Dosing of Anti-il-11rα antibodies in the treatment of thyroid eye disease

Abstract

Provided are methods of treating thyroid eye disease (TED) comprising administering an antibody that binds to human interleukin-11 receptor subunit α (IL-11Rα) and related compositions.

Description

DOSING OF ANTI-IL-1 IRa ANTIBODIES IN THE TREATMENT OF THYROIDEYE DISEASECROSS REFERENCE TO RELATED APPLCATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 657,751, filed on June 7, 2024, the content of which is incorporated by reference herein in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (LASS_010_01WO_SeqList_ST26.xml; Size: 93,637 bytes; and Date of Creation: June 2, 2025) are herein incorporated by reference in its entirety.BACKGROUND

[0003] 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 the initiation and maintenance of fibro-inflammation in disease settings. Thus, IL-11 signaling inhibitors represent a promising therapeutic approach for treating a variety of diseases, including fibro-inflammatory diseases, autoimmune diseases, chronic fibrotic diseases, and cancers.

[0004] Thyroid eye disease (TED), also known as Graves’ ophthalmopathy, is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos) (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 insulinlike 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

[0005] The present disclosure relates to methods of treating thyroid eye disease (TED) by administering an antibody that binds to human interleukin- 11 receptor subunit a (IL-1 IRa).Aspects of the disclosure provide dosing parameters for treating TED in a human subject using an IL-1 IRa antibody of the disclosure.

[0006] In one aspect provided herein is a method of treating thyroid eye disease (TED) in a human subject in need thereof, comprising administering to the subject one or more dose(s) of about 25mg to about 1500mg per dose of an antibody which binds to human interleukin- 11 receptor subunit a (IL-1 IRa). In some embodiments, the IL-1 IRa antibody comprises a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3 selected form table 1. In some embodiments, the IL-1 IRa antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL) selected from table 2 or a sequence with at least 70% thereto. In some embodiments, the antibody comprises a heavy chain (HC) and a light chain (LC) selected from table 3 or a sequence with at least 70% identity thereto.

[0007] In some embodiments, the IL- 1 IRa antibody is a full-length antibody or an antibody fragment.

[0008] In some embodiments, the IL-1 IRa antibody comprises an Fc domain. In some embodiments, the Fc domain is selected form the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence. In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In some embodiments, the Fc domain comprises one or more amino acid substitutions. In some embodiments, the one or more amino acid substitutions comprises a S228P substitution, wherein the position number of the amino acid residue is of the EU numbering scheme. In some embodiments, the one or more amino acid substitutions extend the IL- 1 IRa antibody’s half-life. In some embodiments, the one or more amino acid substitutions are selected from the group consisting of M252Y, S254T, and T256E substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the one or more amino acid substitutions are selected from the group consisting of M428L and N434S substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the one or more amino acid substitutions are selected from the group consisting of L234A, L235A, and P329S substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0009] In some embodiments, the dose of the IL- 1 IRa antibody is about 25 mg, about 100 mg, about 300 mg, about 600 mg, about 1200 mg, or about 1500 mg per dose. In some embodiments, the dose is administered daily, weekly, about every two weeks, about every three weeks, about every four weeks, every month, or every two months. In someembodiments, the dose is administered intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, through inhalation, or through an on-body device or infuser. In some embodiments, the dose is administered intravenously. In some embodiments, the dose is administered subcutaneously. In some embodiments, the dose is achieved by at least 2 to about 5 administrations. In some embodiments, the dose is administered at a volume of about 1 mL, about 2 mL, about 3 mL or about 4 mL. In some embodiments, the dose is administered at a volume of about 1 mL to about 25 mL. In some embodiments, a dose of about 300 mg is administered intravenously to the subject at a volume of about 60 mL about every four weeks. In some embodiments, a dose of about 600 mg is administered intravenously to the subject at a volume of about 60 mL about every four weeks.

[0010] In some embodiments, the dissociation constant (KD) of the IL-1 IRa antibody to human IL-1 IRa is less than about 50 pM. In some embodiments, the IL-1 IRa antibody does not bind to mouse IL-1 IRa or rat IL-1 IRa. In some embodiments, the IL-1 IRa antibody inhibits IL-11 induced phosphorylation of STAT3. In some embodiments, the IL-1 IRa antibody inhibits IL-11 induced phosphorylation of ERK. In some embodiments, the IL- 1 IRa antibody inhibits the proliferation of orbital fibroblasts stimulated with IL-11. In some embodiments, the IL- 1 IRa antibody inhibits hyaluronan secretion from orbital fibroblasts stimulated with IL-11, IGF- 1 or both. In some embodiments, the IL- 1 IRa antibody inhibits IL-11 stimulated pSTAT3 and HA release by orbital fibroblasts. In some embodiments, the IL- 1 IRa antibody inhibits procollagen secretion from orbital fibroblasts stimulated with TGFp. In some embodiments, the TED is associated with hyper-thyroidism. In some embodiments, the TED is associated with hypo-thyroidism. In some embodiments, the TED is associated with euthyroidism. In some embodiments, the hyper-thyroidism is due to Graves' disease.

[0011] In some embodiments, an additional TED therapy is administered during a course of treatment with the IL- 1 IRa antibody. In some embodiments, the additional TED therapy is administered concurrently with the administration of the IL- 1 IRa antibody. In some embodiments, the additional TED therapy is administered after the administration of the IL- 1 IRa antibody. In some embodiments, the additional TED therapy is administered prior to the administration of the IL-1 IRa antibody. In some embodiments, the additional TED therapy is selected from the group consisting of insulin-like growth factor-1 receptor (IGF- lR)-inhibitor therapy, FcRn-inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, steroidtherapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)-inhibitor therapy, interleukin- 17 (IL- 17) inhibitor therapy, and CD-40L inhibitor therapy. In some embodiments, the IGF-lR-inhibitor therapy is selected from teprotumumab, VRDN-001, VRDN-003, Lonigutamab, Linsitinib, a biosimilar of any one of the preceding, and any other IGF-1R targeted therapy. In some embodiments, the IGF-lR-inhibitor therapy is administered 1 to about 2 times, 1 to about 3 times, 1 to about 4 times, 1 to about 5 times, 1 to about 6 times, or 1 to about 7 times during the course of treatment with the IL- 1 IRa antibody. In some embodiments, teprotumumab or other targeted IGF-1R targeted agent is administered during the course of treatment with the IL- 1 IRa antibody according to Figure 39. In some embodiments, the FcRn-inhibitory therapy is selected from the group consisting of batoclimab (IMVT-1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, and any other FcRn targeted therapy. In some embodiments, the IL-6 inhibitor therapy is selected from the group consisting of TOUR006, satralizumab, clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy. In some embodiments, the steroid therapy is selected from the group consisting of methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy. In some embodiments, the CD20-inhibitor therapy is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy. In some embodiments, the TNF-a-inhibitor therapy is selected from the group consisting of adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0012] In another aspect provided herein is a bispecific antibody comprising: a first antigen binding arm that specifically binds to IL- 1 IRa, comprising a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3 selected from table 1 and a second antigen binding arm that specifically binds to an TED associated antigen.

[0013] In some embodiments, the first antigen binding arm comprises a heavy chain variable region (VH) and a light chain variable region (VL) selected from table 2 or a sequence with at least 70% thereto. In some embodiments, the TED associated antigen is selected from the group consisting of insulin-like growth factor-1 receptor (IGF-1R), IGF-1, FcRn, interleukin- 6 (IL-6), IL-6R, CD20, tumor necrosis factor-a (TNF-a), TNFR1, TNFR2, interleukin- 17 (IL-17), IL-17R, CD-40, and CD-40L. In some embodiments, the second antigen binding arm comprises a VH and a VL sequence derived from an antibody selected from the group consisting of teprotumumab, VRDN-001, VRDN-003, Lonigutamab, batoclimab (IMVT-1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, TOUR006, satralizumab clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, tocilizumab, ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, ublituximab, adalimumab, certolizumab, golimumab, and infliximab.

[0014] In another aspect provided herein is an antibody-drug conjugate (ADC) comprising an antibody that specifically binds to IL-1 IRa, wherein the antibody comprising a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3 selected from table 1, a linker; and a therapeutic drug. In some embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL) selected from table 2 or a sequence with at least 70% identity thereto. In some embodiments, the TED therapeutic drug is selected from the group consisting of nintedanib, pirfenidone, TGFP inhibitors (e.g. galunisertib), ROCK inhibitors (e.g. belumosidil), PI3K / mTOR inhibitors (e.g. omipalisib), and (Src inhibitors e.g. saracatinib). In some embodiments, the linker is a cleavable linker.BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 shows IL-11 expression in TED patient derived orbital fibroblasts resulting from qPCR. Data were from 2 control and 5 TED donors.

[0016] FIG. 2 shows a summary chart of mAb5 binding, potency, and TED efficacy data.

[0017] FIG. 3 shows HA release and cell proliferation in TED patient derived orbital fibroblasts after treatment with 1.1, 3.3, and lO ng / mL IL- 11, which is reversed by 10 pg / mL mAb5. Data were from 4 independent experiments using cells from 3 TED donors.

[0018] FIG. 4 shows pSTAT3 and HA production from TED patient derived orbital fibroblasts treated with IL-11 (10 ng / mL) and escalating concentrations of mAb5 (0.001 - 10 pg / mL). Data were from 4-6 donors in duplicate.

[0019] FIG. 5 shows HA production from TED patient derived orbital fibroblasts treated with IGF-1 (100 ng / mL) and escalating doses of teprotumumab biosimilar (Tepro) (1 - 100 pg / mL). #### p<0.0001 vs Veh. : ***p<0.001. ****p<0.0001 vs IGF-1 alone by one way ANOVA w / Dunnett’s post-test.

[0020] FIG. 6 shows HA production in TED patient derived orbital fibroblasts treated with IL-11 (10 ng / mL) and escalating doses of mAb5 (1 - 10 pg / mL) or Tepro (10 pg / mL). Data were from n=22 donors; #### p<0.0001 vs Veh ; ****p<0.0001 vs. Isotype alone by one way ANOVA w / Dunnett’s post-test.

[0021] FIG. 7 shows a depiction of IL-11 signaling and pSTAT3 activation / HA release in response to treatment with IL-11 (10 ng / mL), which is attenuated by mAb5 (1 - 10 pg / mL) but not Tepro (10 pg / mL). Data were from n=7-8 TED donors run in duplicate, ****p<0.0001. **p<0.01 vs IL-11; #### p<0.0001 vs Veh by one way ANOVA w / Dunnett’s post-test.

[0022] FIG. 8 shows cell proliferation in TED patient derived orbital fibroblasts treated with IL-11 (10 ng / mL). Proliferation was reversed by either treatment with mAb5 (10 pg / mL) or Tepro (10 pg / mL). Data were from n=7 donors; ####, p<0.0001 versus vehicle; **** p<0.0001 versus isotype control using a one-way ANOVA with Dunnett’s post-test.

[0023] FIG. 9 shows HA production in response to 100 ng / mL IGF-1 treatment and subsequent attenuation with mAb5 (3 pg / mL) or Tepro (10 pg / mL). Data were from n=3 donors analyzed in duplicate. #### p<0.0001, ###p<0.001 vs Veh.,** p<0.01, *** p<0.001 vs IGF-1, by one way ANOVA w / Dunnett’s post-test.

[0024] FIG. 10 shows HA production in response to 100 ng / mL IGF-1 and 10 ng / mL IL-11 co-treatment and subsequent attenuation with mAb5 (1 - 10 pg / mL) or Tepro (10 pg / mL). Data were from n=20 donors; #### p<0.0001 vs Veh; * p<0.05, ** p<0.01 vs. Isotype alone by one way ANOVA w / Dunnett’s post-test.

[0025] FIG. 11 shows cell proliferation in TED patient derived orbital fibroblasts treated with IL-11 (10 ng / mL) and IGF-1 (100 ng / mL). Proliferation was reduced by either treatment with mAb5 (10 pg / mL) or Tepro (10 pg / mL), * p<0.05, **p<0.01 vs Isotype; #### p<0.0001 vs Veh by one way ANOVA w / Dunnett’s post-test.

[0026] FIG. 12 shows the combinatory effect of mAb5 / Tepro on IL-11 and IGF-1 induced HA production. FIG. 12 (left) shows a depiction of IL-11 / IGF-l signaling leading to HA release. FIG. 12 (right) shows HA production in response to treatment with IL-11 and IGF-1 which is attenuated by co-treatment with mAb5 and Tepro in a dose dependent manner, greater than either treatment alone. Data were from n>8 donors from 2 separate studies. #### p<0.0001 vs Veh., *** p<0.001; ****p<0.0001 vs IGF-1 + IL-11, <Dp<0.05 vs. Tepro + mAb5 combo by one way ANOVA w / Dunnett’s post-test.

[0027] FIG. 13 shows the combinatory effect of mAb5 and Tepro on cell proliferation after stimulation with IL-11 + IGF-1 in orbital fibroblasts. Data from n = 5 donors, analyzed in duplicate. ### p<0.001 vs Veh. * p<0.01 vs IGF-1 + IL-11, 4> p<0.01 vs mAb5 alone, a p<0.05 vs Tepro alone by one way ANOVA w / Dunnett’s post-test. IGF-1 100 ng / mL, IL-11 10 ng / mL, Tepro 10 pg / mL.

[0028] FIG. 14 shows the ability of mAb5 to inhibit TGFP-induced procollagen secretion in TED patient derived orbital fibroblasts. Data from n= 6 donors, ### p<0.001 vs Vehicle; **p<0.01 vs TGFP by one way ANOVA w / Dunnett’s post-test; TGFP at 5 ng / mL, mAb5 at 3 pg / mL; Tepro at 10 pg / mL.

[0029] FIG. 15 shows the ability of mAb5 to inhibit IL-11+TGFP-induced procollagen secretion in TED patient derived orbital fibroblasts. Data from n= 6 donors, ## p<0.01 vs Vehicle; **p<0.01 vs TGFP+ IL-11 by one way ANOVA w / Dunnett’s post-test; TGFP at 5 ng / mL, mAb5 at 3 pg / mL; Tepro at 10 pg / mL.

[0030] FIG. 16 shows the correlation between TGFP -stimulated IL-11 release and procollagen I production.

[0031] FIG. 17 shows a heatmap of additional cytokines produced in TED patient derived orbital fibroblasts by IGF-1 + IL-11, using a custom cytokine multi -plex assay (Eve Technologies, Calgary, CA.) with and without additional treatments with mAb5 (10 pg / mL) and Tepro (10 pg / mL). Data from 6-7 donors.

[0032] FIG. 18 shows the ability of mAb5 to block BAFF and Granzyme B release from orbital fibroblasts. Data from n=7 donors, # p<0.05 versus Veh; ** p<0.01, ****p<0.0001 vs IGF-1 + IL-11 + isotype control by one way ANOVA w / Dunnett’s post-test; IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL, mAb5 at 10 pg / mL and Tepro at 10 pg / mL.

[0033] FIG. 19 shows the ability of mAb5 to Block IL-6, IL-8 and MCP-1 release from orbital fibroblasts. Data from n=7 donors; # p<0.05 versus Veh; ** p<0.01, ****p<0.0001 versus IL-11 + IGF-1 + isotype control by one way ANOVA w / Dunnett’s post-test; IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL, mAb5 at 10 pg / mL and Tepro at 10 pg / mL.

[0034] FIG. 20 shows the ability of mAb5 to reduce MCP-1 release from orbital fibroblasts after stimulation with IGF-1, IL-11 and in combination. Data from n=7 donors; # p<0.05. ## p<0.01 versus Veh; ***p<0.001 vs IL-11 + isotype control by one way ANOVA w / Dunnett’s post-test; IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL, mAb5 at 10 pg / mL and Tepro at 10 pg / mL.

[0035] FIG. 21 shows the variability of donors exhibiting MCP-1 responses to combination treatment; mAb5 inhibits MCP-1 in responsive donors. Data from n=3 donors, IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL, mAb5 at 0.3, 1, 3, 10 pg / mL.

[0036] FIG. 22 shows the ability of mAb5 to reduce IL-6 release from orbital fibroblasts after stimulation with IGF-1, IL-11 and in combination. Data from n=7 donors; # p<0.05 versus Veh; * p<0.05, vs IL-11 + isotype control by one way ANOVA w / Dunnett’s post-test; IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL, mAb5 at 10 pg / mL and Tepro at 10 pg / mL.

[0037] FIG. 23 shows the variability of donors exhibiting IL-6 responses to mAb5 treatment; mAb5 inhibits IL-6 in responsive donors. Data from n=3 donors, IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL, mAb5 at 0.3, 1, 3, 10 pg / mL.

[0038] FIG. 24 shows the ability of mAb5 to block IL-6 release in orbital fibroblasts.

[0039] FIG. 25 shows a lack of IL-6 mediated HA release in orbital fibroblasts and confirmation of IL-6 pathway activation in TED patient derived orbital fibroblasts.

[0040] FIG. 26 shows a lack of IL-6 mediated HA release in orbital fibroblasts. Data from n=8 donors analyzed in duplicate; IL-11 lOng / mL; IL-6 100 ng / mL; Tepro 10 pg / mL; mAb5 3 pg / mL; Tocilizumab 10 pg / mL.

[0041] FIG. 27 demonstrates that mAb5 blocks M22 stimulated HA in “responsive” donors (M22 stimulates HA very weakly). Data from n=3 M22 responsive donors at day 4. M22 at 45 pg / mL, mAb 5 at 1 and 10 pg / mL

[0042] FIG. 28 shows a western blot depicting IL-11 and IGF-1 additive signaling through PI3K / AKT, that is reduced by mAb5. Data from n=4 donors at 15-minute timepoint; ## p<0.01 versus Veh by one way ANOVA w / Dunnett’s post-test; IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL.

[0043] FIG. 29 shows a western blot depicting IL-11 and IGF-1 additive signaling through ERK which is significantly inhibited by mAb5. Data from n=5 donors at 15-minute timepoint; # p<0.05; ## p<0.01 versus Veh; * p<0.05; ** p<0.01 vs IGF-1 + IL-11 by one way ANOVA w / Dunnett’s post-test; IL-11 at 10 ng / mL, IGF-1 at 100 ng / mL.

[0044] FIG. 30A-C shows attenuation of HA secretion by a PI3K / AKT inhibitor and mTOR inhibitor but not by a MEKZERK inhibitor. Data from n=6 donors; # # p<0.01, #### p<0.0001 versus Veh; ** p<0.01, *** p<0.001, ****p<0.0001 vs IGF-1 + IL-11 by one way ANOVA w / Dunnett’s post-test; IL- 11 at 10 ng / mL, IGF-1 at 100 ng / mL.

[0045] FIG. 31 shows a summary schematic of the human PK and safety study.

[0046] FIG. 32 shows mAb5 serum concentrations at the indicated doses for the single ascending dose (SAD) (FIG. 32, left) and multiple ascending dose (MAD) (FIG. 32, right) studies.

[0047] FIG. 33 shows a hyper IL- 11 -induced pSTAT3 activity in monocytes at each sampling timepoint by treatment regimen in subjects the MAD study.

[0048] FIG. 34 shows a hyper IL- 11 -induced pSTAT3 activity in monocytes at each sampling timepoint by treatment regimen in subjects the SAD study.

[0049] FIG. 35 shows the relationship between hyper IL-11 induced pSTAT3 activity in monocytes and mAb5 serum concentrations (pooled data from the SAD and MAD studies).

[0050] FIG. 36 shows a summary chart of the healthy volunteer SAD / MAD safety data.

[0051] FIG. 37 shows a summary schematic of the human TED efficacy study.

[0052] FIG. 38 shows the dosing scheme of the human TED efficacy study.

[0053] FIG. 39 depicts an example of a weekly administration protocol of an IL-1 IRa antibody of the disclosure administered in IGF-1R inhibitor therapy (e.g. teprotumumab biosimilar).

[0054] FIGS. 40A-40G shows subcutaneous dosing ranges translated from PK simulations. 40A shows a table comparing SC dosing regimens at different IV dose equivalents. FIG. 40B shows a table outlining acceptable SC dosing limits. FIG. 40C-40E show PK simulation summary tables comparing SC doses to 300 mg IV doses. FIG. 40F shows alternative SC dosing regimens across different dosing intervals and bioavailability assumptions. FIG. 40G shows a PK simulation summary table comparing SC doses to 600 mg IV a dose.DETAILED DESCRIPTIONDefinitions

[0055] Where elements are presented in a list format (e.g., in a Markush group), it should be understood that each possible subgroup of the elements is also disclosed, and that any one or more elements can be removed from the list or group.

[0056] It should be understood that, unless clearly indicated, in any method described or disclosed herein that includes more than one act, the order of the acts is not necessarily limited to the order in which the acts of the method are recited, but the disclosure encompasses exemplary embodiments in which the order of the acts is so limited.

[0057] The terms used throughout the specification are defined as follows unless otherwise limited in specific instances. As used in the specification and the claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. All technical and scientific terms, acronyms, and abbreviates used in the specification and claims have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains, unless defined or stated otherwise. All numerical ranges are inclusive of the values defining the range as well as all integer values in between, unless indicated or defined otherwise.

[0058] The term antibody as used herein throughout is used in the broadest sense and includes a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, non-human antibody, chimeric antibody, a monovalent antibody, full-length antibody, and an antibody fragment.

[0059] In some embodiments, the IL- 1 IRa antibodies provided herein are antibody fragments, retaining IL- 1 IRa antigen binding specificity. In some embodiments, the antibody fragments are antigen -binding fragments (Fab), variable fragments (Fv) containing heavy chain variable region (VH) and light chain variable region (VL) sequences, single chain variable fragments (scFv) containing VH and VL sequences linked together in one chain, single chain antibody fragments (scAb) or other antibody variable region fragments, such as Fab’, F(ab’)2, dsFv diabody, and Fd polypeptide fragments.

[0060] The term full-length antibody refers to an antibody having a structure substantially similar to a native antibody structure comprising a tetrameric polypeptide, wherein the tetrameric polypeptide comprises two heavy chain polypeptides consisting of an N-terminal to a C-terminal direction of a heavy chain variable domain (VH), constant heavy chain domain 1 (CHI), hinge region (HR), and a fragment crystallizable (Fc) region comprising a constant heavy chain domain 2 (CH2) and a constant heavy chain domain 3 (CH3), abbreviated as VH-CH1-HR-CH2-CH3; and two light chain polypeptides consisting of an N- terminal to a C-terminal direction of a light chain variable domain (VL) and a constant light chain domain (CL), abbreviated VL-CL. The light chain polypeptide may be either a K (kappa) or (lambda) classification.

[0061] In exemplary embodiments, the IL- 1 IRa antibodies provided herein are monoclonal antibodies. In exemplary embodiments, the IL- 1 IRa antibodies provided herein are human antibodies. In exemplary embodiments, the IL- 1 IRa antibodies provided herein are monoclonal human antibodies. In other exemplary embodiments, the IL-1 IRa antibodies provided herein are humanized antibodies.

[0062] 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. Epitopescan be contiguous or non-contiguous in relation to the primary structure of the antigen, for example, an IL- 1 IRa polypeptide.

[0063] 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 or other amino acid in the antibody variable region. 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.

[0064] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.I. IL-1 IRa Antibodies

[0065] Provided herein are antibodies that bind to IL- 1 IRa, and methods of treating TED using such antibodies. The antibodies may be useful for treating TED by blocking IL-11 mediated signaling.

[0066] The antibodies that bind to IL-1 IRa may be interchangeably referred to herein as IL- 1 IRa antibodies, anti-IL-1 IRa antibodies, IL-1 IRa-directed antibodies and the like.

[0067] In some embodiments, the antibody binds human IL-1 IRa. In some embodiments, the antibody binds to a fibronectin type-III domain of human IL-1 IRa. In some embodiments, the antibody antagonizes the binding and / or signaling activity between IL- 1 IRa and IL-11. In some embodiments, IL-1 IRa antibody prevents assembly of the IL-11 / IL-l 1R signaling complex with gpl30. In some embodiments, the IL-1 IRa antibody does not bind mouse IL- 1 IRa. In some embodiments, the IL-1 IRa antibody does not bind rat IL-1 IRa. In some embodiments, the IL- 1 IRa antibody does not bind mouse or rat IL- 1 IRa.

[0068] In some embodiments, the Fc domain of an IL- 1 IRa antibody of the disclosure comprises one or more Fc amino acid substitutions. In some embodiments, the Fcsubstitutions increase the half-life of the IL-1 IRa antibody. In some embodiments, the Fc substitutions include M252Y, S254T, and / or T256E wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc substitutions include M428L and / or N434S wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc substitutions include L234A, L235A, and / or P329S wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0069] In some embodiments, the IL-1 IRa antibodies of the disclosure contain an Fc domain. In some embodiments, the Fc domain (interchangeably referred to as a Fc sequence, Fc region, or simply Fc) of the IL-1 IRa antibodies is a human Fc domain. In some embodiments, the Fc domain of the IL-1 IRa antibodies is human IgGl, human IgG2, human IgG3, or human IgG4.

[0070] In some embodiments, the Fc domain of the IL- 1 IRa antibodies of the disclosure is a human IgGl Fc sequence. An exemplary, but non-limiting, sequence of heavy chain constant regions of human IgGl encompassing Fc domains of interest are provided as SEQ ID NO: 1.ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1)

[0071] In some embodiments, the Fc domain of an IL- 1 IRa antibody of the disclosure is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 1) containing one or more Fc amino acid substitutions. In some embodiments, the Fc substitutions increase the half-life of the IL-1 IRa antibody. In some embodiments, the Fc substitutions include M252Y, S254T, and / or T256E wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc substitutions include M428L and / or N434S wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc substitutions include L234A, L235A, and / or P329S wherein the position numbers of the amino acid residues are of the EU numbering scheme. In exemplary embodiments, the Fc substitutions include L234A, L235A, P329S, M252Y, S254T, and T256E.

[0072] The EU numbering scheme is one of many available antibody numbering schemes based on the residue numbers assigned to a canonical antibody sequence. Accordingly, askilled artisan would understand that reference to a particular residue using the EU numbering scheme may or may not be exactly the residue in one of the IL- 1 IRa antibodies of the disclosure. For example, if an IL-1 IRa antibody of the disclosure comprises a M428L substitution in the Fc, wherein the position number of the amino acid residue is of the EU numbering scheme, the residue may not be the actual residue 428 in that particular IL-1 IRa antibody. It may be actual residue number 427, or 428, or 429, or others. Accordingly, a skilled artisan will understand how to correspond the recited residue using the EU numbering scheme, to the actual residue in an IL-1 IRa antibody of the disclosure. The EU numbering system for antibodies is known in the art and is described, for example, at imgt.org / IMGT S ci entifi cChart / Numb ering / Hu IGHGnb er . html .

[0073] In some embodiments, the Fc domain of the IL- 1 IRa antibodies of the disclosure is a human IgG4 Fc sequence. An exemplary, but non-limiting, sequence of heavy chain constant region of human IgG4 encompassing Fc domain of interest is provided as SEQ ID NO: 2. SEQ ID NO: 2 provides the canonical human IgG4 heavy chain constant region sequence. SEQ ID NO: 3 provides the canonical human IgG4 heavy chain constant region sequence with an S228P substitution wherein the position numbers of the amino acid residues are of the EU numbering scheme.ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD HKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:2)ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD HKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:3)

[0074] In some embodiments, the Fc domain of an IL- 1 IRa antibody of the disclosure is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 2) containing one or more Fc amino acid substitutions. An exemplary, but non-limiting, sequence of heavy chain constant region of human IgG4 encompassing Fc domain of interest with an Fc amino acid substitution is provided as SEQ ID NO: 3. In some embodiments, the Fc substitutions increase the half-life of the IL- 1 IRa antibody. In some embodiments, the Fc substitutions include M252Y, S254T, and / or T256E wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc substitutions include M428L and / or N434S wherein the position numbers of the amino acid residues are of the EUnumbering scheme. In some embodiments, the Fc substitutions include L234A, L235A, and / or P329S wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc substitutions include S228P wherein the position numbers of the amino acid residues are of the EU numbering scheme. In exemplary embodiments, the Fc substitutions include S228P, M252Y, S254T, and T256E.

[0075] In some embodiments, the IL- 1 IRa antibodies of the disclosure contain a light chain constant domain. In some embodiments, the light chain constant domain of the IL-1 IRa antibodies is a human K (kappa) or human (lambda) constant domain sequence. An exemplary, but non-limiting, sequence of a human K (kappa) constant domain sequence is provided as SEQ ID NO: 4.RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 4)A. Exemplary IL-llRa Antibodies - Complementarity Determining Region (CDR) Sequences

[0076] Provided herein are sequences for exemplary IL- 1 IRa antibodies of the disclosure. As referred below, a light chain variable (VL) domain CDR1 region is referred to as LCDR1; a VL CDR2 region is referred to as LCDR2; a VL CDR3 region is referred to as LCDR3; a heavy chain variable (VH) domain CDR1 region is referred to as HCDR1; a VH CDR2 region is referred to as HCDR2; and a VH CDR3 region is referred to as HCDR3. Table 1 provide exemplary CDR triplets for the light chains and heavy chains of IL- 1 IRa antibodies of the disclosure.

[0001] Table 1: Exemplary IL-llRa antibody CDR Combinations

[0077] In some embodiments, the IL-1 IRa antibodies of the disclosure comprise 1, 2, 3, or 4 modifications to any one of the CDRs presented in the CDR sequence combinations of Table 1.

[0078] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0079] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0080] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0081] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0082] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0083] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0084] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0085] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0086] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0087] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0088] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0089] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0090] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0091] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0092] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 22, respectively;

[0093] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0094] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0095] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0096] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0097] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0098] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0099] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0100] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0101] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0102] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0103] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0104] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0105] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0106] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0107] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0108] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively; or

[0109] In some embodiments, the IL- 1 IRa antibody of the disclosure comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 40, 9, and 10, respectively.B. Exemplary IL-1 IRa Antibodies - Variable Region Sequences

[0110] The term variable region and variable domain are used interchangeably and refer to the portions of the light and heavy chains of an antibody that include the complementarity determining regions and framework regions (FRs).[OHl] Table 2 provides amino acid sequences for the variable domains of exemplary IL- 1 IRa antibodies of the disclosure. Accordingly, in some embodiments an IL-1 IRa antibody of the disclosure comprises a variable heavy chain (VH) comprising an amino acid sequence of any VH sequence listed in Table 2 or at least 70% sequence identity thereto. In some embodiments an IL-1 IRa antibody of the disclosure comprises a variable light chain (VL) comprising an amino acid sequence of any VL sequence listed in Table 2 or at least 70% sequence identity thereto. In some embodiments an IL- 1 IRa antibody of the disclosure comprises a variable heavy chain (VH) comprising an amino acid sequence of any VH sequence listed in Table 2 or at least 70% sequence identity thereto; and comprises a variable light chain (VL) comprising an amino acid sequence of any VL sequence listed in Table 2 or at least 70% sequence identity thereto.

[0112] In some embodiments, an IL-1 IRa antibody of the disclosure comprises the combination of VH / VL variable chain sequences as presented in Table 2.Table 2: Exemplary Variable Heavy Chain and Variable Light Chain Amino Acid Sequences

[0113] In some embodiments, provided herein is an IL-1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0114] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43.

[0115] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0116] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43.

[0117] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0118] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43.

[0119] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0120] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0121] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0122] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0123] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0124] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0125] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0126] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 53 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0127] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54.

[0128] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0129] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 56 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0130] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0131] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0132] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0133] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0134] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0135] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 62 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0136] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0137] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0138] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0139] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0140] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0141] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0142] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0143] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.

[0144] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42.C. Exemplary IL-1 IRa Antibodies - Full-Length Heavy Chain and Light Chain Sequences

[0145] As used herein, the term heavy chain (HC) refers to a polypeptide comprising at least a heavy chain variable region with or without a leader sequence. In some embodiments, the heavy chain comprises at least a portion of a heavy chain constant region.

[0146] As used herein, the term light chain (LC) refers to a polypeptide comprising at least a light chain variable region with or without a leader sequence. In some embodiments, the light chain comprises at least part of a light chain constant region.

[0147] Table 3 provides amino acid sequences for full-length HC / LC of exemplary IL-1 IRa antibodies of the disclosure. The underlined sequence regions of Table 3 denote the signal peptide sequences. The italicized sequence regions of Table 3 denote the constant domain sequences. Accordingly, in some embodiments an IL-1 IRa antibody of the disclosure comprises a full-length HC comprising an amino acid sequence of SEQ ID NOS: 72, 74, 87, 88, or 89 or at least 70% sequence identity thereto. In some embodiments an IL-1 IRa antibody of the disclosure comprises a full-length LC comprising an amino acid sequence of SEQ ID NO: 73 or at least 70% sequence identity thereto.

[0148] In some embodiments, an IL-1 IRa antibody of the disclosure comprises the combination of full-length HC / LC sequences of mAb5 presented in Table 3. In someembodiments, an IL-1 IRa antibody of the disclosure consist of the combination of VH / VL variable chain sequences of mAb29 presented in Table 3.Table 3: Exemplary Heavy Chain and Light Chain Amino Acid Sequences

[0149] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 72, and the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73.

[0150] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibodycomprises the amino acid sequence of SEQ ID NO: 74, and the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73.

[0151] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 87 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 87, and the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73.

[0152] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 88 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 88, and the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73.

[0153] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibodycomprises the amino acid sequence of SEQ ID NO: 89, and the full-length LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73.

[0154] Table 4 provides nucleic acid sequences for full-length HC / LC of exemplary IL-1 IRa antibodies of the disclosure. The underlined sequence regions of Table 4 denote the signal peptide sequences. The italicized sequence regions of Table 4 denote the constant domain sequences. The bolded sequence regions of Table 4 denote the stop codons. Accordingly, in some embodiments an IL- 1 IRa antibody of the disclosure comprises a full-length HC comprising a nucleic acid sequence of SEQ ID NOS: 78 or 80 or at least 70% sequence identity thereto. In some embodiments an IL- 1 IRa antibody of the disclosure comprises a full-length LC comprising a nucleic acid sequence of SEQ ID NO: 79 or at least 70% sequence identity thereto.

[0155] In some embodiments, an IL-1 IRa antibody of the disclosure comprises the combination of full-length HC / LC nucleic acid sequences of mAb5 presented in Table 4. In some embodiments, an IL-1 IRa antibody of the disclosure consist of the combination of VH / VL variable chain nucleic acid sequences of mAb29 presented in Table 4.Table 4: Exemplary Heavy Chain and Light Chain Nucleic Acid Sequences

[0156] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 78 or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 79, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibody comprises the nucleic acid sequence of SEQ ID NO: 78, and the full-length LC of the antibody comprises the nucleic acid sequence of SEQ ID NO: 79.

[0157] In some embodiments, provided herein is an IL- 1 IRa antibody, wherein the full- length HC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 80 or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the full-length LC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 79, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity thereto. In some embodiments, the full-length HC of the antibody comprises the nucleic acid sequence of SEQ ID NO: 80, and the full-length LC of the antibody comprises the nucleic acid sequence of SEQ ID NO: 79.

[0158] In some embodiments, the IL- 1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 60 pM or less. In some embodiments, the IL- 1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 50 pM or less. In some embodiments, the IL-1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 40 pM or less. In some embodiments, the IL- 1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 30 pM or less. In some embodiments, the IL-1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 20 pM or less. In some embodiments, the IL- 1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 10 pM or less. In some embodiments, the IL-1 IRa antibodies of the disclosure have a measurable dissociation constant (KD) of about 1 pM or less.

[0159] In some embodiments, the IL- 1 IRa antibodies of the disclosure inhibit IL-11 induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). In some embodiments, the IL- 1 IRa antibodies of the disclosure inhibit IL-11 induced phosphorylation of extracellular signal-regulated kinase (ERK). In some embodiments, the IL- 1 IRa antibodies of the disclosure inhibit the proliferation of orbital fibroblasts stimulated with IL- 11. In some embodiments, the IL- 1 IRa antibodies of the disclosure inhibit hyaluronan (HA) secretion from orbital fibroblasts stimulated with IL-11. In some embodiments, the IL-1 IRa antibodies of the disclosure inhibit hyaluronan (HA) secretion from orbital fibroblasts stimulated with IGF-1. In some embodiments, the IL-1 IRa antibodies of the disclosure inhibit hyaluronan (HA) secretion from orbital fibroblasts stimulated with both IL-11 and IGF-1. In some embodiments, the IL-1 IRa antibodies of the disclosure inhibit both IL-11 stimulated phosphorylation of STAT3 and IL-11 stimulated HA release by orbital fibroblasts. In some embodiments, the IL- 1 IRa antibodies of the disclosure inhibit procollagen secretion from orbital fibroblasts stimulated with TGFp.D. Exemplary IL-1 IRa Antibodies - Epitope

[0160] In some embodiments, the IL- 1 IRa antibodies of the disclosure bind to a fibronectin type-III domain of human IL-1 IRa, or approximately residues 90-197 of SEQ ID NO: 85. Insome embodiments, the IL- 1 IRa antibodies bind to the second extracellular domain of IL- HRa.

[0161] In some embodiments, the IL- 1 IRa antibodies of the disclosure bind to an epitope that spans residues 115-134 in in mature IL-1 IRa. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the VH sequence of SEQ ID NO: 45, and the VL sequence of SEQ ID NO: 42. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the VH sequence of SEQ ID NO: 68, and the VL sequence of SEQ ID NO: 42.

[0162] In certain embodiments, the IL-1 IRa antibody, or antigen binding fragment thereof, binds to an epitope comprising the residues ISGLPTRYLTSYRKKTVLGA (SEQ ID NO: 86). 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: 86). In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the VH sequence of SEQ ID NO: 45, and the VL sequence of SEQ ID NO: 42. In exemplary embodiments, the antibodies of the disclosure which exhibits such binding comprises the VH sequence of SEQ ID NO: 68, and the VL sequence of SEQ ID NO: 42.Table 5. Exemplary IL-1 IRa SequencesII. Treatment of TED using IL-llRa Antibodies

[0163] Provided herein are antibodies that bind to IL- 1 IRa. The antibodies disclosed herein may be used for the treatment of TED in a subject. In some embodiments, the subject is human. The subject can be of any age.

[0164] In some embodiments, the TED is associated with hyper-thyroidism. In some embodiments, the hyper-thyroidism is associated with Graves’ disease. In some embodiments, the TED is associated with hypo-thyroidism. In some embodiments, the TED is associated with euthyroidism.A. Administration of IL-llRa Antibodies

[0165] As contemplated herein, the IL-1 IRa antibodies of the present disclosure, and pharmaceutical compositions comprising the IL-1 IRa antibodies of the present disclosure are administered for TED treatment in therapeutically effective amounts.

[0166] Administration of the IL-1 IRa antibodies of the present disclosure may be performed with any suitable pharmaceutically acceptable excipients, carriers, or other agents to provide suitable or improved tolerance, transfer, delivery, and the like.

[0167] In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once daily. In some embodiments, the IL-1 IRa antibodies of the present disclosure are administered at least once about every 2 days. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 3 days. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 4 days. In some embodiments, the IL-1 IRa antibodies of the present disclosure are administered at least once about every 5 days. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 6 days. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every week. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 2 weeks. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 3 weeks. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 4 weeks. In some embodiments, the IL-1 IRa antibodies of the present disclosure are administered at least once about every month. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 2 months. In some embodiments, the IL-1 IRa antibodies of the present disclosure are administered at least once about every 3 months. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 4 months. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 5 months. In some embodiments, the IL- 1 IRa antibodies of the present disclosure are administered at least once about every 6 months.

[0168] The administration of the IL-1 IRa antibodies of the present disclosure may be carried out intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, through inhalation, or through an on-body device or infuser. Intravenous administration may be carried out via injection or infusion. In exemplary embodiments, the IL-1 IRa antibodies of the present disclosure are administered intravenously. In other exemplary embodiments, the IL- 1 IRa antibodies of the present disclosure are administered subcutaneously.

[0169] In some embodiments, administration of the IL- 1 IRa antibodies of the present disclosure comprises administering one or more doses of the IL- 1 IRa antibody of about 25 mg, of about 50 mg, of about 75 mg, of about 100 mg, of about 150 mg, of about 200 mg, ofabout 250 mg, of about 300 mg, of about 400 mg, of about 500 mg, of about 600 mg, of about 700 mg, of about 800 mg, of about 900 mg, of about 1000 mg, of about 1100 mg, of about 1200 mg, of about 1300 mg, of about 1400 mg, or of about 1500 mg per dose.

[0170] In some embodiments, administration of the IL- 1 IRa antibodies of the present disclosure comprises administering one or more doses of the IL- 1 IRa antibody of at least about 25 mg, of at least about 50 mg, of at least about 75 mg, of at least about 100 mg, of at least about 150 mg, of at least about 200 mg, of at least about 250 mg, of at least about 300 mg, of at least about 400 mg, of at least about 500 mg, of at least about 600 mg, of at least about 700 mg, of at least about 800 mg, of at least about 900 mg, of at least about 1000 mg, of at least about 1100 mg, of at least about 1200 mg, of at least about 1300 mg, of at least about 1400 mg, or of at least about 1500 mg per dose.

[0171] In some embodiments, administration of the IL- 1 IRa antibodies of the present disclosure comprises administering one or more doses of the IL- 1 IRa antibody of about 25 mg to about 50 mg, of about 25 mg to about 75 mg, of about 25 mg to about 100 mg, of about 25 mg to about 150 mg, of about 25 mg to about 200 mg, of about 25 mg to about 250 mg, of about 25 mg to about 300 mg, of about 25 mg to about 400 mg, of about 25 mg to about 500 mg, of about 25 mg to about 600 mg, of about 25 mg to about 700 mg, of about 25 mg to about 800 mg, of about 25 mg to about 900 mg, of about 25 mg to about 1000 mg, of about 25 mg to about 1100 mg, of about 25 mg to about 1200 mg, of about 25 mg to about 1300 mg, of about 25 mg to about 1400 mg, of about 25 mg to about 1500 mg, of about 50 mg to about 75 mg, of about 50 mg to about 100 mg, of about 50 mg to about 150 mg, of about 50 mg to about 200 mg, of about 50 mg to about 250 mg, of about 50 mg to about 300 mg, of about 50 mg to about 400 mg, of about 50 mg to about 500 mg, of about 50 mg to about 600 mg, of about 50 mg to about 700 mg, of about 50 mg to about 800 mg, of about 50 mg to about 900 mg, of about 50 mg to about 1000 mg, of about 50 mg to about 1100 mg, of about 50 mg to about 1200 mg, of about 50 mg to about 1300 mg, of about 50 mg to about 1400 mg, of about 50 mg to about 1500 mg, of about 75 mg to about 100 mg, of about 75 mg to about 150 mg, of about 75 mg to about 200 mg, of about 75 mg to about 250 mg, of about 75 mg to about 300 mg, of about 75 mg to about 400 mg, of about 75 mg to about 500 mg, of about 75 mg to about 600 mg, of about 75 mg to about 700 mg, of about 75 mg to about 800 mg, of about 75 mg to about 900 mg, of about 75 mg to about 1000 mg, of about 75 mg to about 1100 mg, of about 75 mg to about 1200 mg, of about 75 mg to about 1300 mg, of about 75 mg to about 1400 mg, of about 75 mg to about 1500 mg, of about 100 mg to about 150mg, of about 100 mg to about 200 mg, of about 100 mg to about 250 mg, of about 100 mg to about 300 mg, of about 100 mg to about 400 mg, of about 100 mg to about 500 mg, of about 100 mg to about 600 mg, of about 100 mg to about 700 mg, of about 100 mg to about 800 mg, of about 100 mg to about 900 mg, of about 100 mg to about 1000 mg, of about 100 mg to about 1100 mg, of about 100 mg to about 1200 mg, of about 100 mg to about 1300 mg, of about 100 mg to about 1400 mg, of about 100 mg to about 1500 mg, of about 150 mg to about 200 mg, of about 150 mg to about 250 mg, of about 150 mg to about 300 mg, of about 150 mg to about 400 mg, of about 150 mg to about 500 mg, of about 150 mg to about 600 mg, of about 150 mg to about 700 mg, of about 150 mg to about 800 mg, of about 150 mg to about 900 mg, of about 150 mg to about 1000 mg, of about 150 mg to about 1100 mg, of about 150 mg to about 1200 mg, of about 150 mg to about 1300 mg, of about 150 mg to about 1400 mg, of about 150 mg to about 1500 mg, of about 200 mg to about 250 mg, of about 200 mg to about 300 mg, of about 200 mg to about 400 mg, of about 200 mg to about 500 mg, of about 200 mg to about 600 mg, of about 200 mg to about 700 mg, of about 200 mg to about 800 mg, of about 200 mg to about 900 mg, of about 200 mg to about 1000 mg, of about 200 mg to about 1100 mg, of about 200 mg to about 1200 mg, of about 200 mg to about 1300 mg, of about 200 mg to about 1400 mg, of about 200 mg to about 1500 mg, of about 250 mg to about 300 mg, of about 250 mg to about 400 mg, of about 250 mg to about 500 mg, of about 250 mg to about 600 mg, of about 250 mg to about 700 mg, of about 250 mg to about 800 mg, of about 250 mg to about 900 mg, of about 250 mg to about 1000 mg, of about 250 mg to about 1100 mg, of about 250 mg to about 1200 mg, of about 250 mg to about 1300 mg, of about 250 mg to about 1400 mg, of about 250 mg to about 1500 mg, of about 300 mg to about 400 mg, of about 300 mg to about 500 mg, of about 300 mg to about 600 mg, of about 300 mg to about 700 mg, of about 300 mg to about 800 mg, of about 300 mg to about 900 mg, of about 300 mg to about 1000 mg, of about 300 mg to about 1100 mg, of about 300 mg to about 1200 mg, of about 300 mg to about 1300 mg, of about 300 mg to about 1400 mg, of about 300 mg to about 1500 mg, of about 400 mg to about 500 mg, of about 400 mg to about 600 mg, of about 400 mg to about 700 mg, of about 400 mg to about 800 mg, of about 400 mg to about 900 mg, of about 400 mg to about 1000 mg, of about 400 mg to about 1100 mg, of about 400 mg to about 1200 mg, of about 400 mg to about 1300 mg, of about 400 mg to about 1400 mg, of about 400 mg to about 1500 mg, of about 500 mg to about 600 mg, of about 500 mg to about 700 mg, of about 500 mg to about 800 mg, of about 500 mg to about 900 mg, of about 500 mg to about 1000 mg, of about 500 mg to about 1100 mg, of about 500 mg to about 1200 mg, of about 500 mg to about 1300 mg, of about 500 mgto about 1400 mg, of about 500 mg to about 1500 mg, of about 600 mg to about 700 mg, of about 600 mg to about 800 mg, of about 600 mg to about 900 mg, of about 600 mg to about 1000 mg, of about 600 mg to about 1100 mg, of about 600 mg to about 1200 mg, of about 600 mg to about 1300 mg, of about 600 mg to about 1400 mg, of about 600 mg to about 1500 mg, of about 700 mg to about 800 mg, of about 700 mg to about 900 mg, of about 700 mg to about 1000 mg, of about 700 mg to about 1100 mg, of about 700 mg to about 1200 mg, of about 700 mg to about 1300 mg, of about 700 mg to about 1400 mg, of about 700 mg to about 1500 mg, of about 800 mg to about 900 mg, of about 800 mg to about 1000 mg, of about 800 mg to about 1100 mg, of about 800 mg to about 1200 mg, of about 800 mg to about 1300 mg, of about 800 mg to about 1400 mg, of about 800 mg to about 1500 mg, of about 900 mg to about 1000 mg, of about 900 mg to about 1100 mg, of about 900 mg to about 1200 mg, of about 900 mg to about 1300 mg, of about 900 mg to about 1400 mg, of about 900 mg to about 1500 mg, of about 1000 mg to about 1100 mg, of about 1000 mg to about 1200 mg, of about 1000 mg to about 1300 mg, of about 1000 mg to about 1400 mg, of about 1000 mg to about 1500 mg, of about 1100 mg to about 1200 mg, of about 1100 mg to about 1300 mg, of about 1100 mg to about 1400 mg, of about 1100 mg to about 1500 mg, of about 1200 mg to about 1300 mg, of about 1200 mg to about 1400 mg, of about 1200 mg to about 1500 mg, of about 1300 mg to about 1400 mg, of about 1300 mg to about 1500 mg, or of about 1400 mg to about 1500 mg.

[0172] In some embodiments, the subject is administered one or more priming doses. Without being held to theory or mechanism, the priming dose could act to reduce infusion reaction severity.

[0173] In some embodiments, administration of the IL- 1 IRa antibodies of the present disclosure comprises administering one or more doses of the IL- 1 IRa antibody at a volume of about 0.5mL, of about ImL, of about 2mL, of about 3mL, of about 4mL, of about 5mL, of about lOmL, of about 20mL, of about 30mL, of about 40mL, of about 50mL, of about 60mL, of about 70mL, of about 80mL, of about 90mL, or of about lOOmL per dose.

[0174] In some embodiments, administration of the IL- 1 IRa antibodies of the present disclosure comprises administering one or more doses of the IL- 1 IRa antibody at a volume of at least about 0.5mL, of at least about ImL, of at least about 2mL, of at least about 3mL, of at least about 4mL, of at least about 5mL, of at least about lOmL, of at least about 20mL, of at least about 30mL, of at least about 40mL, of at least about 50mL, of at least about 60mL,of at least about 70mL, of at least about 80mL, of at least about 90mL, or of at least about lOOmL per dose.

[0175] In some embodiments, administration of the IL- 1 IRa antibodies of the present disclosure comprises administering one or more doses of the IL- 1 IRa antibody at a volume of about 0.5 mL to about 1 mL, of about 0.5 mL to about 2 mL, of about 0.5 mL to about 3 mL, of about 0.5 mL to about 4 mL, of about 0.5 mL to about 5 mL, of about 0.5 mL to about 10 mL, of about 0.5 mL to about 20 mL, of about 0.5 mL to about 30 mL, of about 0.5 mL to about 40 mL, of about 0.5 mL to about 50 mL, of about 0.5 mL to about 60 mL, of about 0.5 mL to about 70 mL, of about 0.5 mL to about 80 mL, of about 0.5 mL to about 90 mL, of about 0.5 mL to about 100 mL, of about 1 mL to about 2 mL, of about 1 mL to about 3 mL, of about 1 mL to about 4 mL, of about 1 mL to about 5 mL, of about 1 mL to about 10 mL, of about 1 mL to about 20 mL, of about 1 mL to about 30 mL, of about 1 mL to about 40 mL, of about 1 mL to about 50 mL, of about 1 mL to about 60 mL, of about 1 mL to about 70 mL, of about 1 mL to about 80 mL, of about 1 mL to about 90 mL, of about 1 mL to about 100 mL, of about 2 mL to about 3 mL, of about 2 mL to about 4 mL, of about 2 mL to about 5 mL, of about 2 mL to about 10 mL, of about 2 mL to about 20 mL, of about 2 mL to about 30 mL, of about 2 mL to about 40 mL, of about 2 mL to about 50 mL, of about 2 mL to about 60 mL, of about 2 mL to about 70 mL, of about 2 mL to about 80 mL, of about 2 mL to about 90 mL, of about 2 mL to about 100 mL, of about 3 mL to about 4 mL, of about 3 mL to about 5 mL, of about 3 mL to about 10 mL, of about 3 mL to about 20 mL, of about 3 mL to about 30 mL, of about 3 mL to about 40 mL, of about 3 mL to about 50 mL, of about 3 mL to about 60 mL, of about 3 mL to about 70 mL, of about 3 mL to about 80 mL, of about 3 mL to about 90 mL, of about 3 mL to about 100 mL, of about 4 mL to about 5 mL, of about 4 mL to about 10 mL, of about 4 mL to about 20 mL, of about 4 mL to about 30 mL, of about 4 mL to about 40 mL, of about 4 mL to about 50 mL, of about 4 mL to about 60 mL, of about 4 mL to about 70 mL, of about 4 mL to about 80 mL, of about 4 mL to about 90 mL, of about 4 mL to about 100 mL, of about 5 mL to about 10 mL, of about 5 mL to about 20 mL, of about 5 mL to about 30 mL, of about 5 mL to about 40 mL, of about 5 mL to about 50 mL, of about 5 mL to about 60 mL, of about 5 mL to about 70 mL, of about 5 mL to about 80 mL, of about 5 mL to about 90 mL, of about 5 mL to about 100 mL, of about 10 mL to about 20 mL, of about 10 mL to about 30 mL, of about 10 mL to about 40 mL, of about 10 mL to about 50 mL, of about 10 mL to about 60 mL, of about 10 mL to about 70 mL, of about 10 mL to about 80 mL, of about 10 mL to about 90 mL, of about 10 mL to about 100 mL, of about 20 mL to about 30 mL, ofabout 20 mL to about 40 mL, of about 20 mL to about 50 mL, of about 20 mL to about 60 mL, of about 20 mL to about 70 mL, of about 20 mL to about 80 mL, of about 20 mL to about 90 mL, of about 20 mL to about 100 mL, of about 30 mL to about 40 mL, of about 30 mL to about 50 mL, of about 30 mL to about 60 mL, of about 30 mL to about 70 mL, of about 30 mL to about 80 mL, of about 30 mL to about 90 mL, of about 30 mL to about 100 mL, of about 40 mL to about 50 mL, of about 40 mL to about 60 mL, of about 40 mL to about 70 mL, of about 40 mL to about 80 mL, of about 40 mL to about 90 mL, of about 40 mL to about 100 mL, of about 50 mL to about 60 mL, of about 50 mL to about 70 mL, of about 50 mL to about 80 mL, of about 50 mL to about 90 mL, of about 50 mL to about 100 mL, of about 60 mL to about 70 mL, of about 60 mL to about 80 mL, of about 60 mL to about 90 mL, of about 60 mL to about 100 mL, of about 70 mL to about 80 mL, of about 70 mL to about 90 mL, of about 70 mL to about 100 mL, of about 80 mL to about 90 mL, of about 80 mL to about 100 mL, or of about 90 mL to about 100 mL.

[0176] In some embodiments, a dose is achieved by a plurality of administrations. Each administration may contain a partial dose, and the administrations may occur sequentially during a single dosing session or over a defined dosing period. In some embodiments, the total dose is divided evenly among administrations. For example, a dose of about 1200mg may be achieved by 4 administrations of about 300mg. In some embodiments, the dose is achieved by at least 2 to about 5 administrations. In some embodiments, the dose is achieved by at least 2 administrations. In some embodiments, the dose is achieved by at least 3 administrations. In some embodiments, the dose is achieved by at least 4 administrations. In some embodiments, the dose is achieved by at least 5 administrations.B. Pharmaceutical Compositions

[0177] The disclosure also provides pharmaceutical compositions comprising any one of the IL- 1 IRa antibodies disclosed herein, and optionally a pharmaceutical acceptable excipient or carrier. In some embodiments, the pharmaceutical composition is sterile. The pharmaceutical compositions may be formulated to be compatible with their intended routes of administration. In some embodiments, the pharmaceutical compositions of the disclosure are suitable for administration to a human subject.C. Combination Therapies

[0178] The administration of any one of the IL- 1 IRa antibodies provided herein may be in combination with one or more known drugs or treatments for diseases or conditions. In someembodiments, at least one additional TED therapy is administered during a course of treatment with the IL- 1 IRa antibody.

[0179] In some embodiments, the at least one additional TED therapy is administered prior to the administration of a single dose of the IL1 IRa antibodies of the disclosure. In some embodiments, at least one additional TED therapy is administered simultaneously to the administration of a single dose of the IL 1 IRa antibodies of the disclosure. In some embodiments, the at least one additional TED therapy is administered after the administration of a single dose of the IL 1 IRa antibodies of the disclosure. In some embodiments, at least one additional TED therapy is administered within the same composition as the IL1 IRa antibodies of the disclosure. In some embodiments, at least one additional TED therapy is administered in a separate composition as the IL 1 IRa antibodies of the disclosure. In some embodiments, the at least one additional TED therapy is administered as a loading dose. In some embodiments, the loading dose occurs for a duration of about 1 to about 6 months.

[0180] In some embodiments, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered simutaneously to the administration of a single dose of the IL1 IRa antibodies of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered prior to the administration of a single dose of the IL 1 IRa antibodies of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF- 1R targeted agent) is administered after the administration of a single dose of the IL 1 IRa antibodies of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered within the same composition as the IL1 IRa antibodies of the disclosure. In some embodiments, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered in a separate composition as the IL1 IRa antibodies of the disclosure.

[0181] In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or teprotumumab biosimilar) is administered about 1 to about 2 times during a course of treatment with the IL-1 IRa antibodies of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered about 1 to about 3 times during a course of treatment with the IL-1 IRa antibodies of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered about 1 to about 4 times during a course oftreatment with the IL-1 IRa antibodies of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered about 1 to about 5 times during a course of treatment with the IL-1 IRa antibodies of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent ) is administered about 1 to about 6 times during a course of treatment with the IL-1 IRa antibodies of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered about 1 to about 7 times during a course of treatment with the IL-1 IRa antibodies of the disclosure. In some embodiements, the IGF-1R inhibitor therapy (e.g. teprotumumab or other targeted IGF-1R targeted agent) is administered during a course of treatment with the IL- 1 IRa antibodies of the disclosure as demonstrated in FIG. 39.

[0182] The administration of the at least one additional TED therapy may be carried out intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, through inhalation, or through an on-body device or infuser.D. Bispecific antibodies

[0183] The disclosure also provides bispecific antibodies which target IL- 1 IRa and a second target antigen. The bispecific antibody of the disclosure may be generated by any known method in the art. In some embodiments, the bispecific antibody comprises a first antigen binding arm that specifically binds IL-1 IRa and a second antigen binding arm that specifically binds to a TED-associated antigen. In some embodiments, the first antigen binding arm is derived from any one of the IL-1 IRa antibodies of the disclosure.

[0184] In some embodiments, the first antigen binding arm that specifically binds to IL- 1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0185] In some embodiments, the first antigen binding arm that specifically binds to IL- 1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0186] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and10, respectively;

[0187] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and11, respectively;

[0188] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and10, respectively;

[0189] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and11, respectively;

[0190] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0191] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0192] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0193] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0194] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0195] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0196] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0197] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0198] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 22, respectively;

[0199] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0200] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0201] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0202] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0203] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0204] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0205] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0206] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0207] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0208] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0209] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0210] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0211] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0212] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0213] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0214] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively; or

[0215] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 40, 9, and 10, respectively.

[0216] In some embodiments, the first antigen binding arm that specifically binds to IL-1 IRa, comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

[0217] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0218] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0219] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0220] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0221] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0222] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0223] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0224] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0225] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0226] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0227] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0228] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0229] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0230] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0231] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0232] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0233] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0234] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0235] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0236] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0237] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0238] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0239] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0240] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0241] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0242] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0243] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0244] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0245] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0246] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0247] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0248] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0249] In some embodiments, the TED associated antigen is selected from the group consisting of insulin-like growth factor-1 receptor (IGF-1R), IGF-1, FcRn, interleukin-6 (IL- 6), IL-6R, CD20, tumor necrosis factor-a (TNF-a), TNFR1, TNFR2, interleukin- 17 (IL-17), IL-17R, CD-40, and CD-40L. In some embodiments, the second antigen binding arm comprises a VH and a VL sequence that binds insulin-like growth factor- 1 receptor (IGF-1R),IGF-1, FcRn, interleukin-6 (IL-6), IL-6R, CD20, tumor necrosis factor-a (TNF-a), TNFR1, TNFR2, interleukin- 17 (IL-17), IL-17R, CD-40, or CD-40L.In some embodiments, the second antigen binding arm comprises a VH and a VL sequence derived from an antibody selected from the group consisting of teprotumumab, VRDN-001, VRDN-003, Lonigutamab, batoclimab (IMVT-1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, TOUR006, satralizumab clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, tocilizumab, ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, ublituximab, adalimumab, certolizumab, golimumab, and infliximab.E. Antibody-drug conjugates

[0250] The disclosure also provides antibody-drug conjugates (ADCs). ADCs generally comprise: an antibody or antigen binding fragment, a small molecule drug and an optional linker coupling the antibody or antigen binding fragment and the drug. In some embodiments, the linker is a cleavable linker. In some embodiments, the ADC comprises any one of the IL- 1 IRa antibodies of the disclosure linked to a therapeutic drug. In some embodiments, the therapeutic drug is an anti-fibrotic agent. In some embodiments, the therapeutic drug is selected from the group consisting of nintedanib, pirfenidone, TGFP inhibitors (e.g. galunisertib), ROCK inhibitors (e.g. belumosidil), PI3K / mTOR inhibitors (e.g. omipalisib), and (Src inhibitors e.g. saracatinib).

[0251] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0252] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0253] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0254] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0255] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0256] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 11, respectively;

[0257] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0258] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0259] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0260] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0261] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0262] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0263] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0264] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0265] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 22, respectively;

[0266] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0267] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0268] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0269] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0270] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0271] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0272] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0273] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0274] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0275] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0276] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0277] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0278] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0279] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0280] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively;

[0281] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 8, 9, and 10, respectively; or

[0282] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 40, 9, and 10, respectively

[0283] In some embodiments, IL- 1 IRa antibody linked to the therapeutic drug, comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

[0284] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0285] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0286] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0287] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0288] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0289] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0290] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0291] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0292] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0293] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0294] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0295] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0296] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0297] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0298] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0299] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0300] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0301] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0302] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0303] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0304] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0305] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0306] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0307] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0308] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0309] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0310] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0311] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0312] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises theamino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0313] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0314] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0315] the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0316] In some embodiments, the IL- 1 IRa antibodies of the disclosure used in the ADC function as a therapeutic agent. In some embodiments, the IL- 1 IRa antibodies of the disclosure used in the ADC function as a delivery agent, delivering the conjugated drug to an IL-1 IRa expressing cell. In some embodiments, the IL-1 IRa antibodies of the disclosureused in the ADC function as both a therapeutic agent and as a delivery agent, delivering the conjugated drug to an IL- 1 IRa expressing cell.Enumerated Embodiments

[0317] The following non-limiting enumerated embodiments are provided as exemplary.

[0318] Embodiment 1. A method of treating thyroid eye disease (TED) in a human subject in need thereof, comprising administering to the subject one or more dose(s) of about 25mg to about 1500mg per dose of an antibody which binds to human interleukin- 11 receptor subunit a (IL- 1 IRa).

[0319] Embodiment 2. The method of Embodiment 1, wherein the IL-1 IRa antibody comprises a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3, wherein:

[0320] a) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0321] b) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0322] c) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0323] d) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0324] e) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0325] f) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0326] g) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0327] h) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0328] i) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0329] j) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0330] k) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0331] 1) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0332] m) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0333] n) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0334] o) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 22, respectively;

[0335] p) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0336] q) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0337] r) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0338] s) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0339] t) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0340] u) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0341] v) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0342] w) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0343] x) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0344] y) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0345] z) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0346] aa) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0347] bb) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0348] cc) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0349] dd) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0350] ee) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; or

[0351] ff) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 40, 9, and 10, respectively.

[0352] Embodiment 3. The method of Embodiment 1 or Embodiment 2, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

[0353] a) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0354] b) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0355] c) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0356] d) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0357] e) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0358] f) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0359] g) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0360] h) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0361] i) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0362] j) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0363] k) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0364] 1) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0365] m) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0366] n) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0367] o) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0368] p) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibodycomprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0369] q) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0370] r) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0371] s) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0372] t) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0373] u) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0374] v) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0375] w) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0376] x) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0377] y) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0378] z) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0379] aa) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0380] bb) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0381] cc) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0382] dd) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0383] ee) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0384] ff) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0385] Embodiment 4. The method of any one of Embodiment 1 -Embodiment 2, wherein the IL- 1 IRa antibody is a full-length antibody.

[0386] Embodiment 5. The method of any one of Embodiment 1 -Embodiment 2, wherein the IL- 1 IRa antibody is an antibody fragment.

[0387] Embodiment 6. The method of any one of Embodiment 1 -Embodiment 5, wherein the IL-1 IRa antibody comprises an Fc domain.

[0388] Embodiment 7. The method of Embodiment 6, wherein the Fc domain is selected form the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence.

[0389] Embodiment 8. The method of Embodiment 7, wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0390] Embodiment 9. The method any one of Embodiment 6-Embodiment 8, wherein the Fc domain comprises one or more amino acid substitutions.

[0391] Embodiment 10. The method of Embodiment 9, wherein the one or more amino acid substitutions comprises a S228P substitution, wherein the position number of the amino acid residue is of the EU numbering scheme.

[0392] Embodiment 11. The method of Embodiment 9 or Embodiment 10, wherein the one or more amino acid substitutions extend the IL-1 IRa antibody’s half-life.

[0393] Embodiment 12. The method of any one of Embodiment 9-Embodiment 11, wherein the one or more amino acid substitutions are selected from the group consisting of M252Y, S254T, and T256E substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0394] Embodiment 13. The method of any one of Embodiment 9-Embodiment 12, wherein the one or more amino acid substitutions are selected from the group consisting of M428L and N434S substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0395] Embodiment 14. The method of Embodiment 9, wherein the one or more amino acid substitutions are selected from the group consisting of L234A, L235A, and P329S substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0396] Embodiment 15. The method of any one of Embodiment 1 -Embodiment 14, wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:

[0397] a) the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0398] b) the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 74, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0399] c) the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 87, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0400] d) the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 88, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0401] e) the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 89, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0402] Embodiment 16. The method of any one of Embodiment 1 -Embodiment 15, wherein the antibody wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:

[0403] a) the HC of the antibody is encoded by the nucleic acid sequence of SEQ IDNO: 78 or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the LC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 79, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0404] b) the HC of the antibody is encoded by the nucleic acid sequence of SEQ IDNO: 80 or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the LC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 79, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0405] Embodiment 17. The method of any one of Embodiment 1-Embodiment 13, wherein the dose of the IL-1 IRa antibody is about 25 mg, about 100 mg, about 300 mg, about 600 mg, about 1200 mg, or about 1500 mg per dose.

[0406] Embodiment 18. The method of any one of Embodiment 1-Embodiment 16, wherein the dose is administered daily, weekly, about every two weeks, about every three weeks, about every four weeks, every month, or every two months.

[0407] Embodiment 19. The method of any one of Embodiment 1-Embodiment 17, wherein the dose is administered intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, through inhalation, or through an on-body device or infuser.

[0408] Embodiment 20. The method of any one of Embodiment 1-Embodiment 17, wherein the dose is administered intravenously.

[0409] Embodiment 21. The method of any one of Embodiment 1-Embodiment 17, wherein the dose is administered subcutaneously.

[0410] Embodiment 22. The method of any one of Embodiment 1 -Embodiment 20, wherein the dose is achieved by at least 2 to about 5 administrations.

[0411] Embodiment 23. The method of any one of Embodiment 1 -Embodiment 20, wherein the dose is administered at a volume of about 1 mL, about 2 mL, about 3 mL or about 4 mL.

[0412] Embodiment 24. The method of any one of Embodiment 1 -Embodiment 20, wherein the dose is administered at a volume of about 1 mL to about The method of any one of Embodiment 1-Embodiment 13, wherein a dose of about 300 mg is administered intravenously to the subject at a volume of about 60 mL about every four weeks.

[0413] Embodiment 25. The method of any one of Embodiment 1-Embodiment 13, wherein a dose of about 600 mg is administered intravenously to the subject at a volume of about 60 mL about every four weeks.

[0414] Embodiment 26. The method of any one of Embodiment 1-Embodiment 25, wherein the dissociation constant (KD) of the IL- 1 IRa antibody to human IL- 1 IRa is less than about 50 pM.

[0415] Embodiment 27. The method of any one of Embodiment 1-Embodiment 26, wherein the IL-1 IRa antibody does not bind to mouse IL-1 IRa or rat IL-1 IRa.

[0416] Embodiment 28. The method of any one of Embodiment 1-Embodiment 27, wherein the IL- 1 IRa antibody inhibits IL-11 induced phosphorylation of STAT3.

[0417] Embodiment 29. The method of any one of Embodiment 1-Embodiment 28, wherein the IL- 1 IRa antibody inhibits IL-11 induced phosphorylation of ERK.

[0418] Embodiment 30. The method of any one of Embodiment 1-Embodiment 29, wherein the IL- 1 IRa antibody inhibits the proliferation of orbital fibroblasts stimulated with IL-11.

[0419] Embodiment 31. The method of any one of Embodiment 1-Embodiment 30, wherein the IL- 1 IRa antibody inhibits hyaluronan secretion from orbital fibroblasts stimulated with IL-11, IGF- 1 or both.

[0420] Embodiment 32. The method of any one of Embodiment 1-Embodiment 31, wherein the IL- 1 IRa antibody inhibits IL-11 stimulated pSTAT3 and HA release by orbital fibroblasts.

[0421] Embodiment 33. The method of any one of Embodiment 1-Embodiment 32, wherein the IL- 1 IRa antibody inhibits procollagen secretion from orbital fibroblasts stimulated with TGFp.

[0422] Embodiment 34. The method of any one of Embodiment 1-Embodiment 33, wherein the TED is associated with hyper-thyroidism.

[0423] Embodiment 35. The method of any one of Embodiment 1-Embodiment 33, wherein the TED is associated with hypo-thyroidism.

[0424] Embodiment 36. The method of any one of Embodiment 1-Embodiment 33, wherein the TED is associated with euthyroidism.

[0425] Embodiment 37. The method of Embodiment 34, wherein the hyper-thyroidism is due to Graves' disease.

[0426] Embodiment 38. The method of any one of Embodiment 1-Embodiment 37, wherein an additional TED therapy is administered during a course of treatment with the IL- 11 Ra antibody.

[0427] Embodiment 39. The method of Embodiment 31, wherein the additional TED therapy is administered concurrently with the administration of the IL-1 IRa antibody.

[0428] Embodiment 40. The method of Embodiment 31, wherein the additional TED therapy is administered after the administration of the IL- 1 IRa antibody.

[0429] Embodiment 41. The method of Embodiment 31, wherein the additional TED therapy is administered prior to the administration of the IL-1 IRa antibody.

[0430] Embodiment 42. The method of any one of Embodiment 31-Embodiment 41, wherein the additional TED therapy is selected from the group consisting of insulin-like growth factor-1 receptor (IGF- lR)-inhibitor therapy, FcRn-inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, steroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)-inhibitor therapy, interleukin- 17 (IL-17) inhibitor therapy, and CD-40L inhibitor therapy.

[0431] Embodiment 43. The method of Embodiment 42, wherein the IGF-lR-inhibitor therapy is selected from teprotumumab, VRDN-001, VRDN-003, Lonigutamab, Linsitinib, a biosimilar of any one of the preceding, and any other IGF-1R targeted therapy.

[0432] Embodiment 44. The method of Embodiment 42 or Embodiment 43, wherein the IGF-lR-inhibitor therapy is administered 1 to about 2 times, 1 to about 3 times, 1 to about 4 times, 1 to about 5 times, 1 to about 6 times, or 1 to about 7 times during the course of treatment with the IL-1 IRa antibody.

[0433] Embodiment 45. The method of Embodiment 42 or Embodiment 43, wherein teprotumumab or other targeted IGF-1R targeted agent is administered during the course of treatment with the IL-1 IRa antibody according to Figure 39.

[0434] Embodiment 46. The method of Embodiment 42, wherein the FcRn-inhibitory therapy is selected from the group consisting of batoclimab (IMVT-1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, and any other FcRn targeted therapy.

[0435] Embodiment 47. The method of Embodiment 42, wherein the IL-6 inhibitor therapy is selected from the group consisting of TOUR006, satralizumab, clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.

[0436] Embodiment 48. The method of Embodiment 42, wherein the steroid therapy is selected from the group consisting of methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy.

[0437] Embodiment 49. The method of Embodiment 42, wherein the CD20-inhibitor therapy is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

[0438] Embodiment 50. The method of Embodiment 42, wherein the TNF-a-inhibitor therapy is selected from the group consisting of adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0439] Embodiment 51. A bispecific antibody comprising:

[0440] a) a first antigen binding arm that specifically binds to IL-1 IRa, comprising a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3, wherein:

[0441] i) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0442] ii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0443] iii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0444] iv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0445] v) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0446] vi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0447] vii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0448] viii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0449] ix) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0450] x) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0451] xi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0452] xii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0453] xiii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0454] xiv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0455] xv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 22, respectively;

[0456] xvi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0457] xvii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0458] xviii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0459] xix) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0460] xx) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0461] xxi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0462] xxii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0463] xxiii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0464] xxiv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0465] xxv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0466] xxvi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0467] xxvii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0468] xxviii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0469] xxix) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0470] xxx) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0471] xxxi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; or

[0472] xxxii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 40, 9, and 10, respectively; and

[0473] b) a second antigen binding arm that specifically binds to an TED associated antigen.

[0474] Embodiment 52. The bispecific antibody of Embodiment 51, wherein the first antigen binding arm comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

[0475] a) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0476] b) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0477] c) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0478] d) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0479] e) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0480] f) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with atleast 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0481] g) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0482] h) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0483] i) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0484] j) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0485] k) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0486] 1) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0487] m) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0488] n) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0489] o) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0490] p) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0491] q) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0492] r) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0493] s) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0494] t) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0495] u) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0496] v) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0497] w) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibodycomprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0498] x) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0499] y) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0500] z) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0501] aa) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0502] bb) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0503] cc) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0504] dd) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0505] ee) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0506] ff) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0507] Embodiment 53. The bispecific antibody of Embodiment 51, wherein the TED associated antigen is selected from the group consisting of insulin-like growth factor- 1 receptor (IGF-1R), IGF-1, FcRn, interleukin-6 (IL-6), IL-6R, CD20, tumor necrosis factor-a (TNF-a), TNFR1, TNFR2, interleukin- 17 (IL- 17), IL-17R, CD-40, and CD-40L.

[0508] Embodiment 54. The bispecific antibody of Embodiment 51 or Embodiment 52, wherein the second antigen binding arm comprises a VH and a VL sequence derived from an antibody selected from the group consisting of teprotumumab, VRDN-001, VRDN-003, Lonigutamab, batoclimab (IMVT-1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, TOUR006, satralizumab clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, tocilizumab, ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, ublituximab, adalimumab, certolizumab, golimumab, and infliximab.

[0509] Embodiment 55. An antibody-drug conjugate (ADC) comprising:

[0510] a) an antibody that specifically binds to IL-1 IRa, wherein the antibody comprising a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3, wherein:

[0511] i) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0512] ii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0513] iii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0514] iv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0515] v) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0516] vi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;

[0517] vii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0518] viii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0519] ix) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0520] x) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0521] xi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0522] xii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0523] xiii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0524] xiv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0525] xv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 22, respectively;

[0526] xvi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0527] xvii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0528] xviii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0529] xix) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0530] xx) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0531] xxi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0532] xxii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0533] xxiii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0534] xxiv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0535] xxv) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0536] xxvi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0537] xxvii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0538] xxviii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0539] xxix) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0540] xxx) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;

[0541] xxxi) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; or

[0542] xxxii) the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 40, 9, and 10, respectively;

[0543] b) a linker; and

[0544] c) a therapeutic drug.

[0545] Embodiment 56. The ADC of Embodiment 55, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

[0546] a) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0547] b) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0548] c) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0549] d) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0550] e) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0551] f) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,I l l79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0552] g) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0553] h) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0554] i) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0555] j) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibodycomprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0556] k) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0557] 1) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0558] m) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0559] n) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0560] o) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0561] p) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0562] q) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0563] r) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0564] s) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0565] t) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0566] u) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0567] v) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0568] w) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0569] x) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0570] y) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0571] z) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0572] aa) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibodycomprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0573] bb) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0574] cc) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0575] dd) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;

[0576] ee) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or

[0577] ff) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0578] Embodiment 57. The ADC of Embodiment 55, wherein the TED therapeutic drug is selected from the group consisting of nintedanib, pirfenidone, TGFP inhibitors (e.g. galunisertib), ROCK inhibitors (e.g. belumosidil), PI3K / mTOR inhibitors (e.g. omipalisib), and (Src inhibitors e.g. saracatinib).

[0579] Embodiment 58. The ADC of Embodiment 55 or Embodiment 56, wherein the linker is a cleavable linker.

[0580] Embodiment 59. Use of an antibody which binds to human interleukin- 11 receptor subunit a (IL- 1 IRa) in the manufacture of a medicament for treating thyroid eye disease (TED) in a human subject in need thereof, wherein the antibody is administered to the subject in one or more dose(s) of about 25 mg to about 1500 mg per dose.

[0581] Embodiment 60. An antibody which binds to human interleukin- 11 receptor subunit a (IL- 1 IRa) for use in the treatment of thyroid eye disease (TED) in a human subject in need thereof, wherein the antibody is administered to the subject in one or more dose(s) of about 25 mg to about 1500 mg per dose.

[0582] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.EXAMPLESExample 1: mAb5 Characterization in TED patient derived orbital fibroblasts

[0583] To assess the potential of IL-11 pathway inhibition as a treatment for TED, human orbital fibroblasts were freshly isolated from orbital decompression tissue and used to study the effects of mAb5. Initial qPCR experiments confirmed that IL-11 gene expression was increased in orbital fibroblasts from TED donors (FIG. 1).

[0584] mAb5 (SEQ ID NOS: 72 and 73 of Table 3) binding, potency and efficacy in TED patient derived orbital fibroblasts were characterized as summarized in FIG. 2.

[0585] The effects of these treatments on hyaluronic acid (HA) release and cell proliferation, two events that are linked to TED pathogenesis, were measured. As shown in FIG. 3, (left), recombinant IL-11 stimulated a dose-dependent increase in HA release from orbital fibroblasts, and this was inhibited by mAb5 at all IL-11 doses. Similarly, as shown in FIG. 3, (right), recombinant IL-11 stimulated fibroblast proliferation at all doses, and these effects were blocked by addition of mAb5.

[0586] Increased hyaluronan (HA) production is a key pathologic feature in TED and causes orbital tissue edema and proptosis (eye bulging). Inhibition of HA release by orbital fibroblasts in preclinical studies is a key translational readout and has been correlated with clinical efficacy in TED (Lee et al. Best Pract Res Clin Endocrinol Metab. 37:2. 2023). Canonical IL-11 signaling leads to phosphorylation of STAT3 (pSTAT3) and IL-11 stimulation of orbital fibroblasts promotes HA release. The dose-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. FIG. 4 show that mAb5 inhibits pSTAT3 (FIG. 4, left) with IC50 and IC90 values of 0.007 and 0.06 pg / mL, respectively, and blocks HA release (FIG. 4, right) 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.

[0587] Teprotumumab biosimilar (Tepro) (ichorbio, ICH5128), an antibody that binds to the insulin-like growth factor 1 (IGF-1) receptor used in the treatment of TED was also evaluated alongside mAb5. Tepro’s ability to fully inhibit IGF-1 induced HA production was evaluated in orbital fibroblasts derived from TED patients. The resulting data indicated a maximal Tepro concentration in the range of 10 - 100 pg / mL (FIG. 5).

[0588] Tepro’s ability to fully inhibit IL-11 induced HA production was then evaluated in orbital fibroblasts derived from TED patients and compared to mAb5. Orbital fibroblasts were treated with 10 ng / mL IL-11, followed by either mAb5 or Tepro. Tepro demonstrated no inhibition compared to mAb5 even at the lowest concentration of mAb5 (FIG. 6, 7). Similar experiments were performed to compare Tepro’s ability to block IL-11 induced pSTAT3 activation in TED patient derived orbital fibroblasts, which demonstrated little to noinhibition (FIG. 7, middle). Cell proliferation was also assessed in this experimental setup, demonstrating mAb5 inhibition of IL- 11 induced cell proliferation in TED patient derived orbital fibroblasts (FIG. 8).

[0589] IGF-1 is a cytokine involved in the pathology of TED, therefore the ability of mAb5 and Tepro to block IGF-1 induced HA production was also assessed in TED patient derived orbital fibroblasts. Cells were treated with 100 ng / mL IGF-1, followed by 3 pg / mL mAb5 or 10 pg / mL Tepro. Both mAb5 and Tepro demonstrated a decrease in HA production in three experiments (FIG. 9)

[0590] TED patient derived orbital fibroblasts were then stimulated with both IL-11 and IGF- 1 and either mAb5 or Tepro’ s ability to inhibit HA production was assessed. Cells were treated with 100 ng / mL IGF-1 and 10 ng / mL IL-11, followed by either mAb5 at 1, 3, or 10 pg / mL or Tepro at 10 pg / mL. IL-11 and IGF-1 co-treatment enhanced HA production in TED patient orbital fibroblasts, indicating an interaction between the IGF-1 and IL-11 pathways. mAb5 alone inhibited IL-11+IGF-l stimulated HA production at all three doses (FIG. 10) and Tepro demonstrated inhibition at 10 pg / mL. In addition to HA production, fibroblast proliferation was assessed in response to the IGF-1 and IL-11 combinatory stimulation. mAb5 and Tepro demonstrated an inhibition of proliferation as shown in FIG. 11.

[0591] Activation of IGF-1R is a disease driver in TED and the target of the currently approved TED therapy, Tepro. Based on the previous experiments indicating crosstalk between the IL-11 and IGF-1 pathways in TED (FIG. 12, left), experiments were performed to measure the effects of mAb5, Tepro, and the combination (mAb5 / Tepro) 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 Tepro.

[0592] As shown in FIG. 12, right, combination treatment of mAb5 with increasing doses of Tepro dose-dependently inhibited HA release greater than mAb5 or Tepro alone. These data indicate that treating patients with the anti -IL 1 IRa antibodies described herein, in addition to the standard-of-care drug, Tepro, may have added therapeutic benefit relative to treatment with either agent alone. Cell proliferation was additionally evaluated demonstrating a combinatorial inhibition of IGF-l+IL-11 induced cell proliferation (FIG. 13).

[0593] . TGFP induces transformation of orbital fibroblasts into activated myofibroblasts which produce increased amounts of collagen, leading to pathological orbital tissue remodeling. Procollagen secretion was measured in TED patient derived orbital fibroblasts in response to 5 ng / mL TGFP (FIG. 14, left), which was subsequently reduced by 3 pg / mL mAb5 (FIG. 14, right). Additionally, a similar induced secretion of procollagen was seen when TED patient derived orbital fibroblasts were treated with 5 ng / mL TGFP and 10 ng / mL IL-11 (FIG. 15, left), which was subsequently reduced by 3 pg / mL mAb5 (FIG. 15, right). Tepro did not reduce procollagen secretion under either of these conditions. A correlative analysis indicated a positive correlation between TGFP-stimulated IL-11 release and procollagen production (FIG. 16).

[0594] To identify additional cytokines produced in TED patient derived orbital fibroblasts by IGF-1 + IL-11, heatmaps were produced using data from a custom cytokine multi -plex assay (Eve Technologies, Calgary, CA.) and plotted in Microsoft Excel, with and without treatments with mAb5 and Tepro (FIG. 17). IL-6, MCP-1, Granzyme B and B cell activating factor belonging to the TNF family (BAFF) production were then assessed in TED patient derived orbital fibroblasts by treating with 100 ng / mL IGF-1 and / or 10 ng / mL IL-11, which were subsequently reduced with the treatment of mAb5 and in some instances Tepro (FIGS. 18-24)

[0595] The role of IL-6 was further investigated in TED patient derived orbital fibroblasts. The orbital fibroblasts were exposed to escalating concentrations of IL-6 which failed to stimulate HA release (FIG. 25, left). IL-6 pathway activation was confirmed through the pSTAT3 activation in FIG. 25, right. This finding was confirmed in FIG. 26, in which the anti-IL-6R mAb Tocilizumab (Tocil) demonstrated little to no effect on HA production.

[0596] There is known Thyroid Stimulating Hormone Receptor (TSHR) / IGF-1R crosstalk in TED (Int. J. Mol. Sci. 2020, 21(18), 6561). Orbital fibroblasts from “M22 responsive” TED donors demonstrated weak stimulation of HA in response to the anti-THSR mAb M22 at 45 pg / mL. The weak HA stimulation was reversed with mAb5 treatment (FIG. 27).

[0597] To investigate the mechanism for additivity between the IGF-1 and IL-11 pathways and whether this is blocked by mAb5, western blots were performed on TED patient derived orbital fibroblasts after treatment with IGF-1 and / or IL-11 and / or mAb5. Overall, additive signaling could be observed in pAKT and pERK which were reduced by mAb5 in both cases (FIGS. 28-29). Additionally, HA production was observed with IGF-1 and IL-11 cotreatment which was attenuated by the PI3K / AKT inhibitor, LY294002 (FIG. 30, middle)and mTOR inhibitor, Sirolimus (FIG. 30, right), but not the MEK / ERK inhibitor, U0126 (FIG. 30, left)Example 2: mAb5 Human Pharmacokinetic (PK) and Safety Study

[0598] To determine PK, safety, and target engagement of mAb5 in human subjects, placebo controlled single ascending does (SAD) and multiple ascending dose (MAD) studies were performed in healthy volunteers. A schematic of the study is shown in FIG. 31.

[0599] The SAD study consisted of 5 cohorts with 8 subjects per cohort at a 3: 1 randomization ratio of drug to placebo. The escalating doses included 25 mg, 100 mg, 300 mg, 600 mg, and 1200 mg administered intravenously (FIG. 32, left). Serum was collected over a span of 42 days. The resulting SAD PK data indicated a mAb5 circulating serum concentration of greater than or equal to 10 pg / mL at 28 days reached at doses of 300 mg fixed dose or above.

[0600] The MAD study consisted of 2 cohorts with 8 subjects per cohort at a 3 : 1 randomization ratio of drug to placebo. Two administrations of mAb5 per subject occurred on day 1 and 15 with a dose of either 600 mg or 1200 mg intravenously (FIG. 32, right). Serum was collected over a span of 42 days. The resulting MAD PK data indicated a mAb5 half-life of about 11 days at the 1200 mg dose.

[0601] Serum from the SAD and MAD studies were used in a flow cytometry -based assay to measure the functional activity of mAb5 in whole blood. Hyper IL-11 was used to stimulate whole blood samples obtained from patients before and after dosing with mAb5. Hyper IL-11 is a covalently linked complex of IL-11 and soluble IL-11R that binds and signals through cell surface-associated glycoprotein 130 (Dams-Kozlowska et al. BMC Biotechnol. 12:8 (2012)). Addition of hyper IL-11 to whole blood leads to robust phosphorylation of STAT3 and is measurable by flow cytometry in both the CD3+ T-cell and CD14+ monocyte populations. The presence of mAb5 in whole blood inhibited the ability of hyper IL-11 to phosphorylate STAT3 in a dose dependent manner. (FIGS. 33-34).

[0602] Further analyses were conducted to determine if PK / PD relationships could be elucidated. The near immediacy with which pSTAT3 activity fell after dose administration, coupled with the rapid rebound in activity over time at lower doses, suggested a directional relationship between mAb5 serum concentration and pSTAT3 activity. There was a high degree of correlation between time matched hyper IL-11 induced pSTAT3 activity in monocytes and drug concentration (FIG. 35). The relationship follows a traditional, sigmoidEmax relationship where there is very little effect at the lowest concentrations (ie, <0.3 pg / mL), a rapid decline in pSTAT3 activity associated with concentrations ranging from 0.3 to ~1.0 pg / mL, and a complete inhibition of pSTAT activity at concentrations >1.0 pg / mL. This data shows saturation of pSTAT3 signaling at approximately 1 pg / mL correlating with the predicted therapeutic dose of 300 mg.

[0603] Adverse effects in both the SAD and MAD cohorts were monitored, and treatment emergent adverse events (TEAEs) are reported in FIG. 36. All adverse effects were mild or moderate, with the most frequent adverse effect being headache with a total of 13 instances. No dose relatedness was seen in association of headaches. The data herein is blinded and includes subjects on placebo.

[0604] Additional studies have been initiated with planned multiple doses of 1200 mg in patients with IPF and PF-ILD (Part C) and TED (Part D) as indicated by the study plan schematic in FIG. 31.Example 3: mAb5 Human TED Efficacy Study

[0605] A proof-of-concept, double-masked, randomized, placebo-controlled study will be completed to evaluate the efficacy, safety, tolerability, PK, immunogenicity, and PD of 2 dose levels of mAb5 administered IV Q4W *4 doses in patients with TED.

[0606] The study will include approximately 24 evaluable patients with TED in 3 parallel treatment arms. Patients will be randomized (in a 1 : 1 : 1 ratio) upon enrollment to mAb5 in either a high-dose (600 mg Q4W *4 doses) or low-dose (300 mg Q4W *4 doses) treatment arm or to placebo (Table El).Table El: Multiple Dose Study DesignQ4W = every 4 weeks

[0607] The study schematic and dosing scheme is presented in FIGS. 37-38. The Screening period will last up to 30 days before Day 1, the treatment period will last 85 days (last dose administered on Day 85), and the follow-up period will last approximately 84 days (Days 86- 169).

[0608] mAb5 solution for injection will be supplied as a pure, sterile, colorless to pale brown frozen liquid for thawing and dilution with water for injection (WFI) before infusion (Table E2). Each vial of mAb5 solution for injection will comprise 100 mg pure active ingredient (mAb5).

