embodiments, the variable loop length may be composed of about 10-20 amino acids (including all integers in between), and the scaffold may include any protein that has goodsolubility and compacity properties. Certain exemplary embodiments utilize the bacterial protein Thioredoxin-A as a scaffold protein, the variable loop being inserted within the reducing active site (-Cys-Gly-Pro-Cys- loop in the wild protein), with the two cysteines lateral chains being able to form a disulfide bridge. Methods for identifying peptide aptamers are described, for example, in U.S. Application No. 2003 / 0108532, incorporated by reference. Peptide aptamer selection can be performed using different systems known in the art, including the yeast two- hybrid system.

[0085] In some embodiments, the antibodies or antigen binding fragments described herein are in the form of an avimer. Avimers refer to multimeric binding proteins or peptides engineered using in vitro exon shuffling and phage display. Multiple binding domains are linked, resulting in greater affinity and specificity compared to single epitope immunoglobulin domains. See, e.g., 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, incorporated by reference.(a) In some embodiments, the antibodies or antigen binding fragments described herein are in the form of an adnectin. Adnectins refer to a class of targeted biologies derived from human fibronectin, an abundant extracellular protein that naturally binds to other proteins. See, e.g., U.S. Application Nos. 2007 / 0082365; 2008 / 0139791; and 2008 / 0220049, incorporated by reference. Adnectins typically consists of a natural fibronectin backbone, as well as the multiple targeting domains of a specific portion of human fibronectin. The targeting domains can be engineered to enable an adnectin to specifically recognize an IL-1 IRa polypeptide or an epitope thereof.

[0086] In some embodiments, the antibodies or antigen binding fragments described herein are in the form of an anticalin. Anticalins refer to a class of antibody mimetics that are typically synthesized from human lipocalins, a family of binding proteins with a hypervariable loop region supported by a structurally rigid framework. See, e.g., U.S. Application No. 2006 / 0058510. Anticalins typically have a size of about 20 kDa. Anticalins can be characterized by a barrel structure formed by eight antiparallel P-strands (a stable P-barrel scaffold) that are pairwise connected by four peptide loops and an attached a-helix. In certain aspects, conformational deviations to achieve specific binding are made in the hypervariable loop region(s). See, e.g., Skerra, FEBS J. 275:2677-83, 2008, incorporated by reference.

[0087] In some embodiments, the antibodies or antigen binding fragments described herein are in the form of a designed ankyrin repeat protein (DARPin). DARPins include a class of nonimmunoglobulin proteins that can offer advantages over antibodies for target binding in drug discovery and drug development. Among other uses, DARPins are ideally suited for in vivo imaging or delivery of toxins or other therapeutic payloads because of their favorable molecular properties, including small size and high stability. The low-cost production in bacteria and the rapid generation of many target-specific DARPins make the DARPin approach useful for drug discovery. Additionally, DARPins can be easily generated in multispecific formats, offering the potential to target an effector DARPin to a specific organ or to target multiple receptors with one molecule composed of several DARPins. See, e.g., Stumpp et al., Curr Opin Drug Discov Devel. 10: 153-159, 2007; U.S. Application No. 2009 / 0082274; and PCT / EP2001 / 10454, incorporated by reference.

[0088] Also included are heavy chain dimers, such as antibodies from camelids and sharks. Camelid and shark antibodies comprise a homodimeric pair of two chains of V-like and C-like domains (neither has a light chain). Since the VHof a heavy chain dimer IgG in a camelid does not have to make hydrophobic interactions with a light chain, the region in the heavy chain that normally contacts a light chain is changed to hydrophilic amino acid residues in a camelid. VH domains of heavy-chain dimer IgGs are called VHH domains. Shark Ig-NARs comprise a homodimer of one variable domain (termed a V-NAR domain) and five C-like constant domains (C-NAR domains).

[0089] In camelids, the diversity of antibody repertoire is determined by the complementary determining regions (CDR) 1, 2, and 3 in the VH or VHH regions. The CDR3 in the camelid VHH region 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 CDR3 regions of antibodies of many other species. For example, the CDR3 of mouse VH has an average of 9 amino acids. Libraries of camelid-derived antibody variable regions, which maintain the in vivo diversity of the variable regions of a camelid, can be made by, for example, the methods disclosed in U.S. Patent Application Ser. No. 20050037421, published Feb. 17, 2005

[0090] In certain embodiments, the antibodies or antigen binding fragments thereof are humanized. These embodiments refer to a chimeric molecule, generally prepared using recombinant techniques, having an antigen binding site derived from an immunoglobulin from anon-human species and the remaining immunoglobulin structure of the molecule based upon the structure and / or sequence of a human immunoglobulin. The antigen binding site may comprise either complete variable domains fused onto constant domains or only the CDRs (entire or in part) grafted onto appropriate framework regions in the variable domains. Epitope binding sites may be wild type or modified by one or more amino acid substitutions. This eliminates the constant region as an immunogen in human individuals, but the possibility of an immune response to the foreign variable region remains (LoBuglio et al., PNAS USA 86:4220-4224, 1989; Queen et al., PNAS USA. 86: 10029-10033, 1988; Riechmann et al., Nature. 332:323-327, 1988). Illustrative methods for humanization of antibodies include the methods described in U.S. Patent No. 7,462,697.

[0091] Another approach focuses not only on providing human-derived constant regions, but modifying the variable regions as well so as to reshape them as closely as possible to human form. It is known that the variable regions of both heavy and light chains contain three complementarity-determining regions (CDRs) which vary in response to the epitopes in question and determine binding capability, flanked by four framework regions (FRs) which are relatively conserved in a given species and which putatively provide a scaffolding for the CDRs. When nonhuman antibodies are prepared with respect to a particular epitope, the variable regions can be “reshaped” or “humanized” by grafting CDRs derived from nonhuman antibody on the FRs present in the human antibody to be modified. Application of this approach to various antibodies has been reported by Sato et al., Cancer Res. 53:851-856, 1993; Riechmann et al., Nature 332:323-327, 1988; Verhoeyen et al., Science 239: 1534-1536, 1988; Kettleborough et al., Protein Engineering. 4:773-3783, 1991; Maeda et al., Human Antibodies Hybridoma 2: 124-134, 1991; Gorman et al., PNAS USA. 88:4181-4185, 1991; Tempest et al., Bio / Technology 9:266- 271, 1991; Co et al., PNAS USA. 88:2869-2873, 1991; Carter et al., PNAS USA. 89:4285-4289, 1992; and Co et al., J Immunol. 148: 1149-1154, 1992. In some embodiments, humanized antibodies preserve all CDR sequences (for example, a humanized mouse antibody which contains all six CDRs from the mouse antibodies). In some embodiments, only some of the CDR sequences are grafted from the nonhuman antibody (Bowers et al., J. Biol. Chem. 288:7688-7696, 2013). In certain embodiments, humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody.

[0092] In certain embodiments, the antibodies are “chimeric” antibodies. In this regard, a chimeric antibody is comprised of an antigen binding fragment of an antibody operably linked or otherwise fused to a heterologous Fc portion of a different antibody. In certain embodiments, the Fc domain or heterologous Fc domain is of human origin. In certain embodiments, the Fc domain or heterologous Fc domain is of mouse origin. In other embodiments, the heterologous Fc domain may be from a different Ig class from the parent antibody, including IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, IgG2, IgG3, and IgG4), and IgM. In further embodiments, the heterologous Fc domain may be comprised of CH2 and CH3 domains from one or more of the different Ig classes. As noted above with regard to humanized antibodies, the antigen binding fragment of a chimeric antibody may comprise only one or more of the CDRs of the antibodies described herein (e.g., 1, 2, 3, 4, 5, or 6 CDRs of the antibodies described herein), or may comprise an entire variable domain (VL, VH or both).

[0093] The term “binding” refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and / or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.

[0094] By “coding sequence” is meant any nucleic acid sequence that contributes to the code for the polypeptide product of a gene. By contrast, the term “non-coding sequence” refers to any nucleic acid sequence that does not directly contribute to the code for the polypeptide product of a gene.

[0095] 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.

[0096] By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required ormandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements.

[0097] The term “effector function”, or “ADCC effector function” in the context of antibodies refers to the ability of that antibody to engage with other arms of the immune system, including for example, the activation of the classical complement pathway, or through engagement of Fc receptors. Complement dependent pathways are primarily driven by the interaction of Clq with the Cl complex with clustered 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 an IgG which itself is bound to a target cell. Fc receptors (FcRs) are key immune regulatory receptors connecting the antibody mediated (humoral) immune response to cellular effector functions. Receptors for all classes of immunoglobulins have been identified, including FcyR (IgG), FcsRI (IgE), FcaRI (IgA), FcpR (IgM) and FcSR (IgD). There are at least three classes of receptors for human IgG found on leukocytes: CD64 (FcyRI), CD32 (FcyRIIa, FcyRIIb and FcyRIIc) and CD16 (FcyRIIIa and FcyRIIIb). FcyRI is classed as a high affinity receptor (nanomolar range KD) while FcyRII and FcyRIII are low to intermediate affinity (micromolar range KD). Upon Fc binding a signaling pathway is triggered which results in the secretion of various substances, such as lytic enzymes, perforin, granzymes and tumor necrosis factor, which mediate in the destruction of the target cell. The level of ADCC effector function various for human IgG subtypes. Although this is dependent on the allotype and specific FcvR, in simple terms ADCC effector function is “high” for human IgGl and IgG3, and “low” for IgG2 and IgG4.

[0098] The term “endotoxin free” or “substantially endotoxin free” relates generally to compositions, solvents, and / or vessels that contain at most trace amounts (e.g., amounts having no clinically adverse physiological effects to a subject) of endotoxin, and preferably undetectable amounts of endotoxin. Endotoxins are toxins associated with certain microorganisms, such as bacteria, typically gram-negative bacteria, although endotoxins may be found in gram-positive bacteria, such as Listeria monocytogenes. The most prevalent endotoxins are lipopolysaccharides (LPS) or lipo-oligo-saccharides (LOS) found in the outer membrane of various Gram-negative bacteria, and which represent a central pathogenic feature in the ability of these bacteria to cause disease. Small amounts of endotoxin in humans may produce fever, alowering of the blood pressure, and activation of inflammation and coagulation, among other adverse physiological effects.

[0099] Therefore, in pharmaceutical production, it is often desirable to remove most or all traces of endotoxin from drug products and / or drug containers, because even small amounts may cause adverse effects in humans. A depyrogenation oven may be used for this purpose, as temperatures in excess of 300°C are typically required to break down most endotoxins. For instance, based on primary packaging material such as syringes or vials, the combination of a glass temperature of 250°C and a holding time of 30 minutes is often sufficient to achieve a 3 log reduction in endotoxin levels. Other methods of removing endotoxins are contemplated, including, for example, chromatography and filtration methods, as described herein and known in the art.

[0100] Endotoxins can be detected using routine techniques known in the art. For example, the Limulus Amoebocyte Lysate assay, which utilizes blood from the horseshoe crab, is a very sensitive assay for detecting presence of endotoxin. In this test, very low levels of LPS can cause detectable coagulation of the limulus lysate due a powerful enzymatic cascade that amplifies this reaction. Endotoxins can also be quantitated by enzyme-linked immunosorbent assay (ELISA). To be substantially endotoxin free, endotoxin levels may 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 lipopolysaccharide (LPS) corresponds to about 1-10 EU.

[0101] The term “epitope” includes any determinant, preferably a polypeptide determinant, capable of specific binding to an immunoglobulin or T-cell receptor. An epitope includes a region of an antigen that is bound by an antibody. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl, and may in certain embodiments have specific three-dimensional structural characteristics, and / or specific charge characteristics. Epitopes can be contiguous or non-contiguous in relation to the primary structure of the antigen, for example, an IL-1 IRa polypeptide. In particular embodiments, an epitope comprises, consists, or consists essentially of about, at least about, or no more than about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids (i.e., a linear epitope) or non-contiguous amino acids (i.e., conformational epitope) of a reference sequence (see, e.g., Table Bl) or target molecule described herein.

[0102] An “epitope” includes that 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. Such binding interaction can be manifested as an 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 noncontiguous amino acid sequences (i.e., “conformational” or “discontinuous”). A binding protein can recognize one or more amino acid sequences; therefore an epitope can define more than one distinct amino acid sequence. Epitopes recognized by binding protein can be determined by peptide mapping and sequence analysis techniques well known to one of skill in the art. A “cryptic epitope” or a “cryptic binding site” is an epitope or binding site of a protein sequence that is not exposed or substantially protected from recognition within an unmodified polypeptide, but is capable of being recognized by a binding protein of a denatured or proteolyzed polypeptide. Amino acid sequences that are not exposed, or are only partially exposed, in the unmodified polypeptide structure are potential cryptic epitopes. If an epitope is not exposed, or only partially exposed, then it is likely that it is buried within the interior of the polypeptide. Candidate cryptic epitopes can be identified, for example, by examining the three- dimensional structure of an unmodified polypeptide.

[0103] The term “half maximal effective concentration” or “EC50” refers to the concentration of an agent (e.g., antibody) as described herein at which it induces a response halfway between the baseline and maximum after some specified exposure time; the EC50of a graded dose response curve therefore represents the concentration of a compound at which 50% of its maximal effect is observed. EC50 also represents the plasma concentration required for obtaining 50% of a maximum effect in vivo. Similarly, the “EC90” refers to the concentration of an agent or composition at which 90% of its maximal effect is observed. The “EC90” can be calculated from the “EC50” and the Hill slope, or it can be determined from the data directly, using routine knowledge in the art. In some embodiments, the EC50of an agent (e.g., antibody) is less than about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200 or 500 nM. In some embodiments, an agent will have an EC50value of about InM or less.

