Treatment for Sjögren's syndrome

Abstract

This invention provides a novel method for treating Sjögren's syndrome in individuals requiring treatment. [Solution] A method is provided for treating or preventing Sjögren's syndrome in a person in need, comprising administering a therapeutically effective amount of an anti-BAFFR antibody or a functional fragment thereof to the person. Preferably, the anti-BAFFR antibody or functional fragment thereof is ianarumab.

Description

[Technical Field]

[0001] This disclosure describes the use of antibodies against BAFFR (BAFF receptor), such as ianarumab. This document discusses treatment methods for Sjögren's syndrome (SjS). [Background technology]

[0002] Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease of unknown etiology. Yes, this disease has a significant impact on quality of life (QoL) measures, and comparative analysis is possible. The study found that a quantitative score on the pSS QoL was worse than congestive heart failure or many cancers. This was shown (Segal et al 2009; Kuenstner et al 2009) 002; Komaroff et al 1996). The underlying mechanism of SjS development is , the destruction of the epithelium of the exocrine gland as a result of autoreactive B cells and T cells (Brito -Zeron P., et al, (2016) Treating the Under lying Pathophysiology of Primary Sjogren Syndrome:Recent Advances and Future Pro Spects.Drugs (pp. 1601-1623). Even at a very early stage, self The high prevalence of antibodies, especially antibodies against Ro / SSA, suggests that autoreactive B cells are S It is suggested that this contributes to the pathological mechanism of jS (Nocturne G., et al. 2018)B cells in the pathogenesis of prim ary Sjogren syndrome.Nat Rev Rheumatol p (133-145). Furthermore, since B cell activity increases in pSS, malignant transformation The number of cases increases, and lymphoma develops in 5% of pSS patients.

[0003] The clinical characteristics of Sjögren's syndrome include medically evaluable findings and the patient's symptomatic findings. It can be divided into these two categories. At present, it is possible to capture the disease activity of both of these clinical symptoms of SjS. There is no single evaluation tool. Therefore, "European League Against Rheumatism(EULAR)Sjogren Syndrome(SS)Pat The "Fed Reported Index" (ESSPRI) and EULAR SS D Isease Activity Index (ESSDAI) is used to assess the symptomatic and It is widely accepted and validated for measuring systemic findings (Franceschi Ni F.,et al,(2017),BMC Medicine,15:69).

[0004] Treatment for SjS patients is currently limited to symptomatic care for mucosal signs and symptoms. Currently, there are no evidence-based systemic therapies available for SjS patients. Glucocorticoids Most drugs and typical disease-modifying antirheumatic drugs (DMARDs) are ineffective, and in daily life Pharmacological interventions are ineffective for severe fatigue that impairs daily life. Efficacy confirmation. Despite a lack of concrete evidence, similar autoimmune diseases such as systemic lupus erythematosus... Based on case evidence and experience, antimalarial drugs (Tishler et al.) al 2008), methotrexate (Winzer and Aringer 201 0) or azathioprine (Kaufman et al 1999) is particularly effective in cases of renal lesions or It is sometimes used to treat extraglandular symptoms such as joint lesions.

[0005] The pattern of B-cell autoreactivity is somewhat similar to systemic lupus and rheumatoid arthritis, so Recently, for both the glandular and extraglandular manifestations of SjS and lymphoma management, B-cell depletion therapy using the anti-CD20 monoclonal clonal antibody (mAb) rituximab has been evaluated, and the efficacy has been variable. However, this approach is not currently an approved treatment for SjS. The insufficient efficacy of rituximab may be related to incomplete B-cell depletion in the affected tissues (Brito-Zeron P et al (2016) Treat ing the Underlying Pathophysiology of Pr imary Sjogren Syndrome: Recent Advances a nd Future Prospects. Drugs p.1601-1623).

[0006] Although treatments for SjS are available, new treatment options for SjS patients are still strongly medically needed.

[0007] Antibodies against BAFFR are known, for example, from WO 2010 / 007082 pamphlet, and include antibodies characterized by comprising a VH domain of the amino acid sequence of SEQ ID NO: 1 and a VL domain of the amino acid sequence of SEQ ID NO: 2. Antibody MOR665 4 is one such antibody (IgG1κ). It has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10. This antibody is expressed from SEQ ID NOs: 14 and 15 in a host cell lacking fucosyltransferase, for example, a mammalian cell line having an inactive FUT8(- / -) gene, and is a non-fucosylated anti-BAF with enhanced ADCC preferably, from SEQ ID NOs: 14 and 15, in a host cell lacking fucosyltransferase, for example, a mammalian cell line having an inactive FUT8(- / -) gene, and is a non-fucosylated anti-BAF with enhanced ADCC We can provide FR antibodies. Hereinafter, these antibodies will be referred to as MOR6654B or VAY736. It is either called ianarumab, or based on its international non-trademark name. Non-fucosylated antibody Alternative manufacturing methods are known in the relevant technical field. [Overview of the project]

[0008] The object of the present invention is to treat Sjögren's syndrome in subjects requiring treatment (in this specification) Active Sjögren's syndrome (a syndrome or disease, or a recommended technical term used by health authorities) A novel method for treating (also known as Sjögren's syndrome or SjS), The method involves administering a therapeutically effective dose of an anti-BAFFR antibody such as ianarumab to the target population. It is about providing.

[0009] Human anti-BAFFR antibodies, such as Ianarumab, are used in Sjögren's syndrome (SjS). It has been found to be suitable for treatment. In particular, the antibody ianarumab has been shown in clinical trials to be suitable for treatment. This suggests the potential to provide a novel treatment approach for clinically active SjS. .

[0010] Therefore, this specification describes the treatment of SjS in humans, for example, primary Sjögren's syndrome. This method involves administering an effective therapeutic dose of an anti-BAFFR antibody such as ianarumab. Methods of inclusion are disclosed. [Brief explanation of the drawing]

[0011] [Figure 1] The parotid / submandibular gland echogenic structure shows a tendency towards improvement after a single dose of ianarumab. [Figure 2] This study demonstrates a statistically significant dose-response relationship between ESSDAI and ianarumab treatment in patients with primary Sjögren's syndrome. [Modes for carrying out the invention]

[0012] The BAFFR:BAFF pair is involved in the maturation of transitional B cells, the survival and activation of mature B cells, and It plays a crucial role in isotype class switching in response to T cell-dependent antigens. BAFF and its receptor BAFFR (BAFF receptor) also contribute to the survival of malignant B cells. It is also important for growth. Furthermore, BAFFR is not normally expressed in pre-B cells, but recently And it is expressed in human ALL (B-cell lineage acute lymphoblastic leukemia) cells. This was shown (Parameswaran, 2010, Cancer Res. 70(11 )4346-4356). Autoreactive B1F mediated by excessive BAFF levels in patients. Removal of cells and blocking of improper survival / activation. Therefore, anti-BAFFR antibodies, in detail, anti Blocking the ability of somatic cell-mediated cytotoxicity (ADCC) and ligand binding to BAFFR. Antibodies that possess the ability to do so may provide effective treatments for Sjögren's syndrome. The mechanism involves thorough B cell depletion or at least BAFF: