Compositions and methods for treating non-inflammatory pain in subjects with rheumatoid arthritis

Abstract

The present disclosure relates to the use of anti-IL6 receptor antibodies to treat non-inflammatory pain in subjects with rheumatoid arthritis.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 032,035 filed May 29, 2020, U.S. Provisional Patent Application No. 63 / 077,378 filed September 11, 2020, and European Provisional Patent Application No. 21315081.6 filed May 11, 2021. The full disclosures of each of these applications are incorporated herein by reference in their entirety.

[0002] This disclosure relates to the field of treating non-inflammatory pain in subjects who have had or currently have rheumatoid arthritis. [Background technology]

[0003] Rheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis, affecting about 1% of the population. It is an autoimmune disease in which the body's immune system attacks the inner lining of the membranes surrounding the joints. RA is the cause of chronic inflammation that can lead to joint pain, swelling, and stiffness. Pain is the core-set domain and a troublesome symptom for patients with RA and can also be directly related to inflammation, although non-inflammatory pain (NIP) is also common in patients with RA.

[0004] Sarilumab is an interleukin-6 receptor antagonist for the treatment of adults with moderate to severe rheumatoid arthritis (RA) who have an inadequate response to or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). [Overview of the project] [Means for solving the problem]

[0005] This disclosure presents methods and compositions for treating NIP in subjects with rheumatoid arthritis. In various embodiments, treatment of the subject includes administering a therapeutically effective amount of an antibody that specifically binds to IL-6R.

[0006] In one embodiment, the present disclosure provides a method for treating non-inflammatory pain (NIP) in a subject having rheumatoid arthritis and requiring such treatment, comprising 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 including complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region including complementarity-determining regions 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 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. In various embodiments, the subject has at least 21 tender joints (TJCs). In various embodiments, the number of tender joints differs from the number of swollen joints by at least 5. In various embodiments, the antibody is administered subcutaneously. In various embodiments, the subject is administered an antibody dose of approximately 150 mg or approximately 200 mg. In various embodiments, the antibody is administered to the subject at least once every two weeks. In various embodiments, the subject has moderate to severe active rheumatoid arthritis. In various embodiments, the subject is not administered any other DMARDs in the course of antibody administration. In various embodiments, the subject is also administered one or more additional DMARDs along with the antibody. In various embodiments, the one or more additional DMARDs include methotrexate. In various embodiments, the one or more additional DMARDs include a TNF antagonist. In various embodiments, the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. In various embodiments, subjects have previously received treatment for rheumatoid arthritis with at least one DMARD different from an antibody, but without success. 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 the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. In various embodiments, the subject is intolerant to one or more DMARDs, or is considered unsuitable as a candidate for continued treatment with one or more DMARDs. In various embodiments, the subject has had an inadequate response to one or more DMARDs. 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 the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0007] In another embodiment, the Disclosure provides a method for treating rheumatoid arthritis and NIP in a subject requiring it, comprising selecting a subject having NIP and 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, 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 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. In various embodiments, the subject has at least 21 TJCs. In various embodiments, the number of tender joints is at least 5 less than the number of swollen joints. In various embodiments, the antibody is administered subcutaneously. In various embodiments, the subject is administered an antibody dose of approximately 150 mg or approximately 200 mg. In various embodiments, the antibody is administered to the subject at least once every two weeks. In various embodiments, the subject has moderate to severe active rheumatoid arthritis. In various embodiments, the subject is not administered any other DMARDs in the course of antibody administration. In various embodiments, the subject is also administered one or more additional DMARDs along with the antibody. In various embodiments, one or more additional DMARDs include methotrexate. In various embodiments, one or more additional DMARDs include a TNF antagonist. In various embodiments, the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. In various embodiments, the subject has previously received treatment for rheumatoid arthritis with at least one DMARD other than the antibody, but without success. 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 the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. In various embodiments, the subject is intolerant to one or more DMARDs, or is considered unsuitable as a candidate for continued treatment with one or more DMARDs. In various embodiments, the subject has had an inadequate response to one or more DMARDs. 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 the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0008] In another embodiment, the present disclosure provides an antibody for use in the treatment of NIP in patients with rheumatoid arthritis who require it, the antibody specifically binds to the IL-6 receptor and comprises a heavy chain variable region including complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region including complementarity-determining regions 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 various embodiments, the antibody specifically binds to the IL-6 receptor and comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In various embodiments, the subject has at least 21 TJCs. In various embodiments, the number of tender joints is at least 5 less than the number of swollen joints. In various embodiments, the antibody is administered subcutaneously. In various embodiments, the subject is administered an antibody dose of approximately 150 mg or approximately 200 mg. In various embodiments, the antibody is administered to the subject at least once every two weeks. In various embodiments, the subject has moderate to severe active rheumatoid arthritis. In various embodiments, the subject is not administered any other DMARDs during the course of antibody administration. In various embodiments, the subject is also administered one or more additional DMARDs along with the antibody. In various embodiments, one or more additional DMARDs include methotrexate. In various embodiments, one or more additional DMARDs include a TNF antagonist. In various embodiments, the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. In various embodiments, the subject has previously received treatment for rheumatoid arthritis with at least one DMARD other than the antibody, but without success. In various embodiments, the DMARD is methotrexate. In various embodiments, DMARDs are TNF antagonists.In various embodiments, the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. In various embodiments, the subject is intolerant to one or more DMARDs, or is considered unsuitable as a candidate for continued treatment with one or more DMARDs. In various embodiments, the subject has had an inadequate response to one or more DMARDs. 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 the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0009] The aforementioned and other features and advantages of the present invention will be better understood from the following detailed description of exemplary embodiments in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0010] [Figure 1] This figure shows the percentage of patients with NIP by week 12 and week 24, broken down by treatment. [Figure 2] This figure shows the NIP status of sarilumab or adalimumab responders at week 24. [Modes for carrying out the invention]

[0011] Inflammation is a major cause of pain in rheumatoid arthritis (RA). However, some patients experience more pain than expected based on the amount of synovitis observed, which may indicate the presence of non-inflammatory pain (NIP). This disclosure provides pharmaceutical compositions for the treatment of NIP in subjects with RA and methods for using these compositions. These compositions and methods comprise at least one antibody that specifically binds to the interleukin-6 receptor (hIL-6R).

[0012] Where used in the claims and the summary and detailed description of the invention herein, the term “about” in quantitative terms 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” includes 90 mg to 110 mg, including both ends, and the phrase “about 2500 mg” includes 2250 mg to 2750 mg. Where applied to percentages, the term “about” refers to plus or minus 10% of that percentage. For example, the phrase “about 20%” includes 18 to 22%, and “about 80%” includes 72 to 88%, including both ends. Furthermore, where “about” is used with quantitative terms herein, it is understood that, in addition to plus or minus 10% of the value, the exact value of the quantitative term is also intended and described. For example, the phrase “about 23%” intends, describes, and includes exactly 23%.

[0013] It should be noted that the term “one (a)” or “one (an)” entity refers to one or more of those entities; for example, “one symptom” is understood to represent one or more symptoms. Therefore, the terms “one (a)” (or “one (an)”), “one or more,” and “at least one” can be used interchangeably in this specification.

[0014] Furthermore, as used herein, “and / or” should be interpreted as a specific disclosure of each of two identified features or components, with or without the other. Accordingly, the term “and / or” as used 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” as used in phrases such as “A, B, and / or C” is intended to include 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).

[0015] In this specification, each embodiment is described using the language “comprising,” but it will be understood that other similar embodiments are also provided that are described using the terms “consisting of” and / or “consisting essentially of.”

[0016] The term “pain” refers to an unpleasant sensation caused by a severe or damaging stimulus, including disease, injury, or psychological 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 severe pain.

[0017] As used herein, “acute pain” refers to pain lasting less than three months. In some embodiments, acute pain is associated with soft tissue injury and gradually disappears as the injury heals. It is hypothesized that acute pain is detected by specialized nerve receptors (nociceptors) that detect and respond to strong signals that convey information about danger to the organism, thus allowing the organism to mobilize its defenses. In rheumatoid arthritis (RA), persistent signaling from inflamed joints may cause a decrease in the threshold for nociceptor stimulation, resulting in hypersensitivity to nociceptive stimuli (peripheral sensitization). Local factors such as cytokines are thought to have a direct, non-inflammatory effect on sensory neurons.

[0018] The term “chronic pain” refers to pain that lasts for at least three months. In some embodiments, chronic pain is described as pain that persists beyond the expected healing period. In some embodiments, chronic pain includes unexpectedly prolonged pain in patients with RA who appear to be in remission. Chronic pain is often associated with central sensitization, which can be seen as abnormal neuronal activity due to peripheral sensitization of primary sensory neurons and as a sign of subsequent or additional sensitization of neurons in the CNS. This condition may have little to no connection to previous or current inflammation.

[0019] As used herein, the term "non-inflammatory pain" or "NIP" refers to pain that is not associated with inflammation. In some cases, NIP is caused by arthralgia or polyarthralgia. NIP typically exists without systemic symptoms such as fever or weight loss. NIP may also exist without swelling or warmth. NIP can also be characterized by slight morning stiffness that is intermittent and lasts less than 60 minutes, and / or stiffness that worsens without improvement by activity. In some embodiments, NIP includes acute or chronic pain. In some embodiments, NIP includes allodynia, enhanced pain, and neuropathic pain. In some embodiments, subjects having NIP are also experiencing central sensitization. In some embodiments, subjects having NIP are in the early stages of the course of RA. In some embodiments, these subjects have not been diagnosed with RA and do not exhibit symptoms of inflammation. In some embodiments, subjects having NIP have extra-articular or diffuse pain.

[0020] As used herein, "central sensitization" refers to an abnormality in pain processing in the spinal cord and brain that results in increased pain sensitivity at a site of spread, enhances the overall response state of the central nervous system (CNS) in response to sensory impulses, and is interpreted as pain enhancement in the brain through complex filters. This category may include psychosocial interactions with pain perception in chronic pain states. In central sensitization, for example, new nociceptive pathways are generated by mobilizing mechanoreceptors that transmit pain. This occurs mainly by enhanced sensitization in the spine, and eventually this state may become self-perpetuating without injury and become unrelated to the protective purpose.

[0021] Therefore, some embodiments involve patients with underlying inflammatory pain due to RA, which can essentially cause only mild pain. As used herein, “hyperalgesia” or “pain augmentation” refers to relatively mild pain that is exaggerated and experienced as much more severe pain. The sensation of pain in this state may arise from stimuli that are not normally painful, such as movements that are normally interpreted as informational input (e.g., clenching a fist). As used herein, “allodynia” refers to pain arising from stimuli that are not normally painful. Clinical findings suggest that in some cases of early RA, pain and inflammation are decoupled, for example, small, bilateral, and symmetrical arthralgia may occur before arthritis is objectively demonstrated. Conversely, some patients with RA present only with arthritis (and joint damage) and no pain (the “robust rheumatoid” type). In some embodiments, there is a range of RA symptoms exhibiting phenotypes from patients with primarily identifiable synovitis accompanied by pain to patients presenting only with pain. For example, attempts are being made to identify these RA patients who present only with pain and have non-inflammatory pain early in the course of the disease by using the ratio of the number of swollen joints to the number of tender joints.

[0022] Discrepancies have been reported between patient-reported pain and objective assessments of inflammation, and patient-reported pain does not appear to correlate well with physician assessments and inflammation measurements in studies. The view that pain is not solely due to inflammation is also supported by the observation that pain is sufficiently relieved before inflammation is reduced by anti-cytokine therapy, and that pain persists in approximately 12–50% of patients in remission and in 82% of patients with disease that is "somewhat completely controlled" after treatment of the inflammatory component of RA. Rheumatologists often attribute this residual pain to joint damage underlying fibromyalgia or RA, but the latter explanation seems unlikely, given that radiographic damage has been shown to account for only 2.1% of patient-reported pain. The proportion of patients with RA who meet the classification criteria for fibromyalgia also increases throughout the course of disease progression, which also suggests central pain enhancement.

[0023] RA is a disease involving joints. However, in some embodiments, pain has often been reported to be extra-articular, sometimes diffuse, with extensive pain in remote non-articular sites and joints, and may vary by location and time. This pain does not seem to be related to synovitis and is thought to be due to changes in central pain processing. For example, when pain sensations such as stinging, burning, or cutting are reported, for astute clinicians, the pain profile of patients with RA may be a clue suggesting that it is due to nervous system involvement. CNS involvement is becoming evident, and some form of identifiable neuropathy is involved in a significant proportion of patients with RA. Autonomic neuropathy is also increasingly confirmed to be associated with RA. Therefore, in some embodiments, the CNS is an important associated organ system in RA.

[0024] Many clinically apparent dissociations between pain and inflammation suggest that some of the pain in RA is an independent problem that overlaps with inflammation but is not due solely to inflammation, involving multiple mechanisms. In some embodiments, the pain in patients with RA is derived from a certain form of inflammation or injury. Furthermore, RA patients feel pain that is transmitted by the peripheral nervous system, amplified in the spinal cord, and experienced in the CNS, simultaneously and independently induced (with no or minimal sensory stimuli). In the brain, more distal sensations are mixed with external psychosocial factors. In fact, pain has been described as an "opinion." In various embodiments, this pain is a distinct entity from inflammatory pain, and this form of pain is at least partially due to abnormalities related to cytokine dysregulation.

[0025] In some embodiments, cytokines cause joint inflammation (which in turn causes pain), but there may be other effects of cytokines that extend to other parts of the peripheral and nervous systems, causing pain more directly and not necessarily correlating with inflammation. In some embodiments, cytokine IL-6 plays an important role in this regard.

[0026] In some embodiments, NIP is defined as the difference between the number of tender joints (TJC) and the number of swollen joints (SJC) of 28 joints, using the established formula: TJC-SJC≧7.

[0027] In some embodiments, pain experienced in the previous week is measured. In some embodiments, pain experienced two, three, four, five, six, seven, or eight weeks prior, or longer, is measured. In some embodiments, pain experienced one month prior is measured. In some embodiments, pain experienced two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve months prior, or longer, is measured. In some embodiments, pain experienced one year prior is measured. In some embodiments, pain experienced two, three, four, five, six, seven, eight, nine, or ten years prior, or longer, is measured.

[0028] IL-6 directly interacts with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit, initiating intracellular signaling via the Janus kinase (JAK) signaling factor and activator of transcription (STAT) (JAK / STAT) and the Ras Raf-mitogen-activated protein kinase (MAPK) pathway. IL-6Rα also exists in a soluble form, which is involved in transsignaling, allowing IL-6 to influence cells that do not express IL-6Rα, including synovial cells in the joints.

[0029] Sarilumab (SAR153191), also known as REGN88, is a fully human recombinant IgG1 kappa monoclonal antibody against the α subunit (IL-6Rα) of the IL-6 receptor complex. Sarilumab blocks IL-6 binding, disrupting the cytokine-mediated signaling cascade.

[0030] antibody This disclosure includes a method comprising administering an antibody or an antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term “hIL-6R” means a human cytokine receptor that specifically binds to human interleukin-6 (IL-6). In certain embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hIL-6R.

[0031] 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 their polymers (e.g., IgM). Each heavy chain includes a heavy chain variable region (hereinafter abbreviated as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains CH1, CH2, and CH3. Each light chain includes a light chain variable region (hereinafter abbreviated as LCVR or VL) and a light chain constant region. The light chain constant region contains one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which contain more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or its antigen-binding moiety) may be identical to human germline sequences or may be naturally or artificially modified. The amino acid consensus sequence can be defined based on a parallel analysis of two or more CDRs.

[0032] The term “antibody,” as used herein, also includes the antigen-binding fragment of a complete antibody molecule. Terms such as “antigen-binding portion” and “antigen-binding fragment” of an antibody, as used herein, include any naturally occurring, enzymatically obtained, 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 commercially available sources, DNA libraries (e.g., including phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated using chemical or molecular biological techniques, for example, to sequence one or more variable and / or constant domains into appropriate configurations, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0033] 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 that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as the CDR3 peptide), or constrained FR3-CDR3-FR4 peptides. Other manipulated molecules, such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-implanted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent and bivalent nanobodies), small modular immunotherapy drugs (SMIPs), and shark variable IgNAR domains, are also included in the expression “antigen-binding fragment” as used herein.

[0034] The antigen-binding fragment of an antibody typically contains 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 within a frame of one or more framework sequences. In an antigen-binding fragment having a VH domain associated with a VL domain, the VH and VL domains are positioned relative to each other in any suitable arrangement. For example, the variable region may be a dimer and may 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.

[0035] In certain embodiments, the antigen-binding fragment of an antibody may include at least one variable domain covalently bound to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains found within the 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 either directly linked to each other or linked by a complete or partial hinge or linker region. In various embodiments, the hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, in various embodiments, the antigen-binding fragment of the antibody may include homodimers or heterodimers (or other polymers) of any of the variable and constant domain configurations listed above, non-covalently bonded (e.g., by disulfide bonds) to each other and / or one or more monomeric VH or VL domains.

[0036] In certain embodiments, the antibody or antibody fragment for use in the methods disclosed herein may be a monospecific antibody. In certain embodiments, the antibody or antibody fragment for use in the methods disclosed herein may be a multispecific antibody that is specific to a different epitope of one target polypeptide, or may contain antigen-binding domains specific to epitopes of one or more target polypeptides. 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 With the use of the domain, the first and second IgC H3 The domains differ from each other by at least one amino acid, and this difference of at least one amino acid reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody lacking an amino acid difference. In one embodiment, a first Ig C H3 The domain binds to protein A and the second Ig C H3 The domain contains mutations that reduce or eliminate protein A binding, such as the H95R modification (according to IMGT exon numbering; H435R according to EU numbering). Second C H3 This may further include the Y96F modification (by IMGT; Y436F by EU). Second C H3Further modifications found within the IgG1 antibody include D16E, L18M, N44S, K52N, V57M, and V82I (according to IMGT; D356E, L358M, N384S, K392N, V397M, and V422I according to EU); N44S, K52N, and V82I (according to IMGT; N384S, K392N, and V422I according to EU); and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (according to IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I according to EU). The above-mentioned variations of the bispecific antibody format are considered to be within the scope of certain embodiments. Any polyspecific antibody format, including the exemplary bispecific antibody formats disclosed herein, is adapted in various embodiments for use in association with an antigen-binding fragment of an anti-IL-6R antibody using conventional techniques available in the art.

[0037] 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 region 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 with germline sequences available, for example, from publicly available antibody sequence databases. This disclosure includes antibodies derived from any of the amino acid sequences disclosed herein and their antigen-binding fragments, in which one or more amino acids in the framework and / or CDR region are reverse-mutated to the corresponding germline residue(s) or a conserved amino acid substitution (native or unnatural) of the corresponding germline residue(s) (such sequence changes are referred to herein as “germline reverse mutations”). Those skilled in the art can readily generate a number of antibodies and antigen-binding fragments containing one or more individual germline reverse mutations or combinations thereof starting from the heavy and light chain variable domain sequences disclosed herein. In certain embodiments, all framework residues and / or CDR residues within the VH and / or VL domains are reverse-mutated to germline sequences. In other embodiments, only certain residues are reverse-mutated to germline sequences, for example, only mutant residues found within the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutant residues found within CDR1, CDR2, or CDR3. Furthermore, antibodies are included herein that may include any combination of two or more germline reverse mutations within the framework and / or CDR regions, i.e., certain individual residues are reverse-mutated to germline sequences, while certain other residues that are not germline sequences are maintained. Once obtained, antibodies and antigen-binding fragments containing one or more germline reverse mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or operative biological properties (if applicable), or reduced immunogenicity.Antibodies and antigen-binding fragments obtained by this general method are included in this disclosure.

[0038] The constant region of an antibody is crucial for its ability to bind complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes are selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0039] As used herein, the term “human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies characterized in this disclosure may, in various embodiments, nevertheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutation in vivo), such as CDRs and, in some embodiments, CDR3. However, as used herein, the term “human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been transplanted onto a human framework sequence.

[0040] The term “recombinant human antibody,” as used herein, is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (as further described below), antibodies isolated from recombinant combinatorial human antibody libraries (as further described below), antibodies isolated from animals transgenic to human immunoglobulin genes (e.g., mice), or antibodies prepared, expressed, produced or isolated by any other means involving splicing of human immunoglobulin gene sequences to 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, if animal transgenicity for human Ig sequences is used, in vivo somatic mutagenesis), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and relevant to human germline VH and VL sequences, but sequences that do not naturally exist in vivo within the human antibody germline repertoire.

[0041] Human antibodies can exist in two forms related to hinge heterogeneity. In one embodiment, the immunoglobulin molecule contains a stable quad-chain construct of approximately 150–160 kDa, with the dimer held together by interchain heavy-chain disulfide bonds. In another embodiment, the dimer is not linked via interchain disulfide bonds, and the molecule of approximately 75–80 kDa consists of covalently bonded light and heavy chains (half-antibodies). In certain embodiments, these forms were extremely difficult to separate, even after affinity purification.

[0042] The frequency of occurrence of the second form in various intact IgG isotypes is attributed, but is not limited to, structural differences related to the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using the human IgG1 hinge. In various embodiments, this disclosure includes antibodies having one or more mutations in the hinge, CH2, or CH3 region, which may be desirable, for example, in production to improve the yield of the desired antibody form.

[0043] As used herein, “isolated antibody” means an antibody identified, isolated, and / or recovered from at least one component of its natural environment. For example, an antibody isolated or removed from at least one component of an organism, or from a tissue or cell in which antibodies are naturally present or 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 subjected to at least one purification or isolation step. In various embodiments, an isolated antibody may substantially contain no other cellular material and / or chemicals.

[0044] The term "specifically binds" and the like means that an antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-6R as used herein, when measured by a surface plasmon resonance assay, binds to IL-6R (e.g., human IL-6R) or a portion thereof with 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 about 0.5 nM. 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 may also be characterized by a dissociation constant of at least about 1×10 -6 M or less. In other embodiments, the dissociation constant is at least about 1×10 -7 M, 1×10 -8 M, or 1×10 -9 M. However, an isolated antibody that specifically binds to human IL-6R may have cross-reactivity to other antigens such as IL-6R molecules from other (non-human) species.