[0104] “Immune response” means any immunological response originating from immune system, including responses from the cellular and humeral, innate and adaptive immune systems.Exemplary cellular immune cells include for example, lymphocytes, macrophages, T cells, B cells, NK cells, neutrophils, eosinophils, dendritic cells, mast cells, monocytes, and all subsets thereof. Cellular responses include for example, effector function, cytokine release, phagocytosis, efferocytosis, translocation, trafficking, proliferation, differentiation, activation, repression, cell-cell interactions, apoptosis, etc. Humeral responses include for example IgG, IgM, IgA, IgE, responses and their corresponding effector functions.

[0105] 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 pharmacologic, physiologic, or other activity, relative to such activity at the time of administration into 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 be reduced by half of a starting amount administered into the serum or tissue of an organism, relative to such amount or concentration at the time of administration into the serum or tissue of an organism, or relative to any other defined time-point. The half-life can be measured in serum and / or any one or more selected tissues.

[0106] The terms “modulating” and “altering” include “increasing,” “enhancing” or “stimulating,” as well as “decreasing”, “reducing”, or “inhibiting”, typically in a statistically significant or a 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 that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more times (e.g., 500, 1000 times) (including all integers and ranges in between e.g., 1.5, 1.6, 1.7. 1.8, etc.) the amount produced by no composition (e.g., the absence of agent) or a control composition. A “decreased” or “reduced” or “inhibited” amount is typically a “statistically significant” amount, and may 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 in between) in the amount produced by no composition (e.g., the absence of an agent) or a control composition. Examples of comparisons and “statistically significant” amounts are described herein.

[0107] The terms “polypeptide,” “protein” and “peptide” are used interchangeably and mean a polymer of amino acids not limited to any particular length. The term “enzyme” includes polypeptide or protein catalysts. The terms include modifications such as myristoylation,sulfation, glycosylation, phosphorylation and addition or deletion of signal sequences. The terms “polypeptide” or “protein” means one or more chains of amino acids, wherein each chain comprises amino acids covalently linked by peptide bonds, and wherein said polypeptide or protein can comprise a plurality of chains non-covalently and / or covalently linked together by peptide bonds, having the sequence of native proteins, that is, proteins produced by naturally- occurring and specifically non-recombinant cells, or genetically-engineered or recombinant cells, and comprise molecules having the amino acid sequence of the native protein, or molecules having deletions from, additions to, and / or substitutions of one or more amino acids of the native sequence. In certain embodiments, the polypeptide is a “recombinant” polypeptide, produced by recombinant cell that comprises one or more recombinant DNA molecules, which are typically made of heterologous polynucleotide sequences or combinations of polynucleotide sequences that would not otherwise be found in the cell.

[0108] The term “isolated” polypeptide or protein referred to herein means that a subject protein (1) is free of at least some other proteins with which it would typically be found in nature, (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or non-covalent interaction) with portions of a protein with which the “isolated protein” is associated in nature, (6) is operably associated (by covalent or non-covalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature. Such an isolated protein can be encoded by genomic DNA, cDNA, mRNA or other RNA, of may be of synthetic origin, or any combination thereof. In certain embodiments, the isolated protein is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).

[0109] In certain embodiments, the “purity” of any given agent (e.g., antibody) in a composition may be defined. For instance, certain compositions may comprise an agent that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure on a protein basis or a weight-weight basis, including all decimals and ranges in between, as measured, for example and by no means limiting, by high performance liquid chromatography(HPLC), a well-known form of column chromatography used frequently in biochemistry and analytical chemistry to separate, identify, and quantify compounds.

[0110] The term “reference sequence” refers generally to a nucleic acid coding sequence, or amino acid sequence, to which another sequence is being compared. All polypeptide and polynucleotide sequences described herein are included as references sequences, including those described by name and those described in the Tables and the Sequence Listing.[OHl] Certain embodiments include biologically active “variants” and “fragments” of the polypeptides (e.g., antibodies) described herein, and the polynucleotides that encode the same. “Variants” contain one or more substitutions, additions, deletions, and / or insertions relative to a reference polypeptide or polynucleotide (see, e.g., the Tables and the Sequence Listing). A variant polypeptide or polynucleotide comprises an amino acid or nucleotide sequence with at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% , 99% or more sequence identity or similarity or homology to a reference sequence, as described herein, and substantially retains the activity of that reference sequence. Also included are sequences that consist of or differ from a reference sequences by the addition, deletion, insertion, or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60,70, 80, 90, 100, 110, 120, 130, 140, 150 or more amino acids or nucleotides and which substantially retain the activity of that reference sequence. In certain embodiments, the additions or deletions include C-terminal and / or N-terminal additions and / or deletions.

[0112] The terms “sequence identity” or, for example, comprising a “sequence at least 50% identical to,” as used herein, refer to the extent that sequences are identical on a nucleotide-by- nucleotide basis or an amino acid-by-amino acid basis over a window of comparison. Thus, a “percentage of sequence identity” may be calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. Optimal alignment of sequences for aligning a comparison window may be conducted by computerized implementations of algorithms (GAP, BESTFIT, FASTA, and TFASTA in theWisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, Wis., USA) or by inspection and the best alignment (i.e., resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Reference also may be made to the BLAST family of programs as for example disclosed by Altschul et al., Nucl. Acids Res. 25:3389, 1997.

[0113] The term “solubility” refers to the property of an agent (e.g., antibody) provided herein to dissolve in a liquid solvent and form a homogeneous solution. Solubility is typically expressed as a concentration, either by mass of solute per unit volume of solvent (g of solute per kg of solvent, g per dL (100 mL), mg / ml, etc.), molarity, molality, mole fraction or other similar descriptions of concentration. The maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions, including temperature, pressure, pH, and the nature of the solvent. In certain embodiments, solubility is measured at physiological pH, or other pH, for example, at pH 5.0, pH 6.0, pH 7.0, pH 7.4, pH 7.6, pH 7.8, or pH 8.0 (e.g., about pH 5-8). In certain embodiments, solubility is measured in water or a physiological buffer such as PBS or NaCl (with or without NaPO4). In specific embodiments, solubility is measured at relatively lower pH (e.g., pH 6.0) and relatively higher salt (e.g., 500mM NaCl and 10mM 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, 21, 22, 23, 24, 25°C) or about body temperature (37°C). In certain embodiments, an 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 at 37°C.

[0114] A “subject” or a “subject in need thereof’ or a “patient” or a “patient in need thereof’ includes a mammalian subject such as a human subject.

[0115] “Substantially” or “essentially” means nearly totally or completely, for instance, 95%, 96%, 97%, 98%, 99% or greater of some given quantity.

[0116] By “statistically significant,” it is meant that the result was unlikely to have occurred by chance. Statistical significance can be determined by any method known in the art. Commonly used measures of significance include the p-value, which is the frequency or probability with which the observed event would occur, if the null hypothesis were true. If theobtained p-value is smaller than the significance level, then the null hypothesis is rejected. In simple cases, the significance level is defined at a p-value of 0.05 or less.

[0117] “Therapeutic response” refers to improvement of symptoms (whether or not sustained) based on administration of one or more therapeutic agents.

[0118] As used herein, the terms “therapeutically effective amount”, “therapeutic dose,” “prophylactically effective amount,” or “diagnostically effective amount” is the amount of an agent (e.g., anti-IL-1 IRa antibody) needed to elicit the desired biological response following administration.

[0119] As used herein, “treatment” of a subject (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of a disease or disorder. Treatment includes, but is not limited to, administration of a pharmaceutical composition, and may be performed either prophylactically or subsequent to the initiation of a pathologic event or contact with an etiologic agent. Also included are “prophylactic” treatments, which can be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset. “Treatment” or “prophylaxis” does not necessarily indicate complete eradication, cure, or prevention of the disease or condition, or associated symptoms thereof.

[0120] The term “wild-type” refers to a gene or gene product (e.g., a polypeptide) that is most frequently observed in a population and is thus arbitrarily designed the “normal” or “wild-type” form of the gene.

[0121] Each embodiment in this specification is to be applied mutatis mutandis to every other embodiment unless expressly stated otherwise.Methods of Treatment, Antibodies, and Pharmaceutical Compositions

[0122] Embodiments of the present disclosure relate to methods of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human interleukin-11 receptor subunit a (IL-1 IRa). Thyroid eye disease is the most common inflammatory orbital disorder and is associated withautoimmune thyroid dysfunction. It is a progressive disorder with symptoms and signs that may cause significant facial disfigurement and visual disability, but rarely blindness.

[0123] In some instances, TED is characterized by orbital inflammation due to fibroblast activation (see, for example, Li et al., Curr Opin Ophthalmol. 29(6):528-534, 2018). Studies have demonstrated the importance of orbital CD34+ fibroblasts (see, for example, 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. The CD34+ fibroblasts express thyroglobulin, thyroid-stimulating hormone (TSH), and other thyroid-related peptides. These signal molecules stimulate the TSH receptor and insulin-like growth factor I (IGF-1) complex, cascading to adipogenesis and fibroblast hyaluronic acid synthesis within the orbit (Id.). Increased orbital adipose tissue and glycosaminoglycan sequestration within EOMs leads to soft tissue volume expansion, resulting in increased intraorbital congestion and pressure related to the pathogenic signs of TED.

[0124] Females have a higher incidence of TED, but males are more likely to have severe TED (see, for example, Douglas et al., J Clin Endocrinol Metab. 95(l):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 specific genetic predisposition, and the disease is more by environmental influences and epigenetic changes (see, for example, Yin et al., Thyroid. 22(7):730-6, 2012). TED has numerous risk factors, including being of the female sex, being of middle age, and smoking, which not only increases the development of TED, but also reduces the efficacy of therapy (see, for example, Wang et al., Ther Clin Risk Manag. 15: 1305-1318, 2019). Treatment with radioactive iodine is another exemplary risk factor for TED is (see, for example, Sikder and Weinberg, Ophthalmologica. 224(4): 199-203, 2010).

[0125] Typically, a diagnosis of TED is made by one of two criteria (see, for example, Bartley and Gorman, Am J Ophthalmol. 119(6):792-5, 1995). For example, if eyelid retraction is evident, the additional presence of abnormal thyroid function or regulation, exophthalmos, optic nerve dysfunction, or extraocular muscle (EOM) involvement provides the diagnosis, after excluding confounding causes. If eyelid retraction is absent, then diagnosis is made via exophthalmos, optic nerve dysfunction, or EOM involvement in the setting of abnormal thyroid function or regulation. In many instances, TED is associated with Graves’ disease.

[0126] 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, for example, 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 results in chronic eye exposure, especially during sleep. Initially, such can associate with foreign body sensation, dryness, and tearing. Over time, severe keratopathy may develop, which increases the risk of corneal scarring, ulceration, perforation, and endophthalmitis (see, for example, Douglas, Eye (Lond). 33(2): 183-190, 2019). Exophthalmos, or proptosis, is the second most common clinical sign of TED, mainly due to EOM and / or fat expansion, and may also increase the risk of exposure. Lagophthalmos, or incomplete eye closure, is also seen in some TED patients (see, for example, Smith and Hegedus, supra). Elevation of the temporal portion of the upper eyelid contour, or temporal flare, is often observed. EOM dysfunction is seen in many patients, and often results in diplopia if ocular misalignment ensues (see, for example, Smith and Hegedus, supra). The inferior and medial rectus muscles are most commonly affected, inducing hypotropia (downward deviation), esotropia (inward deviation) and / or potentially limiting eye movements if the muscles fibrose. Dull, pressure-like eye pain is experienced in a number of patients. Eyelid edema and erythema, conjunctival injection, and chemosis (conjunctival edema) are also observed. Fibro-inflammatory responses can also be present in orbital tissues, and the relative proportion of activated Thyl+and Thyl" OFs may determine whether excessive extracellular matrix accumulation or adipogenesis predominates in TED (see, for example, Shan et al., Journal of Neuro-Ophthalmology. 34(2): 177-185, 2014). Dyschromatopsia (color vision loss) or visual acuity loss secondary to compressive optic neuropathy is seen in very few cases, but implies severe disease. TED can be unilateral or highly asymmetric. Thus, in some instances, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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), among others described herein and known in the art.

[0127] The Clinical Activity Score (CAS) system assesses TED activity using history and external exam findings. In some instances, patients are scored at their initial visit, receiving one point for each of the following symptoms: spontaneous orbital pain, gaze-evoked orbital pain,eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and caruncle or plica semilunaris inflammation (see, for example, Mourits et al., Clin Endocrinol (Oxf). 47(1): 9- 14, 1997; and Clin Endocrinol (Oxf). 47(5):632, 1997). A CAS of three of more at initial encounter is considered active disease. In some instances, on follow-up, patients are given an additional point for each of the criteria: >2mm increase in proptosis, decrease in motility of either eye by >5°, or a decrease in visual acuity >1 Snellen line (see, for example, Id.). Scores of four or greater indicate active disease. Thus, in certain embodiments, the patient in need thereof has a Clinical Activity Score (CAS) of 3 or more, or 4 or more, 5 or more, or 6 or more.

[0128] The VISA (vision, inflammation, strabismus, appearance / exposure) classification assesses severity and activity (see, for example, Dolman and Rootman, Ophthalmic Plast Reconstr Surg. 22(5):319-324, 2006). The vision section rules out optic neuropathy by assessing visual acuity, color vision deficits, pupillary responses, and optic nerve appearance. The inflammation section modifies the above CAS criteria by excluding caruncle / plica semilunaris inflammation (including it under 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 lid injection are graded as present or absent, and the score of the worst scoring eyelid (range 0-8) is recorded. The strabismus section tracks progression of EOM dysfunction and diplopia. The appearance / exposure section assesses for symptomatic exophthalmos, eyelid retraction, and dryness. In some embodiments, the patient in need thereof has a VISA score of 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more.

[0129] In certain embodiments, the patient in need thereof has abnormal thyroid function, for example, hyperthyroidism. In some instances, the patient has autoantibody stimulation of thyroid stimulating hormone receptor (TSHR). Thyroid-stimulating immunoglobulin (TSI) is a TSHR antibody that correlates directly with severity and activity of TED (see, for example, Lytton et al., J Clin Endocrinol Metab. 95(5):2123-2131 , 2010), and can be used as a biomarker for disease. Thus, in some embodiments, the patient in need thereof has increased levels of TSI, for example, relative to a control or reference. In some embodiments, the patient has Graves’ disease.

[0130] In some embodiments, the patient has one or more risk factors associated with TED. Examples of one or more risk factors include being female, being of middle age (for example, 40 to 60 or more years old), being a smoker, and undergoing or having undergone treatment withradioactive iodine. In certain embodiments, the patient in need thereof has increased levels of IL- 1 IRa and / or IL-11 in blood or tissue around the eye (e.g., orbital blood, orbital tissue such as orbital fibroblasts), for example, relative to a healthy control or reference. In some embodiments, the patient in need thereof has increased levels of circulatory IL-11.

[0131] Certain embodiments include the step or steps of diagnosing TED in the patient prior to administering a pharmaceutical composition, as described herein. For instance, certain embodiments include the steps of (a) determining if a patient has TED; and (b) administering the pharmaceutical composition to the patient if the patient has TED. The step or steps of determining if a patient has TED can utilize any one or more of the diagnostic procedures described herein and known in the art. For example, in some instances, step (a) comprises measuring one or more clinical signs of TED, including upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0132] Particular embodiments include (a) determining the CAS of the patient; and (b) administering the pharmaceutical composition to the patient if the CAS is 3 or more, or 4 or more, 5 or more, or 6 or more. Also included are the steps of (a) determining the VISA score of the patient; and (b) administering the pharmaceutical composition to the patient if the VISA score is 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more. Some embodiments include the steps of (a) determining thyroid function in the patient; and (b) administering the pharmaceutical composition to the patient if the patient has abnormal thyroid function, for example, hyperthyroidism. Certain embodiments include the steps of (a) determining levels of TSI in the patient; and (c) administering the pharmaceutical composition to the patient if the levels of TSI in the patient are increased relative to a control or reference standard. Some embodiments include the steps of (a) determining levels of IL- 1 IRa and / or IL-11 (e.g., protein expression, mRNA expression) in blood or tissue around the patient’s eye (for example, orbital blood, orbital tissue such as orbital fibroblasts); and (b) administering the pharmaceutical composition to the patient if the levels of IL- 1 IRa and / or IL-11 in the blood or tissue around the patient’s eye are increased relative to a control or reference standard. Certain embodiments include the steps of (a) determining levels of circulatory IL-11 in the patient; and (b)administering the pharmaceutical composition to the patient if the levels of circulatory IL-11 are increased relative to a control or reference standard. The antibodies and antigen-binding fragments thereof of the present disclosure can be used for determining protein expression levels of IL- 1 IRa in the blood or tissue of a patient.

[0133] The methods provided herein can combine any one or more of the diagnostic procedures to arrive at a diagnosis of TED prior to treatment with a pharmaceutical composition that comprises an anti-IL-1 IRa antibody or antigen binding fragment thereof.

[0134] Certain embodiments include obtaining or receiving a biological sample from the subject, and performing a diagnostic assay on the sample. In some embodiments, the tissue sample is a liquid biopsy (for example, a blood sample), a surgical sample, or other biopsy sample obtained from the patient, including a blood or tissue sample from around the eye of the patient (e.g., orbital blood or orbital tissue sample such as orbital fibroblasts). Certain embodiments of step (a) include performing a thyroid function test on a blood or other biological sample, for instance, by measuring the levels TSH, T4, and / or T3 and determining if the patient has abnormal thyroid function, for example, hyperthyroidism. Some embodiments of step (a) include performing a bioassay on a blood or other biological sample obtained from the patient (for example, a bioassay that compares the cyclic adenosine monophosphate (cAMP) production of thyrotropin (TSH)-responsive cells upon exposure to patient serum with that obtained in the same cells after exposure to normal control serum; see Preissner et al., Clin Chem. 49(8): 1402- 1404, 2003) to determine if the patient has increased levels of TSI relative to a reference or control. Certain embodiments include performing a bioassay on a blood or other biological sample obtained from the patient (for example, circulatory blood, orbital blood, or orbital tissue sample such as orbital fibroblasts) to determine if the patient has increased levels of IL- 1 IRa and / or IL-11 (e.g., circulatory IL-11) relative to a reference or control. Examples of a “reference” include a value, amount, sequence, or other characteristic obtained from a database. A “reference” also includes value, amount, sequence, or other characteristic obtained from one or more control tissues, for example, a healthy tissue from one or more controls, for example, one or more control subjects (e.g., a population of control healthy subjects).

[0135] In some embodiments, the patient is treatment-naive to a TED therapy. A “treatment- naive” patient has not been previously subjected to prior TED therapy, for example, as described herein. In some embodiments, the patient has chronic TED.

[0136] In some embodiments, the patient is undergoing or has previously undergone a TED therapy and is intolerant, relapsed, and / or refractory to the (prior) TED therapy. “Relapse” refers to the recurrence of a past condition or disease state, for example, following a period of treatment-related dormancy or disease inactivity. In some embodiments, a relasped TED patient is identified by an initial response to a prior TED therapy measured by a reduction in proptosis, that is subsequently regressed after a period of time despite continued treatment with the same TED therapy. In some embodiments, the reduction in proptosis is greater than about 2mm. In some embodiments, the regression of proptosis is an increase in proptosis back to a pretreatment baseline measurement. In some embodiments, the regression of proptosis is an increase in proptosis from the maximal response to the prior TED therapy. In some embodiments, a relapsed TED patient is identified by an initial response to the TED therapy measured by a reduction in CAS score, that is then subsequently reversed after a period of time despite continued treatment with the same TED therapy. A patient that is “refractory” to a prior TED therapy does not significantly respond to, has previously failed to respond to, or has become non-responsive (e.g., via selection) to the prior TED therapy. In some embodiments, a refractory patient is identified by a lack of improvement in proptosis. In some embodiments, the lack of improvement in proptosis is less than about 2mm. In some embodiments, a refractory patient is identified by little to no change in CAS score. A patient that is “intolerant” refers to an adverse event (AE) profile requiring the disconinuation of a prior TED therapy, or indicating that such discontinuation would be advisable. In some embodiments, the intolerant, relapsed and / or refractory patient has active TED. In some instances, the TED is progressing in the patient. In certain embodiments, a patient in an intolerant / relapsed / refractory disease state has TED that progresses more aggressively in the patient than prior to the TED therapy. In some embodiments, TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and / or an increased VISA score, relative to the clinical signs, CAS scores, and / or VISA scores from prior to the TED therapy. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanism of action relative to the prior (now refractory) TED therapy can provide clinical advantages in treating a progressing disease state, including a more aggressively progressing disease state.

[0137] In some embodiments, the (prior) TED therapy is selected from insulin-like growth factor-1 receptor (IGF- lR)-inhibitor therapy, FcRn-inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy,and tumor necrosis factor-a (TNF-a)-inhibitor therapy, including combinations thereof (e.g., steroid + ORT therapies). In certain embodiments, the IGF-lR-inhibitor therapy is a small molecule. In certain embodiments, the IGF-lR-inhibitor therapy is a IGF-1R antibody. In certain embodiments, the IGF-lR-inhibitor antibody is selected from teprotumumab, 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 particular embodiments, the IL-6 inhibitor 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-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0138] In some embodiments, the patient is undergoing or has previously undergone a teprotumumab therapy and is intolerant, relapsed, and / or refractory to the (prior) teprotumumab therapy. “Relapse” refers to the recurrence of a past condition or disease state, for example, following a period of treatment-related dormancy or disease inactivity. In some embodiments, a relasped TED patient is identified by an initial response to a prior teprotumumab therapy measured by a reduction in proptosis, that is subsequently regressed after a period of time despite continued treatment with the same teprotumumab therapy. In some embodiments, the reduction in proptosis is greater than about 2mm. In some embodiments, the regression of proptosis is an increase in proptosis back to a pretreatment baseline measurement. In some embodiments, the regression of proptosis is an increase in proptosis from the maximal response to the prior teprotumumab therapy. In some embodiments, a relapsed TED patient is identified by an initial response to the teprotumumab therapy measured by a reduction in CAS score, that is then subsequently reversed after a period of time despite continued treatment with the same teprotumumab therapy. A patient that is “refractory” to a prior teprotumumab therapy does not significantly respond to, has previously failed to respond to, or has become non-responsive (e.g., via selection) to the prior teprotumumab therapy. In some embodiments, a refractory patient is identified by a lack of improvement in proptosis. In some embodiments, the lack ofimprovement in proptosis is less than about 2mm. In some embodiments, a refractory patient is identified by little to no change in CAS score. In some embodiments, the intolerant, relapsed and / or refractory patient has active TED. In some instances, the TED is progressing in the patient. In certain embodiments, a patient in an intolerant / relapsed / refractory disease state has TED that progresses more aggressively in the patient than prior to the teprotumumab therapy. In some embodiments, TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and / or an increased VISA score, relative to the clinical signs, CAS scores, and / or VISA scores from prior to the teprotumumab therapy. In certain of these and related embodiments, the potency of the presently claimed antibodies and / or their different mechanism of action relative to the prior (now refractory) teprotumumab therapy can provide clinical advantages in treating a progressing disease state, including a more aggressively progressing disease state. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 1 teprotumumab half life from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 2 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 3 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 4 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 5 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 6 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 7 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 8 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 9 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 10 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of thepresent disclosure, or antigen binding fragment thereof, is administered greater than 10 teprotumumab half lives from the last dose of teprotumumab.

[0139] Certain embodiments include combination therapies, including wherein the methods comprise administering the pharmaceutical composition (comprising an anti-IL-1 IRa antibody, or antigen-binding fragment thereof, as described herein) in combination with at least one additional TED therapy.

[0140] In some embodiments, the at least one additional TED therapy is administered prior to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered simutaneously to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered sequentially to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered within the same composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered in a separate composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.

[0141] In some embodiments, the at least one additional TED therapy is selected from IGF- IR-inhibitor therapy, FcRn-inhibitor therapy, IL-6-inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)- inhibitor therapy, including combinations thereof (e.g., steroid + ORT therapies). In certain embodiments, the IGF-lR-inhibitor therapy is an antibody therapy. In some embodimetns, the IGF-lR-inhibitor antibody therapy is selected from teprotumumab, 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 some embodiments, the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy. In particular 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 ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy. In some embodiments, the TNF-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0142] In some embodiments, the at least one additional TED therapy is a IGF-lR-inhibitor therapy. In certain embodiments, the IGF-1R inhibitor therapy is an IGF-1R antibody, e.g. teprotumumab, ganitumab, dalotuzumab, cixutumumab, or figitumumab therapy. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered simutaneously to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered prior to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered sequentially to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered within the same composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered in a separate composition as the anti- ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 2 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 3 times during the the treatment with the anti-ILl IRa antibodies or antigenbinding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 4 times during the the treatment with the anti- ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 5 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 6 times during the the treatment with the anti-ILl IRa antibodies or antigenbinding fragments of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. IGF-1R antibody) is administered about 1 to about 7 times during the the treatment with the anti- ILl IRa antibodies or antigen-binding fragments of the disclosure.

[0143] In certain embodiments, the methods and compositions described herein are sufficient to result in stable disease. In certain embodiments, the methods and compositions described herein are sufficient to result in clinically relevant reduction or improvement in symptoms of a particular disease indication known to the skilled clinician, administering the pharmaceutical composition to the patient improves one or more clinical signs of TED. For instance, in certain embodiments, the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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). In particular embodiments, administering the pharmaceutical composition to the patient improves the Clinical Activity Score (CAS) of the patient, 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 the pharmaceutical composition to the patient improves the VISA score of the patient, optionally by at least one, two, three, four, or five points, optionally to a VISA or 4 or less, 3 or less, 2 or less, or 1 or less. In some embodiments, administering the pharmaceutical composition to the patient reduces levels of IL- 1 IRa and / or IL-11 in the blood or tissue around the patient’s eye (for example, orbital blood, orbital tissue such as orbital fibroblasts). In particular embodiments, administering the pharmaceutical composition to the patient reduces levels of circulatory IL-11 in the patient.

[0144] As noted above, the methods and compositions described herein utilize one or more antibodies, and antigen binding fragments thereof, which bind to interleukin- 11 receptor subunit a (IL-1 IRa). In some embodiments, an antibody or antigen binding fragment thereof modulates (e.g., interferes with, antagonizes, inhibits) binding of IL-1 IRa to its ligand, interleukin 11 (IL- 11). In certain embodiments, an antibody or antigen binding fragment thereof is characterized by or comprises a heavy chain variable region (VH) that comprises complementary determining region VHCDR1, VHCDR2, and VHCDR3 sequences, and a light chain variable region (VL) that comprises complementary determining region VLCDR1, VLCDR2, and VLCDR3 sequences. Exemplary VH, VHCDR1, VHCDR2, VHCDR3, VL, VLCDR1, VLCDR2, and VLCDR3 sequences are provided in Table Al and Table A2 below.

[0145] Thus, in certain embodiments, an antibody or antigen binding fragment thereof comprises a VHsequence that comprises complementary determining region VHCDR1, VHCDR2, and VHCDR3 sequences selected from Table Al and variants thereof which bind to IL- 1 IRa; and a VLsequence that comprises complementary determining region VLCDR1, VLCDR2, and VLCDR3 sequences selected from Table Al and variants thereof which bind to IL- 1 IRa. In particular embodiments, an antibody comprises a VHsequence that comprises a VHCDR1, a VHCDR2, and a VHCDR3 sequence and a VLsequence that comprises a VLCDR1, a VLCDR2, and a VLCDR3 sequence, wherein all of the CDR sequences are from a single named antibody (e.g. mAbl) in Table Al.

[0146] In certain embodiments, the CDR sequences are as follows: the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 1-3, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 4-6, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 7-9, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 10- 12, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 13-15, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 16- 18, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 19-21, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 22- 24, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 28- 30, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 31-33, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 34- 36, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 37-39, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 40- 42, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 43-45, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 46- 48, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 49-51, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 52- 54, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 55-57, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 58- 60, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 61-63, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 64- 66, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 67-69, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 70- 72, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 73-75, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 76- 78, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 79-81, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 82- 84, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 85-87, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 88- 90, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 91-93, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 94- 96, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 97-99, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 100- 102, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 103-105, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 106- 108, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 109-111, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 112- 114, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 115-117, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 118- 120, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 121-123, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 124- 126, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 127-129, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 130- 132, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 133-135, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 136- 138, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 139-141, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 142- 144, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 145-147, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 148- 150, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 151-153, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 154- 156, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 157-159, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 160- 162, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 163-165, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 166- 168, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 169-171, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 172- 174, respectively; the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 175-177, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 178- 180, respectively;the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 181-183, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 184- 186, respectively; or the VHCDR1, VHCDR2, and VHCDR3 sequences comprise SEQ ID NOs: 187-189, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences comprise SEQ ID NOs: 190- 192, respectively.

[0147] Also included are minor variants the foregoing CDRs. Exemplary variants bind to IL- 1 IRa and have 1, 2, or 3 total alterations in any one or more of the individual CDRs, for example, any one or more the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and / or VLCDR3 sequences described herein. Exemplary “alterations” include amino acid substitutions, additions, and deletions.Exemplary VHand VLsequences are provided in Table A2 below.

[0148] Thus, in certain embodiments, an antibody, or antigen binding fragment thereof, binds to IL-1 IRa and comprises a VHsequence and a corresponding VLsequence selected from Table A2. In certain embodiments, the VHcomprises a sequence least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, including, for example, wherein the VHhas 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in one or more framework regions. In some embodiments, the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2, including, for example, wherein the VLhas 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in one or more framework regions. In particular embodiments, the VH comprises a sequence least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2 and the VLcomprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2 and is from the same single named antibody (e.g. mAbl) as the VHregion. In particular embodiments, the VHcomprises a sequence least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2 and the VLcomprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2 and is from the same single named antibody (e.g. mAbl) as the VH region, wherein any alterations are not found in the CDRs as underlined in Table A2. Hence, an antibody may comprise VHand VLsequences that are at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to the respective sequences from a single named antibody (e.g. mAbl) in Table A2, wherein the antibody comprises the CDRs of said single named antibody (e.g. mAbl) as recited in Table Al.

[0149] In some embodiments, the VHand VLof an antibody or antigen binding fragment are as follows:the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and the VL comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246;the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and the VL comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or the VHcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and the VLcomprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 256.

[0150] Also included are variants thereof that bind to IL- 1 IRa, for example, variants having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in one or more framework regions of any one or more of the foregoing VHand / or VLsequences. Exemplary “alterations” include amino acid substitutions, additions, and deletions.

[0151] As noted above, an antibody or antigen binding fragment thereof, described herein, binds to IL- 1 IRa, for example, membrane-bound IL- 1 IRa. In certain embodiments, an antibody or an antigen binding fragment thereof binds to human IL-1 IRa, or a region or fragment thereof. The amino acid sequence of human IL-1 IRa is provided in Table Bl below.

[0152] Thus, in certain embodiments, an antibody, or antigen binding fragment thereof, binds to an IL-1 IRa sequence in Table Bl, for example, a human IL-1 IRa sequence. In certain embodiments, an antibody, or antigen binding fragment thereof, binds to mature IL- 1 IRa. In certain embodiments, an antibody, or antigen binding fragment thereof, binds to soluble IL- 1 IRa. In certain embodiments, an antibody, or antigen binding fragment thereof, binds to IL- 1 IRa membrane precursor.

[0153] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to a conformational epitope on IL- 1 IRa.

[0154] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to a linear epitope on IL-1 IRa.

[0155] In particular embodiments, an antibody or antigen binding fragment thereof binds to a first fibronectin type-III domain in human IL-1 IRa (also referred to herein as the second extracellular domain of IL-1 IRa), comprising residues 90-197 of SEQ ID NO: 260.

[0156] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to an epitope that spans residues 115-134 in mature IL- 1 IRa. In certain embodiments, an exemplary antibody of the disclosure that exhibits such binding comprises the VHCDR1, VHCDR2, and VHCDR3 sequences of SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences of SEQ ID NOs: 28-30, respectively. In certain embodiments, an exemplary antibody of the disclosure that exhibits such binding comprises the VHsequence of SEQ ID NO: 201, and the VLsequence of SEQ ID NOs: 202.

[0157] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to an epitope comprising the residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 261). In certain embodiments, the IL-1 IRa 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, an exemplary antibody of the disclosure that exhibits such binding comprises the VHCDR1, VHCDR2, and VHCDR3 sequences of SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 sequences of SEQ ID NOs: 28-30, respectively. In certain embodiments, an exemplary antibody of the disclosure that exhibits such binding comprises the VHsequence of SEQ ID NO: 201, and the VLsequence of SEQ ID NOs: 202.

[0158] In some embodiments, an antibody or antigen binding fragment thereof binds to human IL- 1 IRa with a binding affinity of about 1 pM to about 10 pM to about 500 pM, or about, at least about, or less than about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, or 500 pM, or optionally with an affinity that ranges 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 about400 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, an antibody or antigen binding fragment thereof, has increased binding affinity for human IL- 1 IRa relative to that of the TS7 and 8E2 antibodies (see, for example, U.S. Patent Nos. 9,796,782; 9,340,618).

[0159] In some embodiments, an antibody, or antigen binding fragment thereof, is an IL-1 IRa antagonist. In some instances, an antibody, or antigen binding fragment thereof, antagonizes the binding and / or signaling activity between IL-1 IRa and its ligand, IL-11. In some embodiments, an antibody, or antigen binding fragment thereof, antagonizes or reduces the binding and / or signaling activity between IL-1 IRa and IL-11 by about or at least about 10-1000% (e.g., about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000% or more), for example, in a cell-based assay. In some embodiments, an anti-IL-1 IRa antibody or antigen binding fragment thereof reduces IL- 11 -mediated STAT3 phosphorylation. In an exemplary assay, cells expressing IL-1 IRa and gpl30 are cultured in the presence of IL-11 in the presence or absence of the IL-1 IRa-binding protein. The level of STAT3 phosphorylation is then assessed by Western blotting or FACS using an antibody specific for phosphorylated STAT3. An exemplary assay making use of FACS is described in Dams-Kozlowska et al., BMC Biotechnol, 12: 8, 2012. In certain embodiments, an antibody or antigen binding fragment thereof, has increased potency as an IL-11 signaling antagonist relative to that of the TS7 and 8E2 antibodies (see, for example, U.S. Patent Nos. 9,796,782; 9,340,618). In certain embodiments, an antibody or antigen binding fragment thereof has no detectable agonist activity with respect to IL-11 signaling.

[0160] In some embodiments, an antibody, or antigen binding fragment thereof, inhibits or otherwise reduces IL-1 IRa dimerization or complex formation, for example, with gpl30. In certain embodiments, an antibody, or antigen binding fragment thereof, inhibits or otherwise reduces IL-1 IRa dimerization or complex formation by about or at least about 10-1000% (e.g., about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000% or more), for example, in a cell-based assay.

[0161] In some embodiments, an anti-IL-1 IRa antibody or antigen binding fragment thereof reduces proliferation of cells (e.g., BaF3 cells, B9 cells, T10 cells) expressing IL-1 IRa and gpl30 (e.g., cells naturally-expressing or modified to express both proteins) which are 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 with B9 cells or T10 cells are described (see Dams-Kozlowska et al., BMC Biotechnol, 12: 8, 2012; and Yokote et al., J AO AC, 83: 1053-1057, 2000). For T10 cells, proliferation can be measured by colorimetrically detecting reduction of the tetrazolium compound, 4-[3-(4-iodophenyl)-2-(4- nitrophenyl)-2H-5-tetrazolio]-l,3-benzene disulfonate (WST-1). An IL-1 IRa-binding protein that reduces the level of proliferation compared to the level observed in the absence of the IL- 1 IRa-binding protein is considered to reduce or otherwise reduce IL-11R signaling.

[0162] Merely for illustrative purposes, the binding interactions between IL-1 IRa an antibody, or antigen binding fragment thereof, described herein, or the binding / signaling between IL-1 IRa and IL-11, can be detected and quantified using a variety of routine methods, including Biacore® assays (for example, with appropriately tagged soluble reagents, bound to a sensor chip), FACS analyses with cells expressing IL- 1 IRa on the cell surface (either native, or recombinant), immunoassays, fluorescence staining assays, ELISA assays, and microcalorimetry approaches such as ITC (Isothermal Titration Calorimetry). Similarly, the functional properties of anti-IL-1 IRa antibodies may be assessed using a variety of methods known to the skilled person affinity / binding assays (for example, surface plasmon resonance, competitive inhibition assays); cytotoxicity assays, cell viability assays, cell proliferation or differentiation assays, among others. Other assays may test the ability of antibodies described herein to block normal IL-1 IRa-mediated responses. The antibodies described herein may also be tested for in vitro and in vivo efficacy. Such assays may be performed using well-established protocols known to the skilled person (see e.g., Current Protocols in Molecular Biology (Greene Publ. Assoc. Inc. & John Wiley & Sons, Inc., NY, NY); Current Protocols in Immunology (Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober 2001 John Wiley & Sons, NY, NY); or commercially available kits.

[0163] In particular embodiments, the heavy chain constant region or Fc region of an antibody, or antigen binding fragment thereof, comprises, consists, or consists essentially an IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, IgG2, IgG3,and IgG4), or IgM heavy chain constant region or Fc domain, optionally a human Fc domain, or a hybrid and / or variant thereof. In particular embodiments, the heavy chain constant region or Fc region comprises, consists, or consists essentially of the heavy chain constant region or Fc region from human IgGl or IgG4 (see, e.g., Allberse and Schuurman, Immunology. 105:9-19, 2002), or a fragment or variant thereof. Table Fl below provides exemplary heavy chain constant region sequences (CHI, hinge (underlined), CH2, and CH3 regions) from human IgG4. Examples of variant IgG4 sequences that can be employed include the S228P / S241P variant.

[0164] Table F2 below provides exemplary heavy chain sequences for mAb5.

[0165] In certain embodiments, an antibody or antigen binding fragment thereof comprises variant or otherwise modified Fc region(s), including those having altered properties or biological activities relative to wild-type Fc region(s). Examples of modified Fc regions include those having mutated sequences, for instance, by substitution, insertion, deletion, or truncation of one or more amino acids relative to a wild-type sequence, hybrid Fc polypeptides composed of domains from different immunoglobulin classes / subclasses, Fc polypeptides having altered glycosylation / sialylation patterns, and Fc polypeptides that are modified or derivatized, for example, by biotinylation (see, e.g., US 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, elimination rate constant, elimination rate, area under the curve (AUC), clearance, Cmax, tmax, Cmin, fluctuation), its immunogenicity, its complement fixation or activation, and / or the CDC / ADCC / ADCP-related activities of the Fc region, among other properties described herein, relative to a corresponding wild-type Fc sequence of an antibody or antigen binding fragment thereof. Included are modified Fc regions of human and / or mouse origin.

[0166] In certain embodiments, an antibody or antigen binding fragment thereof comprises a hybrid Fc region, for example, an Fc region that comprises 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 comprise derivatized or otherwise modified Fc regions. In certain aspects, the Fc region is modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, famesylation, acetylation, amidation, and the like, for instance, relative to a wildtype or naturally-occurring Fc region. In certain embodiments, the Fc region comprises wildtype or native glycosylation patterns, or alternatively, it comprises increased glycosylation relative to a native form, decreased glycosylation relative to a native form, or it is entirely deglycosylated. As one example of a modified Fc glycoform, decreased glycosylation of an Fc region reduces binding to the Clq region of the first complement component Cl, a decrease in ADCC-related activity, and / or a decrease in CDC-related activity. Certain embodiments thus employ a deglycosylated or aglycosylated Fc region. See, e.g., WO 2005 / 047337 for the production of exemplary aglycosylated Fc regions. Another example of an Fc region glycoform is generated by substituting the Q295 position with a cysteine residue (see, e.g., U.S. Application No. 2010 / 0080794), according to the Kabat et al. numbering system. Certain embodiments include Fc regions where about 80-100% of the glycoprotein in Fc region comprises 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, for instance, to increase affinity for FcyRI, FcyRIa, or FcyRIIIa, and / or to improve phagocytosis by FcyRIIa-expressing cells (see U.S. Application Nos. 2010 / 0249382 and 2007 / 0148170).

[0167] As another example of a modified Fc glycoform, an Fc region of an antibody or antigen binding fragment thereof may comprise oligomannose-type N-glycans, and optionally have one or more of the following: increased ADCC effector activity, increased binding affinity for FcyRIIIA (and certain other FcRs), similar or increased binding specificity for the target of the IL-1 IRa polypeptide, similar or higher binding affinity for the target of the IL-1 IRa polypeptide, and / or similar or lower binding affinity for mannose receptor, relative to a corresponding Fc region that contains complex-type N-glycans (see, e.g., U.S. Application No. 2007 / 0092521 and U.S. Patent No. 7,700,321). As another example, enhanced affinity of Fc regions for Fey Rs has been achieved using engineered glycoforms generated by expression of antibodies in engineered or variant cell lines (see, e.g., Umana et al., Nat Biotechnol. 17:176- 180, 1999; Davies et al., Biotechnol Bioeng. 74:288-294, 2001; Shields et al., J Biol Chem. 277:26733-26740, 2002; Shinkawa et al., 2003, J Biol Chem. 278:3466-3473, 2003; and U.S. Application No. 2007 / 0111281). Certain Fc region glycoforms comprise an increased proportion of N-gly coside bond type complex sugar chains, which do not have the 1 -position of fucose bound to the 6-position of N-acetylglucosamine at the reducing end of the sugar chain (see, e.g., U.S. Application No. 2010 / 0092997). Particular embodiments may include IgG Fc region that is glycosylated with at least one galactose moiety connected to a respective terminal sialic acid moiety by an a-2,6 linkage, optionally where the Fc region has a higher anti-inflammatory activity relative to a corresponding, wild-type Fc region (see U.S. Application No.2008 / 0206246). Certain of these and related altered glycosylation approaches have generated substantial enhancements of the capacity of Fc regions to selectively bind FcRs such as FcyRIII, to mediate ADCC, and to alter other properties of Fc regions, as described herein.

[0168] Certain variant, fragment, hybrid, or otherwise modified Fc regions of an antibody or antigen binding fragment thereof may have altered binding to one or more FcRs, and / or corresponding changes to effector function, relative to a corresponding, wild-type Fc sequence (e.g., same species, same Ig class, same Ig subclass). For instance, such Fc regions may have increased binding to one or more of Fey receptors, Fea receptors, Fes receptors, and / or the neonatal Fc receptor, relative to a corresponding, wild-type Fc sequence. In other embodiments, variant, fragment, hybrid, or modified Fc regions may have decreased binding to one or more of Fey receptors, Fea receptors, Fes receptors, and / or the neonatal Fc receptor, relative to a corresponding, wild-type Fc sequence. Specific FcRs are described elsewhere herein.

[0169] In some embodiments, an antibody comprises an Fc domain, comprising one or more mutations to increase binding to one or more of Fey receptors, Fea receptors, Fes receptors, and / or the neonatal Fc receptor, relative to a corresponding, wild-type Fc sequence. In some embodiments, an antibody comprises an IgGl or IgG3 Fc domain, comprising one or more mutations to increase binding to one or more of Fey receptors, Fea receptors, Fes receptors, and / or the neonatal Fc receptor, relative to a corresponding, wild-type Fc sequence. In some embodiments, an antibody comprises an Fc domain, comprising one or more mutations to increase effector function. In some embodiments the at least one antibody comprises an Fc domain selected from a human IgGl and IgG3, optionally comprising one or more mutations to increase effector function.

[0170] In some embodiments, an antibody comprises an Fc domain, comprising one or more mutations to decrease binding to one or more of Fey receptors, Fea receptors, Fes receptors, and / or the neonatal Fc receptor, relative to a corresponding, wild-type Fc sequence. In some embodiments, an antibody comprises an IgGl or IgG3 Fc domain, comprising one or more mutations to decrease binding to one or more of Fey receptors, Fea receptors, Fes receptors, and / or the neonatal Fc receptor, relative to a corresponding, wild-type Fc sequence. In some embodiments, an antibody comprises an Fc domain, comprising one or more mutations to decrease effector function. In some embodiments, an antibody comprises an Fc domain selected from a human IgG2 and IgG4, comprising one or more mutations to decrease effector function.

[0171] Specific examples of Fc variants having altered (e.g., increased, decreased) effector function / FcR binding can be found, for example, in U.S. Pat. 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 having a one or more substitutions at position 298, 333, and / or 334, for example, S298A, E333 A, and / or K334A (based on the numbering of the EU index of Kabat et al.), which have been shown to increase binding to the activating receptor FcyRIIIa and reduce binding to the inhibitory receptor FcyRIIb. These mutations can be combined to obtain double and triple mutation variants that have further improvements in binding to FcRs. Certain embodiments include a 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 Fcglycoforms that have 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 comprise one or more substitutions selected from 434S, 252Y / 428L, 252Y / 434S, and 428L / 434S (see U.S. Application Nos. 2009 / 0163699 and 20060173170), based on the EU index of Kabat et al.

[0172] Certain variant, fragment, hybrid, or modified Fc regions may have altered effector functions, relative to a corresponding, wild-type Fc sequence. For example, such Fc regions may have increased complement fixation or activation, increased Clq binding affinity, increased CDC-related activity, increased ADCC-related activity, and / or increased ADCP-related activity, relative to a corresponding, wild-type Fc sequence. In other embodiments, such Fc regions may have decreased complement fixation or activation, decreased Clq binding affinity, decreased CDC-related activity, decreased ADCC-related activity, and / or decreased ADCP-related activity, relative to a corresponding, wild-type Fc sequence. As merely one illustrative example, an Fc region may comprise a deletion or substitution in a complement-binding site, such as a Clq- binding site, and / or a deletion or substitution in an ADCC site. Examples of such deletions / substitutions are described, for example, in U.S. Patent No. 7,030,226. Many Fc effector functions, such as ADCC, can be assayed according to routine techniques in the art. (see, e.g., Zuckerman et al., CRC Crit Rev Microbiol. 7: 1-26, 1978). Useful effector cells for such assays includes, but are not limited to, natural killer (NK) cells, macrophages, and other peripheral blood mononuclear cells (PBMC). Alternatively, or additionally, certain Fc effector functions may be assessed in vivo, for example, by employing an animal model described in Clynes et al. PNAS. 95:652-656, 1998.

[0173] Certain variant hybrid, or modified Fc regions may have altered stability or half-life relative to a corresponding, wild-type Fc sequence. In certain embodiments, such Fc regions may have increased half-life relative to a corresponding, wild-type Fc sequence. In other embodiments, variant hybrid, or modified Fc regions may have decreased half-life relative to a corresponding, wild-type Fc sequence. Half-life can be measured in vitro (e.g., under physiological conditions) or in vivo, according to routine techniques in the art, such as radiolabeling, ELISA, or other methods. In vivo measurements of stability or half-life can be measured in one or more bodily fluids, including blood, serum, plasma, urine, or cerebrospinal fluid, or a given tissue, such as the liver, kidneys, muscle, central nervous system tissues, bone, etc. As one example, modifications to an Fc region that alter its ability to bind the FcRn can alterits half-life in vivo. Assays for measuring the in vivo pharmacokinetic properties (e.g., in vivo mean elimination half-life) and non-limiting examples of Fc modifications that alter its binding to the FcRn are described, for example, in U.S. Pat. Nos. 7,217,797 and 7,732,570; and U.S. Application Nos. US 2010 / 0143254 and 2010 / 0143254.

[0174] Additional non-limiting examples of modifications to alter stability or half-life include substitutions / deletions at one or more of amino acid residues selected from 251-256, 285-290, and 308-314 in the CH2domain, and 385-389 and 428-436 in the CH3domain, according to the numbering system of Kabat et al. See U.S. Application No. 2003 / 0190311. Specific 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 glutamate at position 256, substitution with threonine at position 308, substitution with proline at position 309, substitution with serine at position 311, substitution with aspartate at position 312, substitution with leucine at position 314, substitution with arginine, aspartate 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 affinity of the Fc region for the FcRn and thereby increase half-life, relative to a corresponding, wild-type Fc region.

[0175] Certain variant hybrid, or modified Fc regions may have altered solubility relative to a corresponding, wild-type Fc sequence. In certain embodiments, such Fc regions may have increased solubility relative to a corresponding, wild-type Fc sequence. In other embodiments, variant hybrid, or modified Fc regions may have decreased solubility relative to a corresponding, wild-type Fc sequence. Solubility can be measured, for example, in vitro e.g., under physiological conditions) according to routine techniques in the art. Exemplary solubility measurements are described elsewhere herein.

[0176] Variant Fc regions can also have one or more mutated hinge regions, as described, for example, in U.S. Application No. 2003 / 0118592. For instance, one or more cysteines in a hinge region can be deleted or substituted with a different amino acid. The mutated hinge region cancomprise no cysteine residues, or it can comprise 1, 2, or 3 fewer cysteine residues than a corresponding, wild-type hinge region. In some embodiments, an Fc region having a mutated hinge region of this type exhibits a reduced ability to dimerize, relative to a wild-type Ig hinge region.

[0177] In particular embodiments, an antibody or antigen binding fragment thereof has a biological half life at about pH 7.4, at about a 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), of about or at least about 30 minutes, about 1 hour, about 2 hour, 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 intervening half-life, including all ranges in between.

[0178] In some embodiments, an antibody or antigen binding fragment thereof has a Tmof about or at least about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75°C. In some embodiments, an antibody or antigen binding fragment thereof has a Tmof about 65°C or greater, for example, in PBS (phosphate buffered saline).

[0179] For in vivo use, certain embodiments include pharmaceutical compositions, 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 one or more agents is mixed with any pharmaceutical carrier(s) or excipient known to those skilled in the art to be suitable for the particular agent and / or mode of administration. A pharmaceutical carrier may be liquid, semi-liquid or solid. Solutions or suspensions used for parenteral, intradermal, intraocular, subcutaneous, direct instillation into the bladder, or topical application may include, for example, a sterile diluent (such as water), saline solution (e.g., phosphate buffered saline; PBS), fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent; 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 acetates, citrates and phosphates). If administered intravenously (e.g., by IV infusion), suitable carriers includephysiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol and mixtures thereof.

[0180] Administration of 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 serving similar utilities. The therapeutic or pharmaceutical compositions can be prepared by combining an agent-containing composition with an appropriate physiologically acceptable carrier, diluent or excipient, and may 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. In addition, other pharmaceutically active ingredients (including other small molecules as described elsewhere herein) and / or suitable excipients such as salts, buffers and stabilizers may, but need not, be present within the composition.

[0181] Administration may be achieved by a variety of different routes, including oral, parenteral, nasal, intravenous, intraocular, intradermal, intramuscular, subcutaneous, installation into the bladder, or topical. Preferred modes of administration depend upon the nature of the condition to be treated or prevented. Particular embodiments include administration by IV infusion.

[0182] Carriers can include, for example, pharmaceutically- or physiologically-acceptable carriers, excipients, or stabilizers that are non-toxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically-acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; 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™) polyethylene glycol (PEG), and poloxamers (PLURONICS™), and the like.

[0183] In some embodiments, one or more agents can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate)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, 16th edition, Oslo, A., Ed., (1980). The particle(s) or liposomes may further comprise other therapeutic or diagnostic agents.

[0184] The precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by testing the compositions in model systems known in the art and extrapolating therefrom. Controlled clinical trials may also be performed. Dosages may also vary with the severity of the condition to be alleviated. A pharmaceutical composition is generally formulated and administered to exert a therapeutically useful effect while minimizing undesirable side effects. The composition may be administered one time, or may be divided into a number of smaller doses to be administered at intervals of time. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need.

[0185] Typical routes of administering these and related therapeutic or pharmaceutical compositions thus include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, ocular, rectal, vaginal, and intranasal. The term parenteral as used herein 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 so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a subject or patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a herein described agent in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, 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). The composition to be administered will typically contain a therapeutically effective amount of an agent described herein, for treatment of a disease or condition of interest.

[0186] A therapeutic or pharmaceutical composition can be in the form of a solid or liquid. In some embodiments, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) can be liquid, with the compositions being, for example, an oral oil, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration. When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid. Certain embodiments include sterile, injectable solutions.

[0187] As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, gel, compressed tablet, pill, capsule, chewing gum, wafer or the like. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may 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, com starch 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 may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0188] The therapeutic or pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, gel, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye / colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

[0189] The liquid therapeutic or pharmaceutical compositions, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents 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 mayserve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; 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.

[0190] A liquid therapeutic or pharmaceutical composition intended for either parenteral, intraocular, or oral administration should contain an amount of an agent such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of the agent of interest in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Certain oral therapeutic or pharmaceutical compositions contain between about 4% and about 75% of the agent of interest. In certain embodiments, therapeutic or pharmaceutical compositions and preparations are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of the agent of interest prior to dilution.

[0191] The therapeutic or pharmaceutical compositions may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a therapeutic or pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

[0192] The therapeutic or pharmaceutical compositions may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter, and polyethylene glycol.

[0193] The therapeutic or pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition mayinclude materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule. The therapeutic or pharmaceutical compositions in solid or liquid form may include a component that binds to agent and thereby assists in the delivery of the compound. Suitable components that may act in this capacity include monoclonal or polyclonal antibodies, one or more proteins or a liposome.

[0194] The therapeutic or pharmaceutical composition may consist essentially of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One of ordinary skill in the art, without undue experimentation may determine preferred aerosols.

[0195] The compositions described herein may be prepared with carriers that protect the agents against rapid elimination from the body, such as time 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.

[0196] The pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art. For example, a therapeutic or pharmaceutical composition intended to be administered by injection may comprise one or more of salts, buffers and / or stabilizers, with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non- covalently interact with the agent so as to facilitate dissolution or homogeneous suspension of the agent in the aqueous delivery system.

[0197] The therapeutic or pharmaceutical compositions may be administered in a therapeutically effective amount, which will vary depending upon a variety of factors includingthe activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body 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 instances, a therapeutically effective daily dose is (for a 70 kg mammal) from about 0.001 mg / kg (i.e., ~ 0.07 mg) to about 100 mg / kg (i.e., ~ 7.0 g); preferably a therapeutically effective dose is (for a 70 kg mammal) from about 0.01 mg / kg (i.e., ~ 0.7 mg) to about 50 mg / kg (i.e., ~ 3.5 g); more preferably a therapeutically effective dose is (for a 70 kg mammal) from about 1 mg / kg (i.e., ~ 70 mg) to about 25 mg / kg (i.e., ~ 1.75 g). In some embodiments, the therapeutically effective dose is administered on a weekly, bi-weekly, or monthly basis. In specific embodiments, the therapeutically effective dose is administered on a weekly, bi-weekly, or monthly basis, 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.

[0198] Also provided is an antibody, antigen binding fragment thereof, or pharmaceutical composition of the present disclosure for use as a medicament. An antibody, fragment thereof, or pharmaceutical composition of the present disclosure may be for use in any method of treatment disclosed herein. In particular embodiment, an antibody, fragment thereof, or pharmaceutical composition of the present disclosure may be for use in a method of treating, ameliorating the symptoms of, and / or reducing the progression of TED.

[0199] The methods and compositions provided herein can be combined with other therapeutic modalities for the treatment of TED. Examples include supportive care (e.g., improving thyroid function, smoking cessation, supplemental selenium), corticosteroids, radiotherapy, and surgical management such as eyelid retraction repair, strabismus surgery, and orbital decompression.

