Compositions and methods for treating pain in subjects with rheumatoid arthritis

Abstract

To provide methods and compositions for treating unacceptable pain in subjects with rheumatoid arthritis.SOLUTION: The present disclosure relates to the use of an anti-IL6 receptor antibody for treating unacceptable pain in subjects with rheumatoid arthritis. Subjects with unacceptable pain can have, e.g., refractory pain or strict refractory pain.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 857,247, filed June 4, 2019; U.S. Provisional Patent Application Serial No. 62 / 930,966, filed November 5, 2019, and European Patent Application No. 20305191.7, filed February 27, 2020, the entire disclosures of which are hereby incorporated by reference.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates to the field of therapeutic treatment of intolerable pain in subjects with past or current rheumatoid arthritis. [Background technology]

[0003] Pain is a core-set domain and distressing symptom for patients with rheumatoid arthritis (RA) and can be directly related to inflammation. Unbearable pain (UP) levels can persist in patients despite treatment-induced control of inflammation (IC), i.e., intractable pain (RP).

[0004] Sarilumab is an interleukin-6 receptor antagonist for the treatment of adults with moderately to severely active RA who have had an inadequate response to or are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides methods and compositions for treating intolerable pain in a subject with rheumatoid arthritis. In various embodiments, treating the subject comprises administering a therapeutically effective amount of an antibody that specifically binds to IL-6R.

[0006] In various embodiments, the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2.

[0007] In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises three complementarity determining regions (CDRs) found in the sequence of SEQ ID NO: 1, and the VL comprises three CDRs found in the sequence of SEQ ID NO: 2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0008] In various embodiments, the antibody is sarilumab.

[0009] In various embodiments, the subject has intractable pain. In various embodiments, the subject has UP despite controlling treatment-induced inflammation. In various embodiments, the subject has UP despite at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% reduction in inflammation compared to when the subject was first treated with a DMARD ... In various embodiments, the subject has UP despite having at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% reduction in inflammation compared to when the subject was initially treated with one or more DMARDs other than sarilumab. In various embodiments, the subject has UP despite having at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% reduction in inflammation compared to when the subject was initially treated with one or more DMARDs other than sarilumab. In various embodiments, the subject has UP despite having at least about a 10%, 25%, 25%, 50%, 75%, 95%, or 75% reduction in inflammation compared to when the subject was initially treated with one or more DMARDs other than sarilumab. In various embodiments, the subject has UP despite having at least about a 10%, 25%, 25%, 50%, 75%, 95%, or 75% reduction in inflammation compared to when the subject was initially treated with one or more DMARDs other than sarilumab. In various embodiments, the subject has strict refractory pain. In various embodiments, the subject experiences a reduction in visual analog scale (VAS) to less than 40 after 24 or 52 weeks of treatment.

[0010] In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered weekly or every two weeks. In various embodiments, the antibody is administered weekly or every two weeks.

[0011] In various embodiments, the antibody is administered at a dose of about 150 mg to 200 mg. In various embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various embodiments, the antibody is administered at a dose of 150 mg to 200 mg. In various embodiments, the antibody is administered at a dose of 150 mg or 200 mg.

[0012] In various embodiments, the subject has rheumatoid arthritis. In various embodiments, the subject has moderately to severely active rheumatoid arthritis. In various embodiments, the subject has moderately active rheumatoid arthritis. In various embodiments, the subject has severely active rheumatoid arthritis.

[0013] In various embodiments, the subject has a Disease Activity Score (DAS) of 3.2 to 5.1. In various embodiments, the subject has a DAS greater than 5.1. In various embodiments, the subject has a DAS of 3.2 or greater. In various embodiments, the subject has a DAS of 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 7.5 to 10. A subject's DAS can be readily calculated by one of ordinary skill in the art. A non-limiting description related to the DAS is provided in Fransen and van Riel (Clin Exp Rheumatol. 2005 Sep-Oct;23(5Suppl39):S93-9), the entire contents of which are incorporated herein by reference.

[0014] In various embodiments, no other disease-modifying antirheumatic drugs (DMARDs) are administered with the antibody. In various embodiments, at least one other DMARD is administered to the subject. In various embodiments, at least one other DMARD is administered to the subject in parallel or simultaneously with the antibody. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD other than the antibody, but without success. In various embodiments, the subject is intolerant to one or more DMARDs, or the subject is considered an inappropriate candidate for continued treatment with one or more DMARDs.

[0015] In various embodiments, the DMARD is an sDMARD.In various embodiments, the DMARD is methotrexate.In various embodiments, the DMARD is a TNF antagonist.In various embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab and certolizumab pegol.

[0016] In another aspect, provided herein is a method for treating intolerable pain (UP) in a subject in need thereof, the method comprising the steps of selecting a subject with rheumatoid arthritis and UP, and administering to the subject a therapeutically effective dose of an antibody that specifically binds to the IL-6 receptor.

[0017] In various embodiments, the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2.

[0018] In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises three complementarity determining regions (CDRs) found in the sequence of SEQ ID NO: 1, and the VL comprises three CDRs found in the sequence of SEQ ID NO: 2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0019] In various embodiments, the antibody is sarilumab.

[0020] In various embodiments, the subject has intractable pain. In various embodiments, the subject has treatment-induced severe intractable pain. In various embodiments, the subject experiences a reduction in visual analog scale (VAS) of less than 40 after 24 weeks or 52 weeks of treatment.

[0021] In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered weekly or every two weeks. In various embodiments, the antibody is administered weekly or every two weeks.

[0022] In various embodiments, the antibody is administered at a dose of about 150 mg to 200 mg. In various embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various embodiments, the antibody is administered at a dose of 150 mg to 200 mg. In various embodiments, the antibody is administered at a dose of 150 mg or 200 mg.

[0023] In various embodiments, the subject has rheumatoid arthritis. In various embodiments, the subject has moderately to severely active rheumatoid arthritis. In various embodiments, the subject has moderately active rheumatoid arthritis. In various embodiments, the subject has severely active rheumatoid arthritis.

[0024] In various embodiments, no other disease-modifying antirheumatic drugs (DMARDs) are administered with the antibody. In various embodiments, at least one other DMARD is administered to the subject. In various embodiments, at least one other DMARD is administered to the subject in parallel or simultaneously with the antibody. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD other than the antibody, but the treatment was unsuccessful. In various embodiments, the subject is intolerant to one or more DMARDs, or the subject is considered an inappropriate candidate for continued treatment with one or more DMARDs.

[0025] In various embodiments, the DMARD is a sDMARD. In various embodiments, the DMARD is methotrexate. In various embodiments, the DMARD is a TNF antagonist. In various embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0026] In a further aspect, provided herein is an antibody for use in treating intolerable pain in a patient with rheumatoid arthritis in need of treatment, wherein the antibody specifically binds to the IL-6 receptor.

[0027] In various embodiments, the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2.

[0028] In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises three complementarity determining regions (CDRs) found in the sequence of SEQ ID NO: 1, and the VL comprises three CDRs found in the sequence of SEQ ID NO: 2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0029] In various embodiments, the antibody is sarilumab.

[0030] In various embodiments, the subject has intractable pain. In various embodiments, the subject has treatment-induced severe intractable pain. In various embodiments, the subject experiences a reduction in visual analog scale (VAS) of less than 40 after 24 weeks or 52 weeks of treatment.

[0031] In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered weekly or every two weeks. In various embodiments, the antibody is administered weekly or every two weeks.

[0032] In various embodiments, the antibody is administered at a dose of about 150 mg to 200 mg. In various embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various embodiments, the antibody is administered at a dose of 150 mg to 200 mg. In various embodiments, the antibody is administered at a dose of 150 mg or 200 mg.

[0033] In various embodiments, the subject has rheumatoid arthritis. In various embodiments, the subject has moderately to severely active rheumatoid arthritis. In various embodiments, the subject has moderately active rheumatoid arthritis. In various embodiments, the subject has severely active rheumatoid arthritis.

[0034] In various embodiments, the subject has a Disease Activity Score (DAS) of 3.2 to 5.1. In various embodiments, the subject has a DAS greater than 5.1. In various embodiments, the subject has a DAS of 3.2 or greater. In various embodiments, the subject has a DAS of 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 7.5 to 10. A subject's DAS can be readily calculated by one of ordinary skill in the art. A non-limiting description related to the DAS is provided in Fransen and van Riel (Clin Exp Rheumatol. 2005 Sep-Oct;23(5Suppl39):S93-9), the entire contents of which are incorporated herein by reference.

[0035] In various embodiments, no other disease-modifying antirheumatic drugs (DMARDs) are administered with the antibody. In various embodiments, at least one other DMARD is administered to the subject. In various embodiments, at least one other DMARD is administered to the subject in parallel or simultaneously with the antibody. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD other than the antibody, but the treatment was unsuccessful. In various embodiments, the subject is intolerant to one or more DMARDs, or the subject is considered an inappropriate candidate for continued treatment with one or more DMARDs.

[0036] In various embodiments, the DMARD is an sDMARD.In various embodiments, the DMARD is methotrexate.In various embodiments, the DMARD is a TNF antagonist.In various embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab and certolizumab pegol. [Brief explanation of the drawings]

[0037] [Figure 1-1] 1A-1C are graphs depicting odds ratios from three different randomized clinical trials—MOBILITY, TARGET, and MONARCH. FIG. 1A illustrates the odds ratio for intolerable pain. FIG. 1B illustrates the odds ratio for having intolerable pain despite inflammatory control (IC) or inflammatory control-strict (IC-strict). FIG. 1C illustrates the odds ratio for intractable pain-strict. [Figure 1-2] Continued from Figure 1-1. [Figure 2-1] 2A-2C are graphs depicting descriptive analyses of pain outcomes. FIG. 2A illustrates the analysis of pain outcomes in MOBILITY (weeks 24 and 52). FIG. 2B illustrates the analysis of pain outcomes in TARGET (weeks 24 and 52). FIG. 2C illustrates the analysis of pain outcomes in MONARCH (weeks 24 and 52). [Figure 2-2] Continued from Figure 2-1. DETAILED DESCRIPTION OF THE INVENTION

[0038] The present disclosure provides pharmaceutical compositions and methods of using these compositions for treating intolerable pain (UP) levels. In some embodiments, UP persists despite inflammatory control (IC). In some embodiments, IC is induced by biologic treatment. These compositions and methods include at least one antibody that specifically binds to interleukin-6 receptor (hIL-6R).

[0039] When used in the claims and in the Summary of the Invention and Detailed Description herein, the term "about" in a quantitative term refers to plus or minus 10% of the modified value (rounded to the nearest integer, such as the number of molecules or nucleotides, if the value is not indivisible). For example, the phrase "about 100 mg" encompasses 90 mg to 110 mg, inclusive, and the phrase "about 2500 mg" encompasses 2250 mg to 2750 mg, inclusive. When applied to percentages, the term "about" refers to plus or minus 10% of the percentage. For example, the phrase "about 20%" encompasses 18% to 22%, and "about 80%" encompasses 72% to 88%, inclusive. Furthermore, when "about" is used in conjunction with a quantitative term herein, it is understood that the exact value of the quantitative term is intended and described in addition to the value plus or minus 10%. For example, the term "about 23%" intends, describes, and includes exactly 23%.

[0040] The terms "a" or "an" entity refer to one or more of that entity; for example, "a symptom" is understood to refer to one or more symptoms. It should be noted that the terms "a" (or "an"), "one or more," and "at least one" can therefore be used interchangeably herein.

[0041] Furthermore, as used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone) and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0042] Although any embodiment may be described herein using the language "comprising," it will be understood that other similar embodiments described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0043] The term "pain" refers to discomfort caused by an intense or injurious stimulus, including illness, injury, or mental distress. In some embodiments, pain is experienced as an unpleasant sensation that has both physical and emotional components and can range from mild localized discomfort to excruciating pain.

[0044] The term "unbearable pain" refers to the level measured by the Patient Acceptable Symptom State (PASS), a validated measure of tolerable pain levels. The PASS uses a threshold of 40 mm on a visual analog scale (VAS) ranging from 0 to 100 mm, with a VAS >40 mm indicating unbearable pain. See Lourdudoss et al. (Dietary intake of polyunsaturated fatty acids and pain in spite of inflammatory control among methotrexate-treated early rheumatoid arthritis patients. Arthritis Care and Research. 2018;70(2):205-212); and Pham and Tubach (Patient Acceptable Symptom State (PASS). Joint Bone Spine 2009;76:321-3), each of which is incorporated herein by reference in its entirety. In some embodiments, pain experienced within the past week is measured. In some embodiments, pain experienced 2, 3, 4, 5, 6, 7, 8 weeks or more is measured. In some embodiments, pain experienced one month ago is measured. In some embodiments, pain experienced 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more is measured. In some embodiments, pain experienced one year ago is measured. In some embodiments, pain experienced 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more is measured.

[0045] A subject experiencing "intractable pain" has rheumatoid arthritis, excruciating pain, and a serum level of C-reactive protein (CRP) of less than 10 mg / L. A subject experiencing "severe intractable pain" has rheumatoid arthritis, excruciating pain, a swollen joint count (SJC) of one or less, and a serum level of CRP of less than 10 mg / L. In some embodiments, the rheumatoid arthritis is moderately to severely active rheumatoid arthritis.