[0045] The term "surface plasmon resonance" as used herein refers to an optical phenomenon that enables 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).

[0046] The term "KD," as used herein, is intended to refer to the equilibrium dissociation constant of antibody-antigen interactions.

[0047] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within the variable region of an antibody molecule, known as a paratope. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions on an antigen and have different biological effects. Epitopes can be steric or linear. Steric 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 situations, epitopes may include sugar, phosphoryl, or sulfonyl groups on an antigen.

[0048] Anti-IL-6R antibodies useful in the methods described herein may, in various embodiments, include one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR region of the heavy and light chain variable domains compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from publicly available antibody sequence databases. In various embodiments, this disclosure includes methods involving the use of antibodies derived from any of the amino acid sequences disclosed herein and their antigen-binding fragments, in which one or more amino acids in the framework and / or CDR region are mutated to the corresponding residue(s) of the germline sequence from which the antibody is derived, or to the corresponding residue(s) of another human germline sequence, or to a conserved amino acid substitution of the corresponding germline residue(s) (such sequence changes are collectively referred to herein as “germline mutations”). A number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof can be constructed. In certain embodiments, all framework and / or CDR residues within the VH domain and / or VL domain are reverse-mutated to residues found in the original germline sequence from which the antibody originated. In other embodiments, only certain residues are reverse-mutated to the original germline sequence, for example, only mutant residues found in the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutant residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more framework and / or CDR residues are reverse-mutated to corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody originally originated).Furthermore, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR region, for example, certain individual residues may be mutated to corresponding residues in certain germline sequences, while certain different residues, which are different from the original germline sequence, are maintained or mutated to corresponding residues in different germline sequences. 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 operative biological properties (if applicable), or reduced immunogenicity. The use of antibodies and antigen-binding fragments obtained in this general manner is encompassed in this disclosure.

[0049] The Disclosure also includes methods involving the use of an anti-IL-6R antibody comprising a variant of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the Disclosure includes the use of an anti-IL-6R antibody comprising an HCVR, LCVR, and / or CDR amino acid sequence having, for example, 10 or fewer, 8 or fewer, 6 or fewer, or 4 or fewer conservative amino acid substitutions to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0050] According to this disclosure, an anti-IL-6R antibody or its antigen-binding fragment includes, in various embodiments, a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing any of the amino acid sequences of the anti-IL-6R antibody described in U.S. Patent No. 7,582,298, which is incorporated herein by reference. In certain embodiments, the anti-IL-6R antibody or its antigen-binding fragment includes a heavy chain complementarity-determining region (HCDR) of the HCVR containing the amino acid sequence of SEQ ID NO: 1, and a light chain complementarity-determining region (LCDR) of the LCVR containing the amino acid sequence of SEQ ID NO: 2. In one embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), where 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 another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1, and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0051] In another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the extracellular domain of hIL-6R contains the amino acid sequence of SEQ ID NO: 11. According to certain exemplary embodiments, the method of the present disclosure involves the use of an anti-IL-6R antibody known in the art, or its bioequivalent, called sarilumab.

[0052] The amino acid sequence of Sequence ID No. 1 is: EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSS That is the case.

[0053] The amino acid sequence of Sequence ID No. 2 is: DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK That is the case.

[0054] The amino acid sequence of Sequence ID No. 3 is RFTFDDYA.

[0055] The amino acid sequence of sequence number 4 is ISWNSGRI.

[0056] The amino acid sequence of sequence number 5 is AKGRDSFDI.

[0057] The amino acid sequence of sequence number 6 is QGISSW.

[0058] The amino acid sequence of sequence number 7 is GAS.

[0059] The amino acid sequence of sequence number 8 is QQANSFPYT.

[0060] The amino acid sequence of sequence number 9 is: EVQLVESGGGLVQPGRSLRLSCAAS RFTFDDYA MHWVRQAPGKGLEWVSG ISWNSGRI GYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYC AKGRDSFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK That is the case.

[0061] The amino acid sequence of sequence number 10 is: DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC That is the case.

[0062] The amino acid sequence of sequence number 11 is: MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLA VPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITTVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD That is the case.

[0063] The term "bioequivalence," as used herein, refers to a molecule that has similar bioavailability (availability and degree of utilization) after administration at the same molar dose and under similar conditions (e.g., the same route of administration) so that it can be expected that its effects are essentially the same as those of a comparison molecule in terms of both efficacy and safety. Two pharmaceutical compositions containing an anti-IL-6R antibody are bioequivalence if they are pharmaceutically equivalent, meaning they contain the same amount of active ingredient (e.g., IL-6R antibody) in the same dosage form to meet the same or equivalent criteria for the same route of administration. Bioequivalence can be determined, for example, by an in vivo study comparing the pharmacokinetic parameters of the two compositions. Parameters commonly used in bioequivalence studies include the maximum plasma concentration (Cmax) and the area under the plasma drug concentration-time curve (AUC).

[0064] The disclosure in certain embodiments relates to a method of administering an antibody comprising a heavy chain variable region containing the sequence of SEQ ID NO: 1 and a light chain variable region containing the sequence of SEQ ID NO: 2.

[0065] This disclosure provides pharmaceutical compositions containing such antibodies, and methods for using these compositions.

[0066] In various embodiments, the antibody comprises a heavy chain variable region containing the sequence of SEQ ID NO: 1 and a light chain variable region containing the sequence of SEQ ID NO: 2, and is an antibody that specifically binds to the human interleukin-6 receptor (hIL-6R). See International Publication No. 2007 / 143168, which is incorporated herein by reference in its entirety. In one embodiment, the antibody comprises a heavy chain variable region containing the sequence of SEQ ID NO: 9 and a light chain variable region containing the sequence of SEQ ID NO: 10. In various embodiments, the antibody is sarilumab.