[0609] Pharmaceutical grade 0.9% sodium chloride will be administered IV as the placebo control.Table E2: Study Intervention(s) Administered

[0610] During determination of eligibility for the study, the more severely affected eye will be defined as the study eye. This will be based on the severity of proptosis in both eyes. If both eyes are affected equally, the PI or designee will select the study eye and may take into account other factors such as CAS (Table E3). Both eyes will be assessed for efficacy and safety at designated study visits, but the study eye will be used to assess the primary clinical end point.Table E3: CAS 7-point ScaleCAS = clinical activity score; TED = thyroid eye diseaseEach item is scored (l=present; 0=absent), and scores for each item are summed for total score.Example 4: SC Dosing Rationale

[0611] Pharmacokinetic (PK) simulations were performed to determine subcutaneous (SC) dosing regimens that provide comparable exposure to a reference intravenous (IV) dosing regimen of mAb5 (FIGS. 40A-40G). The reference IV regimens include both 300mg and 600mg doses administered once every four weeks (Q4W).

[0612] SC regimens tested across various dosing intervals (Q2W, Q3W) and bioavailability assumptions demonstrated that SC doses of 300 mg and 600 mg could provide Cmin values and percent target coverage comparable to those achieved with IV dosing. Based on these results and constraints around acceptable injection volumes (2.0 mL upper limit for standardSC administration) and number of injections (1-4 standard SC injections), SC dose levels up to 1200 mg (e.g. four 2 mL injections of 300 mg each) were projected to be pharmaceutically feasible.

Claims

CLAIMS1. A method of treating thyroid eye disease (TED) in a human subject in need thereof, comprising administering to the subject one or more dose(s) of about 25mg to about 1500mg per dose of an antibody which binds to human interleukin-11 receptor subunit a (IL-l lRa).

2. The method of claim 1, wherein the IL-1 IRa antibody comprises a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3, wherein: a. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; b. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; c. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; d. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; e. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; f. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; g. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; h. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;i. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; j. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; k. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; l. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; m. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; n. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; o. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 22, respectively; p. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; q. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; r. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; s. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;t. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; u. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; v. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; w. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; x. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; y. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; z. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; aa. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; bb. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; cc. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; dd. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;ee. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; or ff. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 40, 9, and 10, respectively.

3. The method of claim 1 or 2, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; b. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; c. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; d. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; e. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; f. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; g. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; h. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; i. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; j . the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; k. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; l. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; m. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; n. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;o. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; p. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; q. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; r. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; s. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; t. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; u. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; v. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; w. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; x. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; y. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; z. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; aa. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; bb. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; cc. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;dd. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; ee. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or ff the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

4. The method of any one of claims 1-2, wherein the IL-1 IRa antibody is a full-length antibody.

5. The method of any one of claims 1-2, wherein the IL-1 IRa antibody is an antibody fragment.

6. The method of any one of claims 1-5, wherein the IL-1 IRa antibody comprises an Fc domain.

7. The method of claim 6, wherein the Fc domain is selected form the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence.

8. The method of claim 7, wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

9. The method any one of claims 6-8, wherein the Fc domain comprises one or more amino acid substitutions.

10. The method of claim 9, wherein the one or more amino acid substitutions comprises a S228P substitution, wherein the position number of the amino acid residue is of the EU numbering scheme.

11. The method of claim 9 or 10, wherein the one or more amino acid substitutions extend the IL-1 IRa antibody’s half-life.

12. The method of any one of claims 9-11, wherein the one or more amino acid substitutions are selected from the group consisting of M252Y, S254T, and T256E substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

13. The method of any one of claims 9-12, wherein the one or more amino acid substitutions are selected from the group consisting of M428L and N434S substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

14. The method of claim 9, wherein the one or more amino acid substitutions are selected from the group consisting of L234A, L235A, and P329S substitutions, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

15. The method of any one of claims 1-14, wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein: a. the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;b. the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 74, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; c. the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 87, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; d. the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 88, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or e. the HC of the antibody comprises the amino acid sequence of SEQ ID NO: 89, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the LC of the antibody comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

16. The method of any one of claims 1-15, wherein the antibody wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein: a. the HC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 78 or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the LC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 79, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or b. the HC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 80 or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and wherein the LC of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 79, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

17. The method of any one of claims 1-13, wherein the dose of the IL-1 IRa antibody is about 25 mg, about 100 mg, about 300 mg, about 600 mg, about 1200 mg, or about 1500 mg per dose.

18. The method of any one of claims 1-16, wherein the dose is administered daily, weekly, about every two weeks, about every three weeks, about every four weeks, every month, or every two months.

19. The method of any one of claims 1-17, wherein the dose is administered intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, through inhalation, or through an on-body device or infuser.

20. The method of any one of claims 1-17, wherein the dose is administered intravenously.

21. The method of any one of claims 1-17, wherein the dose is administered subcutaneously.

22. The method of any one of claims 1-20, wherein the dose is achieved by at least 2 to about 5 administrations.

23. The method of any one of claims 1-20, wherein the dose is administered at a volume of about 1 mL, about 2 mL, about 3 mL or about 4 mL.

24. The method of any one of claims 1-20, wherein the dose is administered at a volume of about 1 mL to about The method of any one of claims 1-13, wherein a dose of about 300 mg is administered intravenously to the subject at a volume of about 60 mL about every four weeks.

25. The method of any one of claims 1-13, wherein a dose of about 600 mg is administered intravenously to the subject at a volume of about 60 mL about every four weeks.

26. The method of any one of claims 1-25, wherein the dissociation constant (KD) of the IL- 1 IRa antibody to human IL-1 IRa is less than about 50 pM.

27. The method of any one of claims 1-26, wherein the IL-1 IRa antibody does not bind to mouse IL-1 IRa or rat IL-1 IRa.

28. The method of any one of claims 1-27, wherein the IL-1 IRa antibody inhibits IL-11 induced phosphorylation of STAT3.

29. The method of any one of claims 1-28, wherein the IL-1 IRa antibody inhibits IL-11 induced phosphorylation of ERK.

30. The method of any one of claims 1-29, wherein the IL-1 IRa antibody inhibits the proliferation of orbital fibroblasts stimulated with IL-11.

31. The method of any one of claims 1-30, wherein the IL-1 IRa antibody inhibits hyaluronan secretion from orbital fibroblasts stimulated with IL-11, IGF- 1 or both.

32. The method of any one of claims 1-31, wherein the IL-1 IRa antibody inhibits IL-11 stimulated pSTAT3 and HA release by orbital fibroblasts.

33. The method of any one of claims 1-32, wherein the IL-1 IRa antibody inhibits procollagen secretion from orbital fibroblasts stimulated with TGFp.

34. The method of any one of claims 1-33, wherein the TED is associated with hyperthyroidism.

35. The method of any one of claims 1-33, wherein the TED is associated with hypothyroidism.

36. The method of any one of claims 1-33, wherein the TED is associated with euthyroidism.

37. The method of claim 34, wherein the hyper-thyroidism is due to Graves' disease.

38. The method of any one of claims 1-37, wherein an additional TED therapy is administered during a course of treatment with the IL-1 IRa antibody.

39. The method of claim 31, wherein the additional TED therapy is administered concurrently with the administration of the IL-1 IRa antibody.

40. The method of claim 31, wherein the additional TED therapy is administered after the administration of the IL- 1 IRa antibody.

41. The method of claim 31, wherein the additional TED therapy is administered prior to the administration of the IL- 1 IRa antibody.

42. The method of any one of claims 31-41, wherein the additional TED therapy is selected from the group consisting of insulin-like growth factor- 1 receptor (IGF-lR)-inhibitor therapy, FcRn-inhibitor therapy, interleukin-6 (IL-6) inhibitor therapy, steroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF- a)-inhibitor therapy, interleukin- 17 (IL-17) inhibitor therapy, and CD-40L inhibitor therapy.

43. The method of claim 42, wherein the IGF-lR-inhibitor therapy is selected from teprotumumab, VRDN-001, VRDN-003, Lonigutamab, Linsitinib, a biosimilar of any one of the preceding, and any other IGF-1R targeted therapy.

44. The method of claim 42 or 43, wherein the IGF-lR-inhibitor therapy is administered 1 to about 2 times, 1 to about 3 times, 1 to about 4 times, 1 to about 5 times, 1 to about 6 times, or 1 to about 7 times during the course of treatment with the IL-1 IRa antibody.

45. The method of claim 42 or 43, wherein teprotumumab or other targeted IGF-1R targeted agent is administered during the course of treatment with the IL-1 IRa antibody according to Figure 39.

46. The method of claim 42, wherein the FcRn -inhibitory therapy is selected from the group consisting of batoclimab (IMVT-1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, and any other FcRn targeted therapy.

47. The method of claim 42, wherein the IL-6 inhibitor therapy is selected from the group consisting of TOUR006, satralizumab, clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.

48. The method of claim 42, wherein the steroid therapy is selected from the group consisting of methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy.

49. The method of claim 42, wherein the CD20-inhibitor therapy is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.

50. The method of claim 42, wherein the TNF-a-inhibitor therapy is selected from the group consisting of adalimumab, certolizumab, etanercept, golimumab, and infliximab.

51. A bispecific antibody comprising: a. a first antigen binding arm that specifically binds to IL-1 IRa, comprising a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3, wherein: i. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; ii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; iii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; iv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; v. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;vi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; vii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; viii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; ix. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5,16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; x. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5,17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5,18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xiii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xiv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 22, respectively; xvi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;xvii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xviii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xix. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xx. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxiii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxiv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxvi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxvii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;xxviii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxix. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxx. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxxi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; or xxxii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 40, 9, and 10, respectively; and b. a second antigen binding arm that specifically binds to an TED associated antigen.

52. The bispecific antibody of claim 51, wherein the first antigen binding arm comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; b. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%,76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; c. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; d. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; e. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; f. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto,and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; g. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; h. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; i. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; j . the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%,77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; k. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; l. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; m. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;n. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; o. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; p. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; q. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; r. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; s. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; t. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; u. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; v. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; w. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; x. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; y. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; z. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; aa. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; bb. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;cc. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; dd. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; ee. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or ff the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

53. The bispecific antibody of claim 51, wherein the TED associated antigen is selected from the group consisting of insulin-like growth factor-1 receptor (IGF-1R), IGF-1, FcRn, interleukin-6 (IL-6), IL-6R, CD20, tumor necrosis factor-a (TNF-a), TNFR1, TNFR2, interleukin- 17 (IL-17), IL-17R, CD-40, and CD-40L.

54. The bispecific antibody of claim 51 or 52, wherein the second antigen binding arm comprises a VH and a VL sequence derived from an antibody selected from the group consisting of teprotumumab, VRDN-001, VRDN-003, Lonigutamab, batoclimab (IMVT- 1401), IMVT-1402, efgartigimod, nipocalimab, orilanolimab, rozanolixizumab, TOUR006, satralizumab clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, tocilizumab, ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, ublituximab, adalimumab, certolizumab, golimumab, and infliximab.

55. An antibody-drug conjugate (ADC) comprising: a. an antibody that specifically binds to IL-1 IRa, wherein the antibody comprising a heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3, and a light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3, wherein: i. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; ii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 6, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; iii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; iv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 7, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively;v. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; vi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 11, respectively; vii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 14, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; viii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 15, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; ix. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5,16, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; x. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5,17, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5,18, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 19, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xiii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 20, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xiv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 21, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 5, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 22, respectively;xvi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 23, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xvii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 24, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xviii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 25, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xix. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 26, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xx. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 27, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 28, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 29, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxiii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 30, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxiv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 31, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxv. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 32, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxvi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 33, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively;xxvii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 34, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxviii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 35, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxix. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 36, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxx. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 37, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; xxxi. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 38, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 8, 9, and 10, respectively; or xxxii. the HCDR1, HCDR2, and HCDR3 sequences comprise SEQ ID NOs: 39, 12, and 13, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise SEQ ID NOs: 40, 9, and 10, respectively; b. a linker; and c. a therapeutic drug.

56. The ADC of claim 55, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;b. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; c. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; d. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; e. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; f. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; g. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; h. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; i. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; j . the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 49, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; k. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 50, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; l. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; m. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; n. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; o. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; p. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto;q. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 56, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; r. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; s. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 58, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; t. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 59, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; u. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 60, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; v. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 61, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; w. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; x. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 63, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; y. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; z. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; aa. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 66, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; bb. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; cc. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; dd. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; ee. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; orff. the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

57. The ADC of claim 55, wherein the TED therapeutic drug is selected from the group consisting of nintedanib, pirfenidone, TGFP inhibitors (e.g. galunisertib), ROCK inhibitors (e.g. belumosidil), PI3K / mTOR inhibitors (e.g. omipalisib), and (Src inhibitors e.g. saracatinib).

58. The ADC of claim 55 or 56, wherein the linker is a cleavable linker.

59. Use of an antibody which binds to human interleukin-11 receptor subunit a (IL-1 IRa) in the manufacture of a medicament for treating thyroid eye disease (TED) in a human subject in need thereof, wherein the antibody is administered to the subject in one or more dose(s) of about 25 mg to about 1500 mg per dose.

60. An antibody which binds to human interleukin- 11 receptor subunit a (IL-1 IRa) for use in the treatment of thyroid eye disease (TED) in a human subject in need thereof, wherein the antibody is administered to the subject in one or more dose(s) of about 25 mg to about 1500 mg per dose.

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