[0046] IL-6 interacts directly with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit. IL-6Rα also exists in a soluble form, which participates in trans-signaling, allowing IL-6 to affect cells that do not express IL-6Rα, including synovial cells within joints (Rose-John et al., J Leukoc Biol. 2006;80(2):227-36). Sarilumab (SAR153191), also known as REGN88, is a fully human recombinant IgG1 kappa monoclonal antibody directed against the α subunit (IL-6Rα) of the IL-6 receptor complex. Sarilumab is a potent and specific inhibitor of IL-6 signaling. By binding to IL-6Rα with high affinity, sarilumab blocks IL-6 binding and disrupts the cytokine-mediated signaling cascade. In certain embodiments, interleukin-6 is a key factor in the pathogenesis of rheumatic conditions, and inhibition of its signaling is an important part of the mechanism of action of sarilumab. In in vivo assays, sarilumab did not exhibit antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) against relevant cell types. Here, sarilumab binding was verified by fluorescence-activated cell sorting (FACS) analysis (Commission for Medicinal Products for Human Use, Assessment Report, April 27, 2017 EMA / 292840 / 2017, available at www_dot_ema_dot_europa_dot_eu / documents / assessment_report / kevzara_epar_public_assessment_report_en_dot_pdf).

[0047] antibody The present disclosure includes methods comprising administering to a subject an antibody or antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term "hIL-6R" refers to a human cytokine receptor that specifically binds to human interleukin-6 (IL-6). In certain embodiments, the antibody administered to a patient specifically binds to the extracellular domain of hIL-6R.

[0048] The term "antibody," as used herein, refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an antibody (or antigen-binding portion thereof) can be identical to human germline sequences or are naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0049] The term "antibody," as used herein, also includes antigen-binding fragments of a complete antibody molecule. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from complete antibody molecules using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques, including, for example, the manipulation and expression of DNA encoding antibody variable and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. NAs can be sequenced and manipulated using chemical or molecular biology techniques, for example, to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0050] Non-limiting examples of antigen-binding fragments include (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment" as used herein.

[0051] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains are arranged relative to each other in any suitable configuration. For example, the variable region may be dimeric and include VH-VH, VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0052] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains found in an antigen-binding fragment of an antibody include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains are directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region, in various embodiments, can consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies, in various embodiments, can comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above that are non-covalently associated (e.g., by disulfide bonds) with each other and / or with one or more monomeric VH or VL domains.

[0053] In certain embodiments, antibodies or antibody fragments for use in the methods disclosed herein may be monospecific antibodies. In certain embodiments, antibodies or antibody fragments for use in the methods disclosed herein may be multispecific antibodies that may be specific for different epitopes of a single target polypeptide, or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bispecific antibody format that can be used in connection with certain embodiments is a first immunoglobulin (Ig) C H3 domain and second IgC H3 The first and second IgCs involve the use of H3 The domains differ from each other by at least one amino acid and have at least The single amino acid difference reduces binding of the bispecific antibody to Protein A compared to a bispecific antibody lacking the amino acid difference. H3 The domain binds to protein A and binds to a second Ig C H3 The domain contains a mutation that reduces or abolishes Protein A binding, such as the H95R modification (according to IMGT exon numbering; H435R according to EU numbering). H3 can further comprise a Y96F modification (by IMGT; Y436F by EU). H3Further modifications found within include, for IgG1 antibodies, D16E, L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU); for IgG2 antibodies, N44S, K52N and V82I (by IMGT; N384S, K392N and V422I by EU); and for IgG4 antibodies, Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I by EU). Variations on the above-described bispecific antibody formats are considered within the scope of certain embodiments. Any of the multispecific antibody formats, including the exemplary bispecific antibody formats disclosed herein, in various embodiments, can be adapted for use in conjunction with antigen-binding fragments of anti-IL-6R antibodies using routine techniques available in the art.

[0054] The fully human anti-IL-6R antibodies disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present disclosure includes antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions are backmutated to the corresponding germline residue(s) or conservative amino acid substitutions (natural or non-natural) of the corresponding germline residue(s) (such sequence changes are referred to herein as "germline backmutations"). Starting from the heavy and light chain variable region sequences disclosed herein, one of skill in the art can easily generate numerous antibodies and antigen-binding fragments containing one or more individual germline backmutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the VH and / or VL domains are backmutated to the germline sequence. In other embodiments, only certain residues are backmutated to the germline sequence, e.g., only the mutated residues found within the first eight amino acids of FR1 or the last eight amino acids of FR4, or only the mutated residues found within CDR1, CDR2, or CDR3. Additionally, antibodies are included herein that can contain any combination of two or more germline backmutations within the framework and / or CDR regions, i.e., certain individual residues are backmutated to the germline sequence while certain other residues that differ from the germline sequence are maintained. Once obtained, antibodies and antigen-binding fragments containing one or more germline backmutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.Antibodies and antigen-binding fragments obtained by this general method are encompassed by the present disclosure.

[0055] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody is selected based on whether it is desirable for the antibody to mediate cytotoxicity. The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies featured in this disclosure, in various embodiments, include antibodies that are derived from human germline immunoglobulin sequences. Nevertheless, they may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), e.g., in the CDRs and, in some embodiments, CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0056] The term "recombinant human antibody," as used herein, is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, including, for example, antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295, incorporated herein by reference in its entirety), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally exist within the human antibody germline repertoire in vivo.

[0057] Human antibodies can exist in two forms related to hinge heterogeneity. In one embodiment, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa, with the dimer held together by an interchain heavy chain disulfide bond. In another embodiment, the dimer is not linked via an interchain disulfide bond, and the approximately 75-80 kDa molecule is composed of covalently linked light and heavy chains (half antibodies). In certain embodiments, these forms have been extremely difficult to separate, even after affinity purification.

[0058] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody's hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105, incorporated by reference in its entirety) to levels typically observed with human IgG1 hinges. The present disclosure, in various embodiments, encompasses antibodies with one or more mutations in the hinge, CH2, or CH3 regions, which may be desirable, for example, to improve the yield of the desired antibody form in production.

[0059] As used herein, an "isolated antibody" refers to an antibody that has been identified, separated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." In various embodiments, an isolated antibody also includes an antibody in situ within a recombinant cell. In other embodiments, an isolated antibody is an antibody that has been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody can be substantially free of other cellular material and / or chemicals.

[0060] The term "specifically binds" or the like refers to an antibody or antigen-binding fragment thereof that binds to a target molecule under physiological conditions. "Specific binding" means forming a relatively stable complex with the antigen at a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured by surface plasmon resonance assay. In some embodiments, the antibody binds to IL-6R (e.g., human IL-6Rα) with a KD of about 0.1 nM to about 1000 nM, or about 1 nM to about 100 nM. In some embodiments, the antibody binds to IL-6R (e.g., human IL-6Rα) with a KD of about 1 pM to about 100 pM, or about 40 pM to about 60 pM. Specific binding is at least about 1 x 10 -6 In some embodiments, the dissociation constant is at least about 1×10 -7 M, 1 x 10 -8 M, or 1 x 10 -9 M. However, an isolated antibody that specifically binds human IL-6R may have cross-reactivity to other antigens, such as IL-6R molecules from other (non-human) species.

[0061] The term "surface plasmon resonance," as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIACORE system (Biacore Life Sciences Division of GE Healthcare, Piscataway, NJ).

[0062] The term "KD," as used herein, is intended to refer to the equilibrium dissociation constant of an antibody-antigen interaction.

[0063] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as a paratope. A single antigen can have more than one epitope. Thus, different antibodies can bind to different regions on an antigen and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are generated by spatially aligned amino acids from different segments of a linear polypeptide chain. Linear epitopes are generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes can include sugar, phosphoryl, or sulfonyl moieties on an antigen.

[0064] Anti-IL-6R antibodies useful in the methods described herein may, in various embodiments, contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody was derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present disclosure, in various embodiments, includes methods involving the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions are mutated to the corresponding residue(s) in the germline sequence from which the antibody was derived, or to the corresponding residue(s) in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are collectively referred to herein as "germline mutations"). Numerous antibodies and antigen-binding fragments can be constructed containing one or more individual germline mutations or combinations thereof. In certain embodiments, the VH and / or VL domains All of the framework and / or CDR residues are backmutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1, or the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more framework and / or CDR residue(s) are mutated to the corresponding residue(s) in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). Furthermore, an antibody can contain any combination of two or more germline mutations in the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a certain germline sequence, while certain different residues that differ from the original germline sequence are either maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed by the present disclosure.

[0065] The present disclosure also includes methods involving the use of anti-IL-6R antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein, with one or more conservative substitutions. For example, the present disclosure includes the use of anti-IL-6R antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, for example, 10 or less, 8 or less, 6 or less, 4 or less, or other conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0066] According to the present disclosure, an anti-IL-6R antibody or antigen-binding fragment thereof, in various embodiments, comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) comprising any of the amino acid sequences of the anti-IL-6R antibodies described in U.S. Patent No. 7,582,298, which is incorporated herein by reference in its entirety. In certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR) of the HCVR comprising the amino acid sequence of SEQ ID NO:1, and a light chain complementarity-determining region (LCDR) of the LCVR comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1, and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0067] In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11. According to certain exemplary embodiments, the methods of the present disclosure involve the use of an anti-IL-6R antibody called sarilumab and known in the art, or a biological equivalent thereof.

[0068] The amino acid sequence of SEQ ID NO: 1 is EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLF LQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSS is.

[0069] The amino acid sequence of SEQ ID NO: 2 is DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK is.

[0070] The amino acid sequence of SEQ ID NO: 3 is RFTFDDYA.

[0071] The amino acid sequence of SEQ ID NO: 4 is ISWNSGRI.

[0072] The amino acid sequence of SEQ ID NO:5 is AKGRDSFDI.

[0073] The amino acid sequence of SEQ ID NO: 6 is QGISSW.

[0074] The amino acid sequence of SEQ ID NO: 7 is GAS.

[0075] The amino acid sequence of SEQ ID NO: 8 is QQANSFPYT.

[0076] The amino acid sequence of SEQ ID NO: 9 is EVQLVESGGGLVQPGRSLRLSCAAS RFTFDDYA MHWVRQAPGKGLEWVSG ISWNSGRI GYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYC AKGRDSFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK is.

[0077] The amino acid sequence of SEQ ID NO: 10 is DIQMTQSPSSVSASVGDRVTITCRAS QGISSW LAWYQQKPGKAPKLLIY GAS SLESGVPSRFSGSGSGTFTLTISSLQPEDFASYYC QQANSFPYT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC is.

[0078] The amino acid sequence of SEQ ID NO: 11 is MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAED FQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITTVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD is.

[0079] The term "bioequivalent," as used herein, refers to a molecule that has similar bioavailability (rate and extent of utilization) after administration at the same molar dose and under similar conditions (e.g., the same route of administration) so that the effects in terms of both efficacy and safety can be expected to be essentially the same as those of the reference molecule. Two pharmaceutical compositions containing an anti-IL-6R antibody are bioequivalent if they are pharmaceutically equivalent, meaning that they contain the same amount of active ingredient (e.g., an IL-6R antibody) in the same dosage form for the same route of administration, meeting the same or equivalent criteria. Bioequivalence can be determined, for example, by in vivo testing comparing the pharmacokinetic parameters of two compositions. Parameters commonly used in bioequivalence testing include maximum plasma concentration (Cmax) and area under the plasma drug concentration-time curve (AUC).

[0080] In certain embodiments, the disclosure relates to methods comprising administering to a subject an antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:1 and a light chain variable region comprising the sequence of SEQ ID NO:2.

[0081] The present disclosure provides pharmaceutical compositions comprising such antibodies, and methods of using these compositions.

[0082] In various embodiments, the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, and specifically binds to the human interleukin-6 receptor (hIL-6R). See WO 2007 / 143168, which is incorporated herein by reference in its entirety. In one embodiment, the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 9 and a light chain variable region comprising the sequence of SEQ ID NO: 10. In various embodiments, the antibody is sarilumab.

[0083] DMARD Disease-modifying antirheumatic drugs (DMARDs) are drugs defined by their use to delay disease progression in rheumatoid arthritis. DMARDs have been classified as synthetic (sDMARDs) and biological (bDMARDs). Synthetic DMARDs include, but are not limited to, methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. Biological DMARDs include, but are not limited to, adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, and tocilizumab. In some embodiments, the DMARD is a TNF antagonist. TNF antagonists include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0084] Administration and formulation The methods described herein comprise administering a therapeutically effective amount of an anti-IL-6R antibody to a subject. As used herein, an "effective amount" or "therapeutically effective amount" is a dose of a therapeutic agent that results in the treatment of intolerable pain (UP). In certain embodiments, an effective amount is a dose of a therapeutic agent that results in the treatment of UP that persists despite inflammatory control (IC). As used herein, "treating" refers to causing a detectable improvement in one or more symptoms associated with UP, or to the development of a biological effect (e.g., specific biomarkers) that correlates with the underlying pathological mechanism causing the condition or symptom(s). For example, a dose of an anti-IL-6R antibody that causes a decrease in UP is considered a "therapeutically effective amount."

[0085] "Improvement" of pain-related symptoms refers, in various embodiments, to a reduction in the incidence of pain symptoms, which may correlate with an improvement in one or more pain-related tests, scores, or metrics (described herein). For example, improvement may correlate with a decrease from baseline in one or more pain metrics. In various embodiments, improvement may include a decrease from baseline in the VAS. In various embodiments, the baseline VAS score is 40 mm or greater and decreases to a score of 40 mm or less. As used herein, the term "baseline," with respect to a pain-related parameter, refers to the value of the pain-related parameter for the patient before or at the time of administration of an antibody of the invention. A detectable "improvement" may be detected using at least one test, score, or metric described herein. In various embodiments, improvement is detected using the VAS. In various embodiments, improvement is characterized by its relationship to the subject's PASS status.

[0086] In various embodiments, prior treatment with a DMARD other than an anti-IL-6R antibody (e.g., sarilumab, etc.) was inadequate (e.g., according to the subject's and / or physician's assessment), had no effect, and / or did not result in a detectable improvement in one or more parameters or symptoms associated with pain, and / or did not result in a biological effect correlated with the underlying pathomechanism(s) causing the pain state or symptom(s).

[0087] In various embodiments, the IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is sarilumab.

[0088] In various embodiments, the therapeutically effective amount of anti-IL-6R antibody administered to a subject varies depending on the age and size (e.g., body weight or body surface area) of the subject, as well as the route of administration and other factors known to those skilled in the art.

[0089] In various embodiments, the dose is fixed regardless of the subject's body weight or surface area. In various embodiments, the subject is at least 18 years old. In various embodiments, the subject is 30-100 years old. In various embodiments, the subject is 35-100 years old. In various embodiments, the subject is 35-8 years old. In various embodiments, the subject is 40-70 years old.

[0090] The present disclosure provides methods of using therapeutic compositions comprising an anti-IL-6R antibody or its antigen-binding fragment, and optionally one or more additional therapeutic agents. The therapeutic compositions of the present invention are administered with suitable carriers, excipients, and / or other agents incorporated into the formulation to provide improved transfer, delivery, tolerance, etc. Many suitable formulations are found in formulae known to all medicinal chemists, i.e., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, the entire contents of which are incorporated herein by reference. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (e.g., lipofectin), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311, which is incorporated herein by reference in its entirety.

[0091] Various delivery systems, such as liposomal encapsulation, microparticles, microcapsules, and receptor-mediated endocytosis, are known and can be used to administer the pharmaceutical compositions provided herein (see, for example, Wu et al. (1987) J. Biol. Chem. 262:4429-4432, incorporated herein by reference in its entirety). Introduction methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, such as infusion or bolus injection, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa), and can be administered together with other biologically active agents. Administration can be systemic or local. IL-6R antibodies can be administered subcutaneously.

[0092] Pharmaceutical compositions can also be delivered in vesicles such as liposomes (see Langer (1990) Science 249:1527-1533, incorporated herein by reference in its entirety). In certain embodiments, pharmaceutical compositions can be delivered using a controlled-release system, such as a pump or polymeric material. In certain embodiments, a controlled-release system can be placed in proximity to the target of the composition, thus requiring only a fraction of the systemic dosage.

[0093] Injectable formulations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, local injections, drip infusions, and the like. These injectable formulations can be prepared by known methods. For example, injectable formulations can be prepared by dissolving, suspending, or emulsifying the antibody or its salt in a sterile aqueous or oily medium commonly used for injections. Aqueous injectable media include, for example, saline, which can be used in combination with a suitable solubilizing agent such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), or nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil), etc.), and isotonic solutions containing glucose and other auxiliary agents. Oily media include sesame oil, soybean oil, and the like, which can be used in combination with a solubilizing agent such as benzyl benzoate or benzyl alcohol. The injectable solution prepared in this manner can be filled into appropriate ampoules.

[0094] Antibodies are typically formulated as described herein and in WO 2011 / 085158, which is hereby incorporated by reference in its entirety.

[0095] In various embodiments, the antibody is approximately 21 mM histidine, approximately 45 mM arginine, approximately 0.2% (w / v) polysorbate 20, approximately 5% (w / v) sucrose, and -Antibody of about 100 mg / mL to about 200 mg / mL It is administered as an aqueous buffer solution at about pH 6.0 containing

[0096] In another embodiment, the antibody approximately 21 mM histidine, approximately 45 mM arginine, approximately 0.2% (w / v) polysorbate 20, approximately 5% (w / v) sucrose, and at least about 130 mg / mL of antibody It is administered as an aqueous buffer solution at about pH 6.0 containing

[0097] In another embodiment, the antibody approximately 21 mM histidine, approximately 45 mM arginine, approximately 0.2% (w / v) polysorbate 20, approximately 5% (w / v) sucrose, and Approximately 131.6 mg / mL of antibody It is administered as an aqueous buffer solution at about pH 6.0 containing

[0098] In another embodiment, the antibody approximately 21 mM histidine, approximately 45 mM arginine, approximately 0.2% (w / v) polysorbate 20, about 5% (w / v) sucrose; and Approximately 175 mg / mL of antibody It is administered as an aqueous buffer solution at about pH 6.0 containing

[0099] In other embodiments, the antibody -21mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, 5% (w / v) sucrose, and -100mg / mL to 200mg / mL of antibody It is administered as an aqueous buffer solution at pH 6.0 containing:

[0100] In another embodiment, the antibody -21mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, 5% (w / v) sucrose, and -At least 130 mg / mL of antibody It is administered as an aqueous buffer solution at pH 6.0 containing:

[0101] In another embodiment, the antibody -21mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, 5% (w / v) sucrose, and -131.6mg / mL of antibody It is administered as an aqueous buffer solution at pH 6.0 containing:

[0102] In another embodiment, the antibody -21mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, 5% (w / v) sucrose; and -175mg / mL antibody It is administered as an aqueous buffer solution at pH 6.0 containing:

[0103] In various embodiments, the antibody is prepared by subjecting the antibody to: (i) histidine at a concentration of 25 mM to 100 mM; (ii) arginine at a concentration of 25 mM to 50 mM; (iii) sucrose in an amount of 3% to 10% w / v; and (iv) polysorbate 20 in an amount of 0.1% to 0.2%, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and wherein at least 90% of the native antibody is recovered after 1 month of storage at 45° C., as determined by particle size exclusion chromatography. In various embodiments, about 150 mg of the antibody (e.g., sarilumab) is administered to a subject.

[0104] In various embodiments, the antibody is administered as a stable pharmaceutical formulation comprising: (i) histidine at a concentration of about 10 mM to about 25 mM; (ii) arginine at a concentration of about 25 mM to about 50 mM; (iii) sucrose in an amount of about 5% to about 10% w / v; and (iv) polysorbate in an amount of about 0.1% to about 0.2% w / v, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and wherein at least 90% of the native antibody is recovered after 1 month of storage at 45° C., as determined by size exclusion chromatography. In various embodiments, about 150 mg of antibody (e.g., sarilumab) is administered to a subject.

[0105] Advantageously, the above-mentioned pharmaceutical compositions for oral or parenteral use are prepared in dosage forms with unit doses suitable for the dose of the active ingredient. Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0106] In various embodiments, the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to a patient using any acceptable device or mechanism. For example, administration can be achieved using a syringe and needle, or using a reusable pen and / or autoinjector delivery device. The methods of the present disclosure include the use of a number of reusable pen and / or autoinjector delivery devices for administering the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to, the AUTOPEN (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25 pen, the HUMALOG pen, the HUMALIN 70 / 30 pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN, OPTIPEN PRO, OPTIPEN STARLET, and OPTICLIK (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen and / or autoinjector delivery devices having application in the subcutaneous delivery of pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk), and KWIKPEN (Eli Lilly), SURECLICK Autoinjector (Amgen, Thousand Oaks, CA), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA pen (AbbVie Inc., North Chicago, IL), to name just a few.

[0107] In various embodiments, the antibody is administered in a pre-filled syringe. In various embodiments, the antibody is administered in a pre-filled syringe that includes a safety system. For example, the safety system prevents accidental needlestick injuries. In various embodiments, the antibody is administered in a pre-filled syringe that includes the ERIS safety system (West Pharmaceutical Services Inc.). See also U.S. Patent Nos. 5,215,534 and 9,248,242, which are incorporated herein by reference in their entireties.

[0108] In various embodiments, the antibody is administered using a power injector. In various embodiments, the antibody is administered using a power injector featuring PUSHCLICK technology (SHL Group). In various embodiments, the power injector is a device that includes a syringe that allows for the administration of a dose of the composition and / or antibody to a subject. See also U.S. Patent Nos. 9,427,531 and 9,566,395, which are incorporated herein by reference in their entireties.

[0109] The use of a microinfuser to deliver an anti-IL-6R antibody (or a pharmaceutical formulation containing the antibody) to a patient is also contemplated herein. As used herein, the term "microinfuser" refers to a subcutaneous delivery device designed to slowly administer a large volume (e.g., about 2.5 mL or more) of a therapeutic formulation over an extended period of time (e.g., about 10, 15, 20, 25, 30 minutes or more). See, for example, U.S. Patent No. 6,629,949; U.S. Patent No. 6,659,982; and Meehan et al., J. Controlled Release, Vol. 46:107-116 (1996), which are incorporated herein by reference in their entireties. Microinfusers are particularly useful for delivering large doses of therapeutic proteins at high concentrations (e.g., about 100, 125, 150, 175, 200 mg / mL or more) and / or contained within viscous solutions.

[0110] In various embodiments, an inadequate response to prior treatment refers to a subject whose pain is not adequately controlled after receiving a typical maximum tolerated dose of prior treatment. In some embodiments, an inadequate response to prior treatment refers to a subject who has moderate or high disease activity and poor prognosis characteristics despite prior treatment. In various embodiments, an inadequate response to prior treatment refers to a subject whose pain symptoms (e.g., any of the symptoms listed herein) have not improved or have worsened despite prior treatment.

[0111] Patient population As used herein, "subject" means a human subject or patient.

[0112] In various embodiments, an antibody as described herein is administered to a subject who has rheumatoid arthritis and is suffering from intolerable pain (UP), wherein the UP in the subject is under inflammatory control (IC) or the UP in the subject has severe RP. In various embodiments, the subject has UP and rheumatoid arthritis. In various embodiments, the subject has UP-IC and rheumatoid arthritis. In various embodiments, the subject has UP severe RP and rheumatoid arthritis. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering one or more DMARDs other than an IL-6R antibody, but the treatment was unsuccessful.

[0113] A subject who is considered by the treating physician to have been "treated without success" is, in various embodiments, a subject who has been found to be intolerant to one or more DMARDs tested by the physician and / or who has shown an inadequate response to one or more DMARDs tested by the physician, typically a subject who has previously been administered one or more DMARDs but who is still considered by the physician to exhibit or have a UP.

[0114] In various embodiments, the subject with rheumatoid arthritis is - At least 6 of 66 swollen joints and 8 of 68 tender joints as measured by a physician in a typical swollen and tender joint count test; High-sensitivity C-reactive protein (hs-CRP) ≥ 8 mg / L or ESR ≥ 28 mM / H -DAS28ESR>5.1 It has.

[0115] In various embodiments, the subject who has previously been treated for rheumatoid arthritis by administering at least one DMARD other than an antibody but has not responded effectively is a subject who has previously been treated for UP by administering a DMARD but has not responded effectively.In various embodiments, the DMARD is selected from the group consisting of methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine.In various embodiments, the DMARD is methotrexate.In various embodiments, the DMARD is a TNF-α antagonist.In various embodiments, the DMARD is adalimumab.

[0116] In various embodiments, the subject who has previously been unsuccessfully treated for UP by administering one or more DMARDs other than an antibody is a subject who has had an inadequate response or intolerance to methotrexate.

[0117] In various embodiments, for a subject who has previously been treated for UP by administering one or more DMARDs other than an IL-6R antibody, but without success, the one or more DMARDs are no longer administered to the subject, and in various embodiments, an IL-6R antibody is administered alone in monotherapy to the subject.

[0118] In various embodiments, the subject is intolerant to DMARD due to one or more physical reactions, conditions, or symptoms resulting from treatment with DMARD.The physical reactions, conditions, or symptoms can include allergies, pain, nausea, diarrhea, azotemia, stomach bleeding, intestinal bleeding, stomatitis, thrombocytopenia, small intestinal perforation, bacterial infection, inflammation of the gums or oral cavity, inflammation of the stomach lining or intestinal lining, bacterial sepsis, gastric ulcers, intestinal ulcers, sun sensitivity of the skin, dizziness, loss of appetite, lack of energy, and vomiting.In certain embodiments, intolerance can be determined by the subject or by a medical professional when examining the subject.In various embodiments, the DMARD is selected from the group consisting of methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine.In certain embodiments, the DMARD is methotrexate.

[0119] In certain embodiments, the present disclosure provides a step of administering one or more additional therapeutic agents to a subject in combination with an IL-6R antibody. As used herein, the phrase "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-6R antibody. In certain embodiments, the subject is administered the antibody together with a DMARD and / or a TNF-α antagonist.

[0120] All publications mentioned herein are incorporated by reference in their entirety for all purposes. [Example]

[0121] Odds ratios for intolerable pain (UP) and intolerable pain despite refractory pain control (RC) or rigorous inflammation control (RP-rigorous) in three randomized controlled clinical trials (RCTs) of sarilumab Three randomized controlled trials of sarilumab administered subcutaneously at doses of 150 mg or 200 mg every two weeks have previously observed that sarilumab improves pain in patients with RA compared with other treatments.

[0122] Across all three trials (baseline characteristics by treatment group were similar in each trial, see Table 1), sarilumab administered at 150 mg and 200 mg demonstrated comparable The IFN-γ-glucan-1 (IFN-γ) group was associated with better inflammatory control and reduced rates of UP compared with the control group (see Figures 2A-C), and also reduced odds of UP compared with the comparator (nominal p<0.05, see Figures 1A-C).