[0067] DMARD Disease-modifying antirheumatic drugs (DMARDs) are drugs defined by their use to slow disease progression in rheumatoid arthritis. DMARDs have been classified as synthetic (sDMARDs) and biological (bDMARDs). Synthetic DMARDs include, but are not exhaustive, methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. Biological DMARDs include, but are not exhaustive, adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, and tocilizumab. In some embodiments, DMARDs are TNF antagonists. TNF antagonists include, but are not limited to, etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0068] Method of administration and prescription The methods described herein involve administering a therapeutically effective dose of anti-IL-6R antibody to a target. As used herein, “effective dose” or “therapeutic effective dose” is the dose of the therapeutic agent that results in the treatment of NIP. In certain embodiments, the effective dose is the dose of the therapeutic agent that results in the treatment of NIP that persists despite inflammatory control (IC). As used herein, “to treat” means to cause a detectable improvement in one or more symptoms associated with NIP, or to cause a biological effect (e.g., a decrease in the level of a particular biomarker) that correlates with the underlying pathological mechanism causing the condition or symptoms. For example, the dose of anti-IL-6R antibody that causes a reduction in NIP is considered a “therapeutic effective dose.”

[0069] "Improvement" of NIP-related symptoms refers, in various embodiments, to a reduction in the incidence of pain symptoms that may correlate with an improvement in one or more pain-related tests, scores, or metrics (as described herein). For example, improvement may correlate with a decrease from baseline in one or more pain criteria. In various embodiments, improvement may include a decrease from baseline in a VAS. As used herein, the term "baseline" means a numerical value of a pain-related parameter for a patient before or at the time of administration of the antibody of the Technology, with respect to the pain-related parameter. Detectable "improvement" may also be detected using at least one test, score, or metric described herein. In various embodiments, improvement is detected using a VAS. In various embodiments, improvement is characterized by its relationship to the subject's PASS status.

[0070] In various embodiments, prior treatment with DMARDs other than anti-IL-6R antibodies (e.g., sarilumab) was insufficient (e.g., according to subject and / or physician assessment), ineffective, and / or did not result in a detectable improvement in one or more parameters or symptoms associated with NIP, and / or did not produce a biological effect correlated with the underlying pathological mechanism(s) that causes the NIP condition or symptoms(s).

[0071] In various embodiments, the IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is sarilumab.

[0072] In various embodiments, the therapeutically effective dose of anti-IL-6R antibody administered to a subject varies depending on the subject's age and size (e.g., body weight or body surface area), as well as the route of administration and other factors well known to those skilled in the art.

[0073] In various embodiments, the dose is fixed regardless of the subject's weight or surface area. In various embodiments, the subject is at least 18 years old. In various embodiments, the subject is 30 to 100 years old. In various embodiments, the subject is 35 to 100 years old. In various embodiments, the subject is 35 to 8 years old. In various embodiments, the subject is 40 to 70 years old.

[0074] This disclosure provides a method of using a therapeutic composition comprising an anti-IL-6R antibody or its antigen-binding fragment, and optionally one or more further therapeutic agents. The therapeutic compositions of this disclosure are administered with appropriate carriers, excipients and / or other agents incorporated into the formulation to provide improved mobility, delivery, resistance, etc. Many suitable formulations are found in formulas known to all medicinal chemists, namely Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicle-containing lipids (cationic or anionic) (e.g., LIPOFECTIN®), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowaxes.

[0075] Various delivery systems, such as liposome encapsulation, microparticles, microcapsules, and receptor-mediated endocytosis, are known and can be used to administer the pharmaceutical compositions presented herein. Methods of delivery 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, e.g., infusion or bolus injection, absorption via epithelial or mucocutaneous lining (e.g., oral mucosa, rectal, and intestinal mucosa), and can be administered together with other bioactive agents. Administration may be systemic or local. IL-6R antibodies can be administered subcutaneously.

[0076] Pharmaceutical compositions can also be delivered within vesicles such as liposomes. In certain embodiments, pharmaceutical compositions can be delivered using a release control system, such as a pump or polymer material. In certain embodiments, the release control system can be positioned near the target of the composition, thus requiring only a fraction of the systemic dose.

[0077] Injectable formulations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, local injection, and intravenous infusion. These injectable formulations can be prepared by known methods. For example, an injectable formulation can be prepared by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous injectable media include saline, isotonic solutions containing glucose and other adjuvants, which can be used in combination with suitable solubilizers such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injectable solutions thus prepared can be filled into appropriate ampoules.

[0078] Antibodies are typically formulated as described herein and in their entirety in International Publication No. 2011 / 085158, which is incorporated herein by reference.

[0079] In various embodiments, the antibody is -Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) of polysorbate 20, -Approximately 5% (w / v) sucrose, and - Antibodies at approximately 100 mg / mL to 200 mg / mL It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0080] In another embodiment, the antibody is -Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) of polysorbate 20, -Approximately 5% (w / v) sucrose, and - At least approximately 130 mg / mL of antibodies It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0081] In another embodiment, the antibody is -Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) of polysorbate 20, -Approximately 5% (w / v) sucrose, and - Approximately 131.6 mg / mL of antibodies It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0082] In another embodiment, the antibody is -Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) of polysorbate 20, -Approximately 5% (w / v) sucrose; and - Approximately 175 mg / mL of antibody It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0083] In other embodiments, the antibody is -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and -100 mg / mL to 200 mg / mL antibodies It is administered as an aqueous buffer solution with a pH of 6.0 containing [the substance].

[0084] In another embodiment, the antibody is -21 mM 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 with a pH of 6.0 containing [the substance].