[0200] Also included are patient care kits, comprising (a) an antibody or antigen binding fragment thereof that binds to IL-1 IRa, 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.

[0201] The kits herein may also include a one or more additional therapeutic agents or other components suitable or desired for the indication being treated, or for the desired diagnostic application. The kits herein can also include one or more syringes or other componentsnecessary or desired to facilitate an intended mode of delivery (e.g., stents, implantable depots, etc.).

[0202] In some embodiments, a patient care kit contains separate containers, dividers, or compartments for the composition(s) and informational material(s). For example, the composition(s) can be contained in a bottle, vial, or syringe, and the informational material(s) can be contained in association with the container. In some embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of an antibody and optionally at least one additional therapeutic agent. For example, the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of an antibody and optionally at least one additional therapeutic agent. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and / or light-tight.

[0203] The patient care kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device. In some embodiments, the device is an implantable device that dispenses metered doses of the agent(s). Also included are methods of providing a kit, e.g., by combining the components described herein.

[0204] 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 one of ordinary skill in the art in light of 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 of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.ENUMERATED EMBODIMENTS

[0205] Provided herein are non-limiting exemplary embodiments of the disclosure.

[0206] Embodiment 1-1. A method of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human interleukin- 11 receptor subunit a (IL-1 IRa).

[0207] Embodiment 1-2. The method of embodiment I- 1, wherein the patient has one or more clinical signs of TED.

[0208] Embodiment 1-3. The method of embodiment 1-2, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0209] 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 more, or 4 or more, 5 or more, or 6 or more, wherein the CAS comprises one point for each of: spontaneous orbital pain, gaze-evoked orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and caruncle, and plica semilunaris inflammation.

[0210] Embodiment 1-5. The method of any one of embodiments 1-1 to 1-4, wherein the patient has a VISA (vision, inflammation, strabismus, appearance / exposure) score of 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more.

[0211] Embodiment 1-6. The method of any one of embodiments 1-1 to 1-5, wherein the patient has abnormal thyroid function, optionally hyperthyroidism.

[0212] Embodiment 1-7. The method of any one of embodiments 1-1 to 1-6, wherein the patient has autoantibody stimulation of thyroid stimulating hormone receptor (TSHR).

[0213] Embodiment 1-8. The method of any one of embodiments 1-1 to 1-7, wherein the patient has increased levels of thyroid-stimulating immunoglobulin (TSI).

[0214] Embodiment 1-9. The method of any one of embodiments 1-1 to 1-8, wherein the patient has Graves’ disease.

[0215] Embodiment I- 10. The method of any one of embodiments 1-1 to 1-9, wherein the patient has one or more risk factors associated with TED.

[0216] Embodiment 1-11. The method of embodiment I- 10, wherein the one or more risk factors are selected from being female, being of middle age, being a smoker, and undergoing or having undergone treatment with radioactive iodine.

[0217] Embodiment 1-12. The method of any one of embodiments 1-1 to 1-11, wherein the patient has increased levels of IL-1 IRa and / or IL-11 in blood or tissue around the eye, optionally in orbital fibroblasts, and / or wherein the patient has increased levels of circulatory IL- 11.

[0218] Embodiment 1-13. The method of any one of embodiments 1-1 to 1-12, comprising: a. determining if the patient has TED; and b. administering the pharmaceutical composition to the patient if the patient has TED.

[0219] Embodiment 1-14. The method of embodiment 1-13, wherein (a) comprises measuring one or more clinical signs of TED, optionally selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0220] Embodiment 1-15. The method of embodiment 1-13 or 1-14, comprising: a. determining the CAS of the patient; and b. administering the pharmaceutical composition to the patient if the CAS is 3 or more, or 4 or more, 5 or more, or 6 or more.

[0221] Embodiment 1-16. The method of any one of embodiments 1-13 to 1-15, comprising: a. determining the VISA score of the patient; andb. administering the pharmaceutical composition to the patient if the VISA score is 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more.

[0222] Embodiment 1-17. The method of any one of embodiments 1-13 to 1-16, comprising: a. determining thyroid function in the patient; and b. administering the pharmaceutical composition to the patient if the patient has abnormal thyroid function, optionally hyperthyroidism.

[0223] Embodiment 1-18. The method of any one of embodiments 1-13 to 1-17, comprising: a. determining levels of thyroid-stimulating immunoglobulin (TSI) in the patient; and b. administering the pharmaceutical composition to the patient if the levels of TSI in the patient are increased relative to a control or reference standard.

[0224] Embodiment 1-19. The method of any one of embodiments 1-1 to 1-18, comprising: a. determining levels of IL-1 IRa and / or IL-11 in blood or tissue around the patient’s eye, optionally in orbital fibroblasts; and b. administering the pharmaceutical composition to the patient if the levels of IL-1 IRa and / or IL-11 in the blood or tissue around the patient’s eye (optionally in orbital fibroblasts) are increased relative to a control or reference standard.

[0225] Embodiment 1-20. The method of any one of embodiments 1-1 to 1-19, wherein the patient is treatment-naive to a TED therapy, optionally a patient with chronic TED.

[0226] Embodiment 1-21. The method of any one of embodiments 1-1 to 1-19, wherein the patient is undergoing or has previously undergone a TED therapy and is relapsed / refractory / intolerant to the TED therapy, optionally a patient with active TED.

[0227] Embodiment 1-22. The method of embodiment 1-21, wherein the TED is progressing in the patient, optionally as indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and / or an increased VISA score, relative to the clinical signs or scoresfrom prior to the TED therapy, optionally wherein the TED is progressing more aggressively in the patient than prior to the TED therapy.

[0228] Embodiment 1-23. The method of any one of embodiments 1-20 to 1-22, wherein the TED therapy is selected from insulin-like growth factor- 1 receptor (IGF-lR)-inhibitor therapy, FcRn-inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)-inhibitor therapy.

[0229] Embodiment 1-24. The method of embodiment 1-23, wherein the IGF-lR-inhibitor therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy.

[0230] Embodiment 1-25. The method of embodiment 1-23, wherein the FcRn-inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapy.

[0231] Embodiment 1-26. The method of embodiment 1-23, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.

[0232] Embodiment 1-27. The method of embodiment 1-23, wherein the steroid therapy is selected from methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy.

[0233] Embodiment 1-28. The method of embodiment 1-23, wherein the CD20-inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0234] Embodiment 1-29. The method of embodiment 1-23, wherein the TNF-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0235] Embodiment 1-30. The method of any one of embodiments 1-1 to 1-29, comprising administering the pharmaceutical composition in combination with at least one additional TED therapy.

[0236] Embodiment 1-31. The method of embodiment 1-30, wherein the at least one additional TED therapy is selected from IGF-lR-inhibitor therapy, FcRn-inhibitor therapy, IL-6-inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)-inhibitor therapy.

[0237] Embodiment 1-32. The method of embodiment 1-31, wherein the IGF-lR-inhibitor therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy.

[0238] Embodiment 1-33. The method of embodiment 1-32, wherein the IGF-lR-inhibitor therapy is administered 1 to 7 times either simultaneously or sequentially to the administration the pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human IL-1 IRa.

[0239] Embodiment 1-34. The method of embodiment 1-31, wherein the FcRn-inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapy.

[0240] Embodiment 1-35. The method of embodiment 1-31, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.

[0241] Embodiment 1-36. The method of embodiment 1-31, wherein the steroid therapy is selected from methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy.

[0242] Embodiment 1-37. The method of embodiment 1-31, wherein the CD20-inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0243] Embodiment 1-38. The method of embodiment 1-31, wherein the TNF-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0244] 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 a fibronectin domain III of human IL- 1 IRa, or approximately residues 90-197 of SEQ ID NO: 260.

[0245] Embodiment 1-40. The method of any one of embodiments 1-1 to 1-38, wherein the antibody, or antigen binding fragment thereof, binds to the second extracellular domain of IL- HRa.

[0246] 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.

[0247] Embodiment 1-42. The method of embodiment 1-41, wherein the epitope comprises the residues SI 16, S125, K129, S140 and T143 of SEQ ID NO: 260.

[0248] Embodiment 1-43. The method of any one of embodiments 1-1 to 1-42, wherein the antibody, or antigen binding fragment thereof, comprises: a. a heavy chain variable region (VH) that comprises complementary determining region VHCDR1, VHCDR2, and VHCDR3 amino acid sequences selected from Table Al and variants thereof which specifically bind to IL-1 IRa; and b. a light chain variable region (VL) that comprises complementary determining region VLCDR1, VLCDR2, and VLCDR3 amino acid sequences selected from Table Al and variants thereof which specifically bind to IL-1 IRa.

[0249] Embodiment 1-44. The method of embodiment 1-43, wherein:

[0250] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 1-3, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 4-6, respectively;

[0251] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 7-9, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 10-12, respectively;

[0252] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 13-15, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 16-18, respectively;

[0253] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 19-21, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 22-24, respectively;

[0254] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 28-30, respectively;

[0255] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 31-33, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 34-36, respectively;

[0256] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 34-39, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 40-42, respectively;

[0257] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 43-45, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 46-48, respectively;

[0258] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 49-51, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 52-54, respectively;

[0259] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 55-57, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 58-60, respectively;

[0260] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 61-63, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 64-66, respectively;

[0261] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 67-69, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 70-72, respectively;

[0262] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 73-75, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 76-78, respectively;

[0263] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 79-81, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 82-84, respectively;

[0264] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 85-87, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 88-90, respectively;

[0265] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 91-93, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 94-96, respectively;

[0266] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 97-99, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 100-102, respectively;

[0267] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 103-105, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 106-108, respectively;

[0268] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 109-111, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 112-114, respectively;

[0269] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 115-117, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 118-120, respectively;

[0270] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 121-123, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 124-126, respectively;

[0271] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 127-129, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 130-132, respectively;

[0272] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 133-135, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 136-138, respectively;

[0273] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 139-141, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 142-144, respectively;

[0274] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 145-147, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 148-150, respectively;

[0275] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 151-153, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 154-156, respectively;

[0276] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 157-159, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 160-162, respectively;

[0277] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 163-165, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 166-168, respectively;

[0278] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 169-171, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 172-174, respectively;

[0279] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 175-177, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 178-180, respectively;

[0280] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 181-183, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 184-186, respectively; or

[0281] the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 187-189, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 190-192, respectively.

[0282] Embodiment 1-45. The method of embodiment 1-43 or 1-44, wherein the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to an amino acid sequence selected from Table A2, optionally wherein the VHhas 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in the framework regions.

[0283] Embodiment 1-46. The method of any one of embodiments 1-43 to 1-45, wherein the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to an amino acid sequence selected from Table A2, optionally wherein the VLhas 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 alterations in the framework regions.

[0284] Embodiment 1-47. The method of any one of embodiments 1-43 to 1-46, wherein:

[0285] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194;

[0286] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196;

[0287] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198;

[0288] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200;

[0289] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202;

[0290] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204;

[0291] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206;

[0292] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208;

[0293] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210;

[0294] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212;

[0295] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214;

[0296] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216;

[0297] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218;

[0298] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220;

[0299] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222;

[0300] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224;

[0301] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226;

[0302] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228;

[0303] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230;

[0304] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232;

[0305] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234;

[0306] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236;

[0307] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238;

[0308] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240;

[0309] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242;

[0310] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244;

[0311] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246;

[0312] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248;

[0313] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250;

[0314] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252;

[0315] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or

[0316] the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 256.

[0317] 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: a. has increased binding affinity for human IL- 1 IRa relative to that of the 340 antibody, and increased functional potency relative to that of the 340 antibody, optionally as measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells; b. has a binding affinity for human IL-1 IRa of less than about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 30 pM, and optionally has increased binding affinity for human IL-1 IRa relative to that of the TS7 and 8E2 antibodies; c. antagonizes the binding and / or signaling activity between IL- 1 IRa and IL-11, and optionally has increased potency as an IL-11 signaling antagonist relative to that of the TS7 and 8E2 antibodies; d. reduces IL-1 lRa / gpl30 dimerization or complex formation, optionally in a cell-based assay; and / or e. has reduced N-linked glycosylation in VLCDR3, optionally relative to the TS7 and 8E2 antibodies.

[0318] Embodiment 1-49. The method of any one of embodiments 1-1 to 1-48, wherein the antibody, or antigen binding fragment thereof, comprises an IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or a hybrid and / or variant thereof.

[0319] Embodiment 1-50. The method of embodiment 1-49, wherein the antibody, or antigen binding fragment thereof, comprises an IgG Fc domain with high effector function in humans, optionally an IgGl or IgG3 Fc domain.

[0320] Embodiment 1-51. The method of embodiment 1-49, 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.

[0321] Embodiment 1-52. The method of embodiment 1-49, wherein the antibody, or antigen binding fragment thereof, comprises a human IgGl or IgG4 Fc domain, optionally selected from Table Fl

[0322] Embodiment 1-53. The method of any one of embodiments 1-1 to 1-52, wherein the antibody, or antigen binding fragment thereof, is a monoclonal antibody.

[0323] Embodiment 1-54. The method of any one of embodiments 1-1 to 1-53, 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 that comprises a human IgG4 Fc domain with an S228P mutation (EU numbering).

[0324] Embodiment 1-55. The method of any one of embodiments 1-1 to 1-53, wherein the antibody, or antigen binding fragment thereof, is selected from an Fv fragment, a single chain Fv (scFv) polypeptide, an adnectin, an anticalin, an aptamer, an avimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.

[0325] Embodiment 1-56. The method of any one of embodiments 1-1 to 1-55, wherein the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the at least one antibody or antigen binding fragment, and is substantially aggregate- and endotoxin-free.

[0326] Embodiment 1-57. The method of any one of embodiments 1-1 to 1-56, wherein the composition has reduced or undetectable heterogeneity of N-linked glycosylation (optionally relative to the TS7 and 8E2 antibodies), optionally in the VLCDR3 sequence.

[0327] Embodiment 1-58. The method of any one of embodiments 1-1 to 1-57, wherein the pharmaceutical composition is a sterile, injectable solution, optionally suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.