[0123] Across all 3 RCTs, sarilumab 150 mg and 200 mg were associated with lower odds of intolerable pain when compared with the comparator using OR (Figure 1A): MOBILITY, Week 24, sarilumab 150 mg: 0.46 [0.34, 0.61]; sarilumab 200 mg: 0.39 [0.29, 0.52]), and MOBILITY, Week 52 (sarilumab 150 mg: 0.40 [0.30, 0.54]; sarilumab 200 mg: 0.39 [0.30, 0.53]; all nominal p<0.001) TARGET, sarilumab 150 mg: 0.41 [0.26, 0.65]; sarilumab 200 mg: 0.44 [0.28, 0.69]); nominal p<0.05 MONARCH, sarilumab 200 mg: 0.54 [0.36, 0.81]; nominal p<0.05

[0124] Data from the MOBILITY trial revealed that, compared with placebo, both sarilumab doses reduced the odds of RP despite inflammatory control at week 24 (sarilumab 150 mg: 0.60 [0.38, 0.93]; sarilumab 200 mg: 0.57 [0.37, 0.87]) and week 52 (sarilumab 150 mg: 0.64 [0.37, 1.02]; sarilumab 200 mg: 0.62 [0.37, 1.02]), as well as the odds of RP-strict (MOBILITY trial) at week 52 (sarilumab 150 mg: 0.41 [0.19, 0.90]; sarilumab 200 mg: 0.35 [0.16, 0.76]) (nominal p < 0.05) (Figure 1C). Data from the TARGET trial revealed that sarilumab 150 mg reduced the odds of RP-strict (p<0.05) at week 24 (0.05 [0.01; 0.39]). Higher pain levels were associated with worse FACIT-Fatigue, HAQ, SJC, and TJC levels (all p<0.001), and UP generally had moderate agreement with the likelihood of achieving a minimally clinically important difference in all these outcomes (kappa coefficient values ​​0.41-0.60).

[0125] No significant differences in the odds of refractory pain were observed for sarilumab 200 mg or adalimumab 40 mg compared with placebo in TARGET and MONARCH, respectively.

[0126] Overall study design and plan: Post-hoc analysis of three randomized controlled clinical trials (RCTs) Data from three phase 3 RCTs were collected to determine whether sarilumab contributes to pain improvement in subjects with RA. In the MOBILITY trial [NCT01061736], patients received 150 mg or 200 mg of sarilumab every two weeks for 24 or 52 weeks compared with placebo, along with conventional DMARDs; in the TARGET trial [NCT01709578], patients received sarilumab every two weeks for 24 weeks, along with conventional DMARDs; and in the MONARCH trial [NCT02332590], patients receiving 200 mg of sarilumab monotherapy every two weeks were compared with patients receiving 40 mg of adalimumab monotherapy every two weeks. Pain outcomes: UP (visual analog) Post-hoc analyses were performed on odds ratios (ORs) for the associations between pain and fatigue (FACIT-Fatigue), and disease activity (Health Assessment Questionnaire [HAQ], SJC, and Tender Joint Count [TJC]), RP (UP C-reactive protein <10 mg / L), and RP-strict (RP with swollen joint count ≤1), based on patient accepted symptom status [PASS], with a scale threshold of pain >40 mm [0-100]. Demographic and clinical characteristics of the populations for each trial are outlined in Table 1.

[0127] [Table 1] [Table 2]

Claims

1. 1. A method of treating intolerable pain (UP) in a subject having rheumatoid arthritis in need thereof, comprising administering a therapeutically effective dose of an antibody that specifically binds to an IL-6 receptor, wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising complementarity determining regions LCDR1, LCDR2, and LCDR3; (a) HCDR1 comprises the amino acid sequence of SEQ ID NO:3; (b) HCDR2 comprises the amino acid sequence of SEQ ID NO:4; (c) HCDR3 comprises the amino acid sequence of SEQ ID NO:5; (d) LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; (e) LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and (f) LCDR3 comprises the amino acid sequence of SEQ ID NO: 8 The method.

2. The method of claim 1, wherein the antibody that specifically binds to the IL-6 receptor comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO:

2.

3. 10. The method of claim 1, wherein the subject has intractable pain (RP).

4. The method of claim 1 , wherein the subject has a strict RP.

5. 10. The method of claim 1, wherein the subject experiences a decline in visual analog scale (VAS) to less than 40 mm after 24 weeks of treatment.

6. 10. The method of claim 1, wherein the subject experiences a decline in VAS to less than 40 mm after 52 weeks of treatment.

7. 10. The method of claim 1, wherein the subject has a Disease Activity Score (DAS) of 3.2 to 5.

1.

8. 10. The method of claim 1, wherein the subject has a DAS greater than 5.

1.

9. The method of any one of claims 1 to 8, wherein the antibody is administered subcutaneously.

10. The method of any one of claims 1 to 9, wherein the subject is administered a dose of about 150 mg or about 200 mg of the antibody.

11. The method of any one of claims 1 to 10, wherein the antibody is administered to the subject at least once every two weeks.

12. 12. The method of any one of claims 1 to 11, wherein inflammation in the subject is reduced with a disease-modifying antirheumatic drug (DMARD).

13. 13. The method of claim 12, wherein the DMARD is a sDMARD.

14. 13. The method of claim 12, wherein the DMARD is methotrexate.

15. 15. The method of claim 14, wherein the subject has moderately to severely active rheumatoid arthritis.

16. The method of any one of claims 1 to 15, wherein the subject does not receive any other DMARD during the course of administration of the antibody.

17. The method of any one of claims 1 to 15, wherein the subject is also administered one or more additional DMARDs along with the antibody.

18. 18. The method of claim 17, wherein the one or more additional DMARDs comprise methotrexate.

19. 18. The method of claim 17, wherein the one or more additional DMARDs comprises a TNF antagonist.

20. 20. The method of claim 19, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

21. 21. The method of any one of claims 1 to 20, wherein the subject has previously been treated unsuccessfully for rheumatoid arthritis by administering at least one DMARD other than an antibody.

22. 22. The method of claim 21, wherein the DMARD is methotrexate.

23. 22. The method of claim 21, wherein the DMARD is a TNF antagonist.

24. 24. The method of claim 23, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

25. 25. The method of any one of claims 1 to 24, wherein the subject is intolerant to one or more DMARDs or the subject is considered a poor candidate for continued treatment with one or more DMARDs.

26. The method of any one of claims 1 to 24, wherein the subject has had an inadequate response to one or more DMARDs.

27. 27. The method of claim 25 or 26, wherein the DMARD is methotrexate.

28. 27. The method of claim 25 or 26, wherein the DMARD is a TNF antagonist.