[0085] In another embodiment, the antibody is -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and -131.6 mg / mL antibody It is administered as an aqueous buffer solution with a pH of 6.0 containing [the substance].

[0086] In another embodiment, the antibody is -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose; and -175 mg / mL antibody It is administered as an aqueous buffer solution with a pH of 6.0 containing [the substance].

[0087] In various embodiments, the antibody is administered as a stable pharmaceutical formulation containing (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 approximately 5.8, approximately 6.0, or approximately 6.2, and 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, approximately 150 mg of the antibody (e.g., sarilumab) is administered to the subject.

[0088] In various embodiments, the antibody is administered as a stable pharmaceutical formulation containing (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 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 the subject.

[0089] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in unit doses suitable for adapting to the dose of the active ingredient. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

[0090] In various embodiments, an anti-IL-6R antibody (or a pharmaceutical formulation containing 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 automated injector delivery device. The methods of this disclosure include the use of numerous reusable pens and / or automated injector delivery devices for administering an anti-IL-6R antibody (or a pharmaceutical formulation containing the antibody). Examples of such devices include, but are not limited to, AUTOPEN® (Owen Mumford, Inc., Woodstock, UK), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX® 75 / 25 pen, HUMALOG® pen, HUMALIN® 70 / 30 pen (Eli Lilly and Co., Indianapolis, IN), 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®, and OPTIPEN. This includes STARLET® and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany).Examples of disposable pens and / or autoinjector delivery devices for use in subcutaneous delivery of the pharmaceutical compositions of this 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).

[0091] 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 needle stick injuries. In various embodiments, the antibody is administered in a pre-filled syringe that includes an ERIS safety system (West Pharmaceutical Services Inc.).

[0092] In various embodiments, the antibody is administered using an automated injector. In various embodiments, the antibody is administered using an automated injector featuring PUSHCLICK® technology (SHL Group). In various embodiments, the automated injector is a device comprising a syringe that enables the administration of a certain dose of a composition and / or antibody to a subject.

[0093] The use of microinfusers for delivering anti-IL-6R antibodies (or antibody-containing pharmaceutical formulations) to patients is also intended herein. As used herein, the term “microinfuser” means a subcutaneous delivery device designed to slowly administer large volumes (e.g., about 2.5 mL or more) of a therapeutic formulation over a prolonged period (e.g., about 10, 15, 20, 25, 30 minutes or more). Microinfusers are particularly useful for delivering large doses of therapeutic proteins contained in high concentrations (e.g., about 100, 125, 150, 175, 200 mg / mL or more) and / or viscous solutions.

[0094] In various embodiments, an inadequate response to prior treatment refers to a subject whose pain is not adequately controlled after receiving prior treatment at a representative maximum tolerable dose. In some embodiments, an inadequate response to prior treatment refers to a subject with moderate or severe disease activity and a poor prognosis despite prior treatment. In various embodiments, an inadequate response to prior treatment refers to a subject with pain symptoms (e.g., any of the symptoms listed herein) that have not improved or have worsened despite prior treatment.

[0095] Patient population As used herein, “subject” means a human subject or human patient.

[0096] Antibodies as described herein are administered in various embodiments to subjects having rheumatoid arthritis and also suffering from NIP. In various embodiments, the subjects have NIP and rheumatoid arthritis. In various embodiments, the subjects have previously received treatment for rheumatoid arthritis with one or more DMARDs other than IL-6R antibodies, but without success.

[0097] Subjects considered by the attending physician to have received treatment but without effect are, in various embodiments, subjects who have been found to be intolerant to one or more DMARDs tested by the physician, and / or who have shown an inadequate response to one or more DMARDs tested by the physician, and are typically subjects who, despite having received one or more DMARDs to date, are still considered by the physician to present with or have NIP.

[0098] In various embodiments, the target patients are those with rheumatoid arthritis. -In a typical quantitative examination of swollen and tender joints, when measured by a physician, at least 6 out of 66 swollen joints and 8 out of 68 tender joints were found. - High-sensitivity C-reactive protein (hs-CRP) ≥ 8 mg / L or ESR ≥ 28 mM / H -DAS28ESR>5.1 It holds.

[0099] In various embodiments, subjects who have previously received treatment for rheumatoid arthritis with at least one DMARD different from an antibody but have not responded are subjects who have previously received treatment for NIP with a DMARD but have not responded. 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.

[0100] In various embodiments, subjects who have previously received treatment for NIP with one or more DMARDs other than antibodies but have not responded are subjects who had an insufficient response to or intolerance to methotrexate.

[0101] In various embodiments, subjects who have previously received treatment for NIP with one or more DMARDs other than antibodies but have not responded are those who have had an insufficient response to or intolerance to adalimumab.

[0102] In various embodiments, for subjects who have previously received treatment for NIP with one or more DMARDs other than the IL-6R antibody but have not responded, one or more DMARDs are no longer administered to the subject, and in various embodiments, the IL-6R antibody is administered alone as monotherapy to the subject.

[0103] In various embodiments, subjects are intolerant to DMARDs due to one or more physical reactions, conditions, or symptoms resulting from treatment with DMARDs. Examples of physical reactions, conditions, or symptoms include allergies, pain, nausea, diarrhea, azotemia, gastric bleeding, intestinal bleeding, stomatitis, thrombocytopenia, small intestinal perforation, bacterial infection, inflammation of the gums or oral cavity, inflammation of the gastric or intestinal lining, bacterial sepsis, gastric ulcer, intestinal ulcer, photosensitivity of the skin, dizziness, loss of appetite, energy deficiency, and vomiting. In certain embodiments, intolerance can be determined by the subject or by a healthcare professional upon examination of 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. In certain embodiments, the DMARD is adalimumab.