[0328] Embodiment 1-59. The method of any one of embodiments 1-1 to 1-58, wherein administering the pharmaceutical composition to the patient improves one or more clinical signs of TED.

[0329] Embodiment 1-60. The method of embodiment 1-59, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

[0330] Embodiment 1-61. The method of embodiment 1-59 or 1-60, wherein the administering the pharmaceutical composition to the patient improves the Clinical Activity Score (CAS) of the patient, 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.

[0331] Embodiment 1-62. The method of any one of embodiments 1-59 to 1-61, wherein the administering the pharmaceutical composition to the patient improves the VISA score of the patient, optionally by at least one, two, three, four, or five points, optionally to a VISA or 4 or less, 3 or less, 2 or less, or 1 or less.

[0332] Embodiment 1-63. The method of any one of embodiments 1-1 to 1-62, wherein administering the pharmaceutical composition to the patient reduces levels of IL-1 IRa and / or IL-11 in blood or tissue around the patient’s eye, optionally in orbital fibroblasts.

[0333] Embodiment 1-64. The method of any one of embodiments 1-1 to 1-63, wherein administering the pharmaceutical composition to the patient reduces levels of circulatory IL-11 in the patient.EXAMPLESExample 1: IL-1 IRa Expression is Elevated in TED-Derived Fibroblasts

[0334] Flow cytometry was performed to compare IL-1 IRa expression on primary fibroblasts derived from orbital tissue of a thyroid eye disease (TED) patient relative to that of primary fibroblasts derived from eye tissue of a non-TED individual. The antibody mAb5 was used to detect IL-11R levels on the cell surface. As shown in FIGS. 1A-1C, high levels of IL-1 IRaexpression were detected on fibroblasts from diseased tissue relative to fibroblasts from normal tissue (FIG. 1C). This result evidences that inhibitory anti-IL-1 IRa antibodies have therapeutic utility in the treatment of TED, for example, by inhibiting IL- 1 IRa activity in the tissue around the eye of TED patients.Example 2: Anti-IL-1 IRa Antibody Blocks IL-11 Stimulated HA Release and Cell Proliferation in Orbital Cells from TED Patients

[0335] To assess the role of IL- 11 in thyroid eye disease, fibroblasts were isolated from orbital tissue of patients with Thyroid eye disease (TED) and then stimulated in culture with recombinant human IL-11 in the presence and absence of the IL- 1 IRa blocking antibody, mAb5. The effects of these treatments were measured on hyaluronic acid (HA) release and cell proliferation, two events that are linked to TED pathogenesis.Materials and Methods

[0336] Cell isolation. Orbital adipose / connective tissue was isolated from TED patients during orbital decompression surgery. The donor information is provided in Table El below.

[0337] Following isolation, tissues were minced into 1-2 mm pieces, placed in 6 well culture dishes 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; all from Gibco Laboratories, New York, USA), and incubated at 37 °C with 5% CO2. Culture mediumI l lwas renewed every 3-4 days and tissue was maintained in culture for 2-3 weeks to allow the orbital fibroblasts to migrate out of the tissue.

[0338] Cell proliferation and HA release. Following isolation, orbital fibroblasts (passage <5) were plated in growth medium at a density of 10,000 cells / well on black, clear flat bottom, 96- well plates (Coming Costar, catalog #3603) and maintained in a humidified incubator overnight at 37 °C in 5% CO2. The following day, media was changed to 100 pL of starvation media (high glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 1% fetal bovine serum and 1% penicillin / streptomycin; all from Gibco Laboratories, New York, USA) for 24 hours to synchronize cells. The following day, media was replaced with fresh serum-starvation media and cells were preincubated with media alone (vehicle, no antibody control), mAb5 (at indicated concentrations), teprotumumab (ichorbio, ICH5128, 10 ng / mL), and / or isotype control (10 ng / mL) for 1 hour and then stimulated with human recombinant IL- 11 (1.1, 3.3 or 10 ng / mL) for an additional 96 hours. Following the 96 hour stimulation period, an aliquot of media was removed and frozen at -80 °C for analysis of HA release. To measure cell proliferation, 10 pL of the WST-1 cell proliferation reagent (Sigma-Aldrich, catalog# 11644807001) was added to each well and cell proliferation was assessed after a 2 hour incubation by measuring OD 450 on a Spectramax iD5 plate reader (Molecular Devices, San Jose, CA.). HA release was measured using the Duoset ELISA (R&D Systems, catalog# DY3614) according to manufacturer’s recommendations.Results

[0339] As shown in FIG. 2, recombinant IL-11 stimulated a dose-dependent increase in HA release from orbital fibroblasts (gray bars), and this was inhibited by mAb5 (lined bars) at all IL- 11 doses. Similarly, as shown in FIG. 3, recombinant IL-11 stimulated fibroblast proliferation at all doses, and these effects were blocked by addition of mAb5.

[0340] FIGS. 4A-4C show the dose-dependent effects of IL-11, with mAb5 (10 ng / mL, hatched) and without mAb5 (solid), on hyaluronan release from orbital fibroblasts from patient sample #2 (FIG. 4A, no prior TED therapy), patient sample #1 (FIG. 4B, prior teprotumumab therapy), and patent sample #3 (FIG. 4C, prior corticosteroid therapy). FIGS. 5A-5C show the effects of mAb5 at 3, 10, 30 and lOOpg / mL on IL-11 (10 ng / mL) induced HA release from orbital fibroblasts from patient samples #2, #4, and #5 (FIG. 5A; no prior TED therapy), patientsample # 1 (FIG. 5B, prior teprotumumab therapy), and patient sample #3 (FIG. 5C, prior corticosteroid therapy).

[0341] FIGS. 6A-6C show the comparative inhibitory effects of mAb5 teprotumumab and isotype control (all at lOpg / mL) on HA release induced by lOng / mL IL-11 from orbital fibroblasts from TED patients; FIG. 6A shows the effects on naive patient samples (no prior TED therapy, n=4), FIG. 6B shows the effects on patient sample with prior teprotumumab therapy (n=l), and FIG. 6C shows the effects on patient sample with prior corticosteroid therapy (n=2). FIGS. 7A-7C show the comparative effects of mAb5 teprotumumab (and isotype control antibodies (all at lOpg / mL) on proliferation of orbital fibroblasts induced by lOng / mL IL- 1 Ifrom TED patients; FIG. 7A shows the effects on naive patient samples (no prior TED therapy, n=4), FIG. 7B shows the effects on patient sample with prior teprotumumab therapy (n=l), and FIG. 7C shows the effects on patient samples with prior corticosteroid therapy (n=2).

[0342] Activation of the IGF-1 receptor (IGF-1R) is a disease driver in TED and the target of the currently approved TED therapy, teprotumumab (TEPEZZA), an anti-IGF-lR 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, teprotumumab (ichorbio, ICH5128), and the combination (mAb5 / teprotumumab) on HA release in IGF-1 (100 ng / mL) and IL-11 (10 ng / mL) stimulated orbital fibroblasts from TED patients. Orbital fibroblasts were stimulated with a combination of IL- 11 + IGF-1 and HA release was measured in response to combination treatment of mAb5 with increasing concentrations (1, 3 and 10 pg / mL) of teprotumumab. As shown in FIG. 10, combination treatment of mAb5 with increasing doses of teprotumumab (solid grey bars) dose- dependently increased the inhibition of HA release compared to either mAb5 or teprotumumab alone (black bar and cross-hatched bars). These data indicate that treating patients with the anti- IL1 IRa antibodies described herein, in addition to the standard-of-care drug, teprotumumab, may have added therapeutic benefit relative to treatment with either agent alone.

[0343] Increased HA production is a key pathology in TED and causes orbital tissue edema and proptosis (eye bulging). The ability of teprotumumab to inhibit HA release by orbital fibroblasts in preclinical studies was a key translational readout and has been correlated with clinical efficacy in TED. Canonical IL-11 signaling leads to phosphorylation of STAT3 (pSTAT3) and IL-11 stimulation of orbital fibroblasts promotes HA release. For this reason, thedose-dependent effects of mAb5 on IL- 11 -stimulated pSTAT3 and HA release were examined in orbital fibroblasts to determine the IC50 and IC90 for inhibition of IL-11R. FIGS. 11A-11B show that mAb5 inhibits pSTAT3 (FIG. HA) with IC50 and IC90 values of 0.007 and 0.06 pg / mL, respectively, and blocks HA release (FIG. 11B) with IC50 and IC90 values of 0.05 and 0.48 pg / mL, respectively. These data confirm the potency of the anti-ILl IRa antibodies described herein on IL-11 pathway activation in orbital fibroblasts and their potency in reducing clinically meaningful endpoints in TED, such as HA release.

[0344] One etiology of TED that is not effectively addressed by the current standard of care therapy (teprotumumab) are excessive extracellular matrix accumulation in orbital tissue. Based on the role for IL-11 in this fibro-inflammatory responses outside of the eye and the fact that TGFP, a highly potent pro-fibrotic growth factor, can stimulate large amounts of IL- 11 release, the effects of mAb5 on TGFP-stimulated procollagen I production were investigated and compared to teprotumumab. FIGS. 12A-12B show that TGFP stimulation increased procollagen I release by greater than 3-fold (FIG. 12A), and that this increase was significantly inhibited by the addition of mAb5 (FIG. 12B).

[0345] Overall, these results show that the anti-ILl IRa antibodies described herein can robustly inhibit HA release by, and proliferation of, orbital fibroblasts from TED patients, including TED patients that have undergone prior TED therapy (teprotumumab therapy, corticosteroid therapy) and thus can be expected have more aggressive disease characteristics. These results also support a role for IL-11 and the IL- 1 IRa antibodies described herein in mediating excessive extracellular matrix accumulation in orbital tissue.

[0346] Such evidences the clinical utility of IL-1 IRa-based therapies having a different mechanism of action relative to prior or other TED therapies such as teprotumumab and corticosteroid therapies. It also evidences the beneficial effects of combination therapies with teprotumumab and the anti-IL-1 IRa antibodies described herein.Example 3: Comparative Affinities and Potencies

[0347] Experiments were performed to assess the comparative binding affinities and / or potencies of mAb5 and mAb29 relative to the anti-ILRa monoclonal antibody (“the 340 antibody”) having the HC of SEQ ID NO: 58 / kappa LC of SEQ ID NO: 59 as described in U.S. Application No. 2020 / 0270340. Binding kinetics were measured by Octet® Bio-LayerInterferometry (BLI), and potency was measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells. As shown in FIGS. 8A-8B, mAb5 has a binding affinity for human IL-1 IRa of about 37 pm (FIG. 8A), and the 340 antibody has significantly weaker (-35- fold) binding affinity for human IL- 1 IRa of about 1.3 nM (FIG. 8B). As shown in FIGS. 9A- 9C, mAb5 (FIG. 9A) and mAb29 (FIG. 9B) show strong functional potency as measured by pSTAT3 inhibition; in contrast, the 340 antibody (FIG. 9C) shows no functional activity in this assay.Example 4: Blocking IL-1 IRa inhibits the production of inflammatory cytokines in TED patient derived orbital fibroblasts

[0348] The infiltration of immune cells is a key pathogenic feature of TED and an area of ongoing therapeutic drug research. In particular, the upregulation of cytokines including TNFa, IL-6, IL-8 and MCP-1 / CCL2 is believed to promote activation of immune cells, including T cells, B cells and orbital fibroblasts leading to orbital tissue expansion and remodeling (Fallahy et al., Front Endocrinol (Lausanne). 12:654473 (2021); Lee et al., Best Pract Res Clin Endocrinol Metab. 37(2): 101620 (2023); Zhang et al., J Immunol Res. 2528046 (2022)). We compared the inhibitory effects of mAb5 with the approved therapeutic agent for TED, teprotumumab, on a broad panel of cytokines after stimulation of patient-derived orbital fibroblasts for 96 hours with IL-11 and IGF-1. We then stimulated orbital fibroblasts with IL-11 or the combination of IL-11 and IGF-1 to assess the magnitude of inhibition that mAb5 and teprotumumab have on release of IL-6 and MCP-1 / CCL2, which are both upregulated in TED and believed to play a role in TED pathogenesis (Fallahy et al., Front Endocrinol (Lausanne). 12:654473 (2021)).

[0349] For the cytokine panel studies, orbital fibroblasts were stimulated for 96 hours with the combination of IL-11 + IGF-1 and a panel of 96 cytokines was measured by multiplex analysis, in response to inhibition with mAb5 or teprotumumab (FIG. 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 following stimulation with either IL-11 alone or the combination of IL-11 + IGF-1 (FIG. 14).

[0350] As a single agent, IL-11 stimulated both IL-6 and MCP-1 / CCL2 release (FIG. 14A and 14C), which was not significantly increased by combination stimulation with IL-11 + IGF- 1. Notably, mAb5 inhibited IL-6 and MCP-1 / CCL2 release under all treatment conditionswhereas teprotumumab had no effect (FIG. 14). The ability of IL- 11 to stimulate IL-6 and MCP- 1 / CCL2 to the same degree as combination treatment, combined with the lack of inhibition by teprotumumab, demonstrates that IL-11 is a primary driver of IL-6 and MCP-1 / CCL2 release by orbital fibroblasts under these treatment conditions. These data also suggest that IL-11 is upstream of IL-6 as an inflammatory mediator in TED, which has significant clinical implications considering the current effort to target the IL-6 pathway therapeutically in TED. Combined, these data provide evidence for a pathological role of IL- 11 in driving inflammation- mediated orbital tissue remodeling in TED.Example 5: Comparison of mAb5 with commercially available antibodies to IL-11 and IL- 11R

[0351] A panel of commercially available antibodies to 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 shown in Table E2 below.

[0352] These antibodies were compared directly to mAb5 using assay conditions as described in Example 2 using TED orbital fibroblasts stimulated with IL-11 and IGF-1. Cells from from 12 different tissue donors were used for all antibodies except MM09 (6 donors used), and results are shown as mean fold over vehicle conditions. The results, shown in FIG. 15, clearly demonstrate that mAb5 is more efficacious than commercially available antibodies to IL-11 or IL- HR.Example 6: Epitope mapping of mAb5

[0353] The epitope of mAb5 was determined by two mass spectrometry methods, hydrogendeuterium exchange (HDX) and cross-linking / high resolution mass spectrometry (XL-MS). This was carried out using methodology developed by CovalX AG (Pimenova et al., J. Mass Spectrometry 43: 185 (2008)). In short, human IL-1 IRa was allowed to bind to mAb5 and crosslinked with a heterobifunctional linker. The resulting complexes were digested with 5 different proteases (trypsin, chymotrypsin, ASP-N, elastase and thermolysin and the resulting peptides, cross-linked or not, were analyzed by high-resolution mass spectrometry. In addition, for HDX mapping IL-1 IRa was labelled with deuterium before and after complexing with mAb5, allowing sites of differential deuterium labelling to be determined by mass spectrometry.

[0354] The results demonstrated 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- 1 IRa (SEQ ID NO: 260). Mapping by XL-MS localized the epitope to amino acid residues in IL- 1 IRa overlapping and extending the epitope. Cross-links were identified at positions SI 16, S125, K129, S140 and T143 as shown in FIG. 16. These results confirm binding of mAb5 to the second extracellular domain of IL-11R.Example 7: Blocking IL-11 signaling with anti-IL-1 IRa antibody is effective at inhibition of IL-11 signaling in cis and in trans

[0355] IL-11 has been reported to be able to signal both conventionally (in cis) binding IL-1 IRa and forming a complex with the co-receptor gpl30 on the same cell, but also in trans, in which soluble IL-1 IRa forms a complex with IL11 and signals to a gpl30 bearing cell, which may or may not also bear IL-1 IRa (Lokau et al., BBA Mol. Cell Res.1864. 2105-2117 (2017)). Complete blockade of IL- 11 signaling may therefore require inhibition of signaling both in cis and in trans. To compare the ability of mAbs to IL-11 and IL-11R to achieve this, we testedinhibition of IL- 11 signaling in a cell based pSTAT3 reporter assay where pSTAT3 stimulation is stimulated by IL-11 (FIG. 17A) or by a complex of soluble IL-11R / IL-11 (FIG. 17B). The soluble complex of IL-11R and IL-11 was achieved using a fusion protein of IL- 11 and soluble IL-11R known as hyper-IL-11 (Dams-Kozlowska et al., BMC Biotechnol. 12:8 (2012)).

[0356] The STAT3 Reporter (Luc) - HEK293 cell line was purchased from BPS Bioscience, catalog #79800-P and transfected with recombinant IL- 1 IRa. Cells were selected for expression of IL- 1 IRa, and a stable clone isolated which was used for further experiments. Cells were grown, passaged, and assayed as per BPS Bioscience protocols. Cells were added at 25,000 cells per well in a 96-well microtiter dish and incubated at 37 °C for 30-45 minutes in 5% CO2 humidified air. mAbs were added in a dilution series in duplicate columns or rows, and plates were returned to the incubator for an additional 1 hour at 37 °C after which 40 ng / mL IL-11 or hyper-IL-11 was added to each well to initiate the signal transduction cascade and luciferase production. Plates were incubated for 18-24 hours at 37 °C and luciferase was detected using a One-Step Luciferase Assay System (BPS Bioscience, cat. no. 60690-1) as per manufacturer’s instructions.

[0357] Results shown in FIG. 17 demonstrated that when pSTAT3 signaling was initiated by IL-11 both mAb5 (anti-IL-11R) and by an anti-IL-11 mAb with approximately equivalent potency (IC50 5.6nM for mAb5, 4.2nM for anti-IL-11). However, when stimulated with hyper IL-11 the mAb to IL-11 was ineffective whereas the potency of mAb5 was unchanged (IC50 5.4nM). This data confirms that mAb5 is effective at blocking IL-11 signaling both in cis and in trans.Example 8: mAb5 Inhibits production of HA stimulated by autoantibodies to TSHR

[0358] Agonistic autoantibodies to TSHR are thought to be an important driver of TED (Lee & Kahaly, Best Pract Res Clin Endocrinol Metab. 37(2): 101620 (2023)). M22 is a monoclonal agonistic autoantibody which is widely used experimentally to represent patient derived autoantibodies (Krieger et al., J. Clin. Endocrinol. Metab. 101, 2340-2347 (2016)). TED patient derived orbital fibroblasts were cultured and tested as described in Example 2 except PDGF was added to the culture medium to enhance cellular levels of TSHR as described (van Steensel et al., J. Clin. Endocrinol. Metab. 97, E944-E953 (2012)). M22 induced production of HA in orbital fibroblasts from three donors. This was effectively inhibited by both mAb5 and thepositive control antibody teprotumumab (FIG. 18). mAb5 appeared to be more potent and effective than teprotumumab in this study.Example 9: Additional experiments to be performed

[0359] Addtionally, experiments will be performed to determine effect of the use of anti- IL1 IRa antibodies on HA, IL-11, and IL-6 secretion from activated orbital fibroblasts and to determine whether the effects are comparable, synergistic, or additive to IGF1R blockade.

[0360] TED patient derived orbital fibroblasts will be stimulated with anti-thyroid stimulating hormone receptor (TSHR) monoclonal antibody (whose sequence corresponds to M22 from Kronus Bio) alone or in combination with IL-11 in the presence and absence of an anti-IL-1 IRa antibody, teprotumumab, or both to determine the effect on HA IL-11, and IL-6. Supernatant will be collected after 4 days for measurement of HA, IL-11, and IL-6 via ELISA and the levels of IL-11R on the orbital fibroblasts will be determined via immunoblots or staining.

[0361] Experiments will be additionally performed to assess the effects of 0.03, 0.3,3 ng / mL (as well as other doses) of TGFp on orbital fibroblasts and the ability of anti-ILl 1R antibodies to block these effects. Proliferation / myofibroblast formation by orbital fibroblasts, SMA, collagen, fibronectin, and IL-11R will additionally be evaluated after 24-96 hours post treatment, or 48-72 hours post treatment. Additionally, supernatants will be collected at various timepoints the 48-72 hour timepoint and inflammatory cytokines will be measured via ELISA which included: IL-6, IL-8, procollagen, HA, and IL-11.

[0362] IL-11 concentrations in serum / plasma from patients with TED will be compared to healthy individuals. Differences in IL-11 and IL-11R expression in TED patient eye tissue will compared with normal eye tissue, specifically looking at fibroblasts, myoblasts and other appropriate cell types.

Claims

CLAIMS1. 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 an antigen binding fragment thereof, that binds to human interleukin- 11 receptor subunit a (IL-1 IRa).

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 upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

4. The method of any one of claims 1-3, wherein the patient has a Clinical Activity Score (CAS) of 3 or more, or 4 or more, 5 or more, or 6 or more, wherein the CAS comprises one point for each of: 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 1-4, wherein the patient has a VISA (vision, inflammation, strabismus, appearance / exposure) score of 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more.

6. The method of any one of claims 1-5, wherein the patient has abnormal thyroid function, optionally hyperthyroidism.

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

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

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

10. The method of any one of claims 1-9, 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 being female, being of middle age, being a smoker, and undergoing or having undergone treatment with radioactive iodine.

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

13. The method of any one of claims 1-12, comprising: a. determining if the patient has TED; and b. administering the pharmaceutical composition to the patient if the patient has TED.

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), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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 of claim 13 or 14, comprising: a. determining the CAS of the patient; and b. administering the pharmaceutical composition to the patient if the CAS is 3 or more, or4 or more, 5 or more, or 6 or more.

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

17. The method of any one of claims 13-16, comprising: a. determining thyroid function in the patient; and b. administering the pharmaceutical composition to the patient if the patient has abnormal thyroid function, optionally hyperthyroidism.

18. The method of any one of claims 13-17, comprising: a. determining levels of thyroid-stimulating immunoglobulin (TSI) in the patient; and b. administering the pharmaceutical composition to the patient if the levels of TSI in the patient are increased relative to a control or reference standard.

19. The method of any one of claims 1-18, comprising: a. determining levels of IL-1 IRa and / or IL-11 in blood or tissue around the patient’s eye, optionally in orbital fibroblasts; and b. administering the pharmaceutical composition to the patient if the levels of IL-1 IRa and / or IL-11 in the blood or tissue around the patient’s eye (optionally in orbital fibroblasts) are increased relative to a control or reference standard.

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

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

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

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

24. The method of claim 23, wherein the IGF-lR-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 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-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

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

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

32. The method of claim 31, wherein the IGF-lR-inhibitor therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy.

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

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

35. The method of claim 31, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, 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 ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

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

39. The method of any one of claims 1-38, wherein the antibody, or antigen binding fragment thereof, binds to a fibronectin domain III of human IL- 1 IRa, or approximately residues 90- 197 of SEQ ID NO: 260.

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

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 the residues SI 16, S125, K129, S140 and T143 of SEQ ID NO: 260.

43. The method of any one of claims 1-42, wherein the antibody, or antigen binding fragment thereof, comprises: a. a heavy chain variable region (VH) that comprises complementary determining region VHCDR1, VHCDR2, and VHCDR3 amino acid sequences selected from Table Al and variants thereof which specifically bind to IL- 1 IRa; and b. a light chain variable region (VL) that comprises complementary determining region VLCDR1, VLCDR2, and VLCDR3 amino acid sequences selected from Table Al and variants thereof which specifically bind to IL- 1 IRa.

44. The method of claim 43, wherein: a. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 1-3, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 4-6, respectively; b. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 7-9, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 10-12, respectively; c. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 13-15, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 16-18, respectively; d. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 19-21, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 22-24, respectively; e. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 25-27, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 28-30, respectively; f. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 31-33, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 34-36, respectively;g. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 34-39, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 40-42, respectively; h. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 43-45, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 46-48, respectively; i. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 49-51, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 52-54, respectively; j. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 55-57, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 58-60, respectively; k. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 61-63, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 64-66, respectively; l. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 67-69, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 70-72, respectively; m. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 73-75, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 76-78, respectively; n. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 79-81, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 82-84, respectively; o. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 85-87, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 88-90, respectively;p. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 91-93, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 94-96, respectively; q. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 97-99, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 100-102, respectively; r. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 103-105, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 106-108, respectively; s. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 109-111, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 112-114, respectively; t. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 115-117, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 118-120, respectively; u. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 121-123, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 124-126, respectively; v. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 127-129, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 130-132, respectively; w. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 133-135, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 136-138, respectively; x. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 139-141, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 142-144, respectively;y. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 145-147, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 148-150, respectively; z. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 151-153, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 154-156, respectively; dd. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 157-159, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 160-162, respectively; ee. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 163-165, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 166-168, respectively; ff. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 169-171, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 172-174, respectively; gg. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 175-177, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 178-180, respectively; hh. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 181-183, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 184-186, respectively; or ii. the VHCDR1, VHCDR2, and VHCDR3 amino acid sequences comprise SEQ ID NOs: 187-189, respectively, and the VLCDR1, VLCDR2, and VLCDR3 amino acid sequences comprise SEQ ID NOs: 190-192, respectively.

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

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

47. The method of any one of claims 43-46, wherein: a. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194; b. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196; c. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198; d. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 199, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 200; e. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 201, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 202; f. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 203, and the VLcomprises an amino acidsequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 204; g. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 205, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 206; h. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 207, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 208; i. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 209, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 210; j. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 211, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 212; k. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 213, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 214; l. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 215, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 216; m. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 217, and the VLcomprises an amino acidsequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 218; n. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 219, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 220; o. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 221, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 222; p. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 223, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 224; q. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 225, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 226; r. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228; s. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230; t. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 231, and the VLcomprises an amino acidsequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 232; u. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 233, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 234; v. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 235, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 236; w. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 237, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 238; x. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 239, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 240; y. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 241, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 242; z. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244; dd. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 245, and the VLcomprises an amino acidsequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 246; ee. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 247, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 248; ff. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250; gg. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 251, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 252; hh. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 253, and the VLcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 254; or ii. the VHcomprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 255, and the VLcomprises an amino acid sequence 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 1-47, wherein the antibody, or antigen binding fragment thereof, has one or more of the following characteristics: a. has increased binding affinity for human IL-1 IRa relative to that of the 340 antibody, and increased functional potency relative to that of the 340 antibody, optionally as measured by pSTAT3 inhibition in human telomerase reverse transcriptase (hTERT) cells;b. has a binding affinity for human IL-1 IRa of less than about 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 30 pM, and optionally has increased binding affinity for human IL- 1 IRa relative to that of the TS7 and 8E2 antibodies; c. antagonizes the binding and / or signaling activity between IL-1 IRa and IL-11, and optionally has increased potency as an IL-11 signaling antagonist relative to that of the TS7 and 8E2 antibodies; d. reduces IL-1 lRa / gpl30 dimerization or complex formation, optionally in a cellbased assay; and / or e. has reduced N-linked glycosylation in VLCDR3, optionally relative to the TS7 and 8E2 antibodies.

49. The method of any one of claims 1-48, wherein the antibody, or antigen binding fragment thereof, comprises an IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, 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 with high effector function in humans, optionally an IgGl 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 IgGl or IgG4 Fc domain, optionally selected from Table Fl.

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

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

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

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

57. The method of any one of claims 1-56, wherein the composition has reduced or undetectable heterogeneity of N-linked glycosylation (optionally relative to the TS7 and 8E2 antibodies), optionally in the VLCDR3 sequence.

58. The method of any one of claims 1-57, 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 1-58, 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 upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), 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).

61. The method of claim 59 or 60, wherein the administering the pharmaceutical composition to the patient improves the Clinical Activity Score (CAS) of the patient, 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 59-61, wherein the administering the pharmaceutical composition to the patient improves the VISA score of the patient, optionally by at least one,two, three, four, or five points, optionally to a VISA or 4 or less, 3 or less, 2 or less, or 1 or less.

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

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

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