29. 29. The method of claim 28, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

30. 1. A method of treating intolerable pain (UP) in a subject in need thereof, comprising: (i) selecting a subject with rheumatoid arthritis and UP; (ii) administering to the subject a therapeutically effective dose of an antibody that specifically binds to the IL-6 receptor; wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising complementarity determining regions LCDR1, LCDR2, and LCDR3: (a) HCDR1 comprises the amino acid sequence of SEQ ID NO:3; (b) HCDR2 comprises the amino acid sequence of SEQ ID NO:4; (c) HCDR3 comprises the amino acid sequence of SEQ ID NO:5; (d) LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; (e) LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and (f) LCDR3 comprises the amino acid sequence of SEQ ID NO: 8 The method.

31. The method of claim 30, wherein the antibody that specifically binds to the IL-6 receptor comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO:

2.

32. 31. The method of claim 30, wherein the subject has intractable pain (RP).

33. 31. The method of claim 30, wherein the subject has strict RP.

34. 31. The method of claim 30, wherein the subject experiences a decline in visual analog scale (VAS) to less than 40 mm after 24 weeks of treatment.

35. 31. The method of claim 30, wherein the subject experiences a decline in VAS to less than 40 mm after 52 weeks of treatment.

36. 31. The method of claim 30, wherein the subject has a Disease Activity Score (DAS) of 3.2 to 5.

1.

37. 31. The method of claim 30, wherein the subject has a DAS greater than 5.

1.

38. The method of any one of claims 30 to 37, wherein the antibody is administered subcutaneously.

39. 39. The method of any one of claims 30-38, wherein the subject is administered a dose of about 150 mg or about 200 mg of the antibody.

40. 40. The method of any one of claims 30 to 39, wherein the antibody is administered to the subject at least once every two weeks.

41. 31. The method of any one of claims 30 to 30, wherein inflammation in the subject is reduced with a disease-modifying antirheumatic drug (DMARD).

42. 42. The method of claim 41, wherein the DMARD is a sDMARD.

43. 42. The method of claim 41, wherein the DMARD is methotrexate.

44. 31. The method of claim 30, wherein the subject has moderately to severely active rheumatoid arthritis.

45. 45. The method of any one of claims 30 to 44, wherein the subject does not receive any other DMARD during the course of administration of the antibody.

46. 46. ​​The method of any one of claims 30 to 45, wherein the subject is also administered one or more additional DMARDs along with the antibody.

47. 47. The method of claim 46, wherein the one or more additional DMARDs include methotrexate. How to post.

48. 47. The method of claim 46, wherein the one or more additional DMARDs comprises a TNF antagonist.

49. 49. The method of claim 48, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

50. 50. The method of any one of claims 30 to 49, wherein the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD other than an antibody, but has been unsuccessful.

51. 51. The method of claim 50, wherein the DMARD is methotrexate.

52. 51. The method of claim 50, wherein the DMARD is a TNF antagonist.

53. 53. The method of claim 52, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

54. 54. The method of any one of claims 30 to 53, wherein the subject is intolerant to one or more DMARDs or the subject is considered a poor candidate for continued treatment with one or more DMARDs.

55. 55. The method of any one of claims 30 to 54, wherein the subject has had an inadequate response to one or more DMARDs.

56. 56. The method of claim 54 or 55, wherein the DMARD is methotrexate.

57. 56. The method of claim 54 or 55, wherein the DMARD is a TNF antagonist.

58. 58. The method of claim 57, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

59. 1. An antibody for use in treating intolerable pain in a patient with rheumatoid arthritis in need thereof, the antibody specifically binding to an IL-6 receptor, the antibody comprising a heavy chain variable region comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising complementarity determining regions LCDR1, LCDR2, and LCDR3: (a) HCDR1 comprises the amino acid sequence of SEQ ID NO:3; (b) HCDR2 comprises the amino acid sequence of SEQ ID NO:4; (c) HCDR3 comprises the amino acid sequence of SEQ ID NO:5; (d) LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; (e) LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and (f) LCDR3 comprises the amino acid sequence of SEQ ID NO: 8 The antibody.

60. 60. The antibody for use according to claim 59, wherein the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

61. 60. The antibody for use according to claim 59, wherein the subject has intractable pain (RP).

62. 60. The antibody for use of claim 59, wherein the subject has strict RP.

63. 60. The antibody for use of claim 59, wherein the subject experiences a decline in visual analog scale (VAS) of less than 40 mm after 24 weeks of treatment.

64. 60. The antibody for use of claim 59, wherein the subject experiences a reduction in VAS to less than 40 mm after 52 weeks of treatment.

65. 60. The antibody for use according to claim 59, wherein the subject has a Disease Activity Score (DAS) of 3.2 to 5.

1.

66. 60. The antibody for use of claim 59, wherein the subject has a DAS of greater than 5.

1.

67. 67. The antibody for use according to any one of claims 59 to 66, wherein the antibody is administered subcutaneously.

68. 68. The antibody for use of any one of claims 59 to 67, wherein the subject is administered a dose of about 150 mg or about 200 mg of the antibody.

69. 69. The antibody for use according to any one of claims 59 to 68, wherein the antibody is administered to the subject at least once every two weeks.

70. 70. The antibody for use according to any one of claims 59 to 69, wherein inflammation in the subject is reduced by a disease-modifying antirheumatic drug (DMARD).

71. 71. The antibody for use of claim 70, wherein the DMARD is a sDMARD.

72. 71. The antibody for use of claim 70, wherein the DMARD is methotrexate.

73. 73. The antibody for use according to any one of claims 59 to 72, wherein the subject has moderately to severely active rheumatoid arthritis.

74. 74. The antibody for use according to any one of claims 59 to 73, wherein the subject does not receive any other DMARD during the course of administration of the antibody.

75. 74. The antibody for use according to any one of claims 59 to 73, wherein the subject is also administered one or more additional DMARDs together with the antibody.

76. 76. The antibody for use of claim 75, wherein the one or more additional DMARDs comprise methotrexate.

77. 76. The antibody for use of claim 75, wherein the one or more additional DMARDs comprise a TNF antagonist.

78. 78. The antibody for use of claim 77, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

79. 79. The antibody for use according to any one of claims 59 to 78, wherein the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody, but without success.

80. 80. The antibody for use of claim 79, wherein the DMARD is methotrexate.

81. 80. The antibody for use of claim 79, wherein the DMARD is a TNF antagonist.

82. 82. The antibody for use of claim 81, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

83. 83. The antibody for use according to any one of claims 59 to 82, wherein the subject is intolerant to one or more DMARDs or the subject is considered to be a poor candidate for further treatment with one or more DMARDs.

84. 83. The antibody for use according to any one of claims 59 to 82, wherein the subject has had an inadequate response to one or more DMARDs.

85. 85. The antibody for use according to claim 83 or 84, wherein the DMARD is methotrexate.

86. 85. The antibody for use according to claim 83 or 84, wherein the DMARD is a TNF antagonist.

87. 87. The antibody for use of claim 86, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

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