[0104] In certain embodiments, the 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 expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition containing the IL-6R antibody. In certain embodiments, the subject is administered the antibody together with a DMARD and / or a TNF-α antagonist. [Examples]

[0105] Sarilumab, NIP status, and disease activity This study investigated the prevalence of non-inflammatory pain (NIP), the effect of sarilumab on NIP, and the association between sarilumab treatment, disease activity, and NIP status at baseline, and then again at 3 and 6 months after sarilumab treatment.

[0106] Data source Patient data were collected from two placebo-controlled RCTs of sarilumab 150 mg and 200 mg q2w (MOBILITY, NCT01061736; TARGET, NCT01709578), as well as one adalimumab-controlled RCT of sarilumab 200 mg q2w (MONARCH, NCT02332590).

[0107] Trial endpoints NIP is defined by the established formula: TJC - SJC ≥ 7 10、11 NIP was defined as the difference between the number of tender joints (TJC) and the number of swollen joints (SJC) in 28 joints. Patients were assessed for NIP at study baseline and for changes in NIP status at weeks 12 and 24. Finally, the proportion of patients who achieved the American College of Rheumatology 20 / 50 / 70 (ACR20 / 50 / 70) criteria, Clinical Disease Activity Index (CDAI) ≤ 10, and 28-joint disease activity score (DAS28-CRP) < 3.2 at week 24 was assessed in patients with and without baseline NIP.

[0108] result Demographic and baseline disease characteristics based on NIP status Patients with baseline NIP had higher composite disease activity measures than patients without NIP, but inflammation measures were similar (Table 1). Of the 2112 patients included in the analysis, 490 (23%) had baseline NIP (MOBILITY, 25% [294 / 1197]; TARGET, 19% [106 / 546]; MONARCH, 24% [90 / 369]). Patients with and without baseline NIP had similar demographic characteristics at baseline (Table 2).

[0109] [Table 1]

[0110] [Table 2]

[0111] Sarilumab, NIP status, and disease activity Among patients with baseline NIP, those treated with sarilumab were more likely to be NIP-free at weeks 12 and 24 compared to those treated with placebo or adalimumab (Figure 1). In all three studies (MOBILITY, TARGET, and MONARCH), the relative difference between sarilumab and control therapy appeared to increase with treatment duration. In MONARCH, regardless of the presence of baseline NIP, a higher proportion of patients treated with sarilumab achieved a treatment response at week 24 than those treated with adalimumab (Figure 2). The relative differences between treatment groups were greater in patients with baseline NIP in all assessments except ACR50. After 3 and 6 months of treatment, the prevalence of non-inflammatory pain was higher in patients treated with placebo and adalimumab compared to those treated with sarilumab. Furthermore, regardless of non-inflammatory pain at baseline, the proportion of patients achieving low disease activity after 6 months of treatment was higher with sarilumab than with adalimumab.

[0112] conclusion At weeks 12 and 24, the prevalence of NIP was lower in patients treated with sarilumab than in patients treated with placebo or adalimumab. This data demonstrates that NIP contributes to pain in RA patients and that NIP in RA patients can be treated with the compositions of this disclosure.

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Claims

1. A pharmaceutical composition comprising an anti-interleukin-6 receptor (IL-6R) antibody for the treatment or reduction of non-inflammatory pain (NIP) in a subject having rheumatoid arthritis and requiring such treatment, The aforementioned NIP is defined by the difference between the number of tender joints (TJC) and the number of swollen joints (SJC) (TJC - SJC ≥ 7), which is 7 or more. The pharmaceutical composition comprises an antibody comprising three heavy chain complementarity-determining regions (HCDRs) in a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1, and three light chain complementarity-determining regions (LCDRs) in a light chain variable region containing the amino acid sequence of SEQ ID NO:

2.

2. The pharmaceutical composition according to Claim 1, wherein the three HCDRs are HCDR1, HCDR2, and HCDR3, and the three LCDRs are 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.

3. The pharmaceutical composition according to claim 1 or 2, wherein the antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

2.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject has at least 21 tender joints.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the antibody is formulated for subcutaneous administration.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the antibody is to be administered to a subject in a dose of 150 mg or 200 mg.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the antibody is to be administered to a subject at least once every two weeks.

8. The subject having moderate to severe rheumatoid arthritis, the pharmaceutical composition according to any one of claims 1 to 7.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is not to be administered together with any disease-modifying antirheumatic drug (DMARD) other than the antibody during the administration of the antibody.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is to be administered together with one or more additional DMARDs different from the antibody.

11. The pharmaceutical composition according to claim 10, wherein one or more additional DMARDs different from the antibody comprises methotrexate or a TNF antagonist.

12. The pharmaceutical composition according to claim 11, wherein the one or more additional DMARDs comprises a TNF antagonist selected from etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject has previously received treatment for rheumatoid arthritis by administering one or more DMARDs different from the antibody, but without effect, or the subject is intolerant to one or more DMARDs different from the antibody, or the subject is considered unsuitable as a candidate for continued treatment with one or more DMARDs different from the antibody, or the subject has shown an insufficient response to one or more DMARDs different from the antibody.

14. The pharmaceutical composition according to claim 13, wherein one or more DMARDs different from the antibody include methotrexate or a TNF antagonist.

15. The pharmaceutical composition according to claim 14, wherein one or more DMARDs different from the antibody comprises a TNF antagonist selected from etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the antibody is sarilumab.

18. The pharmaceutical composition according to any one of claims 1 to 17, characterized in that administration of the pharmaceutical composition reduces NIP in the subject compared to administration of a TNF antagonist.

19. The pharmaceutical composition according to claim 18, wherein the TNF antagonist is adalimumab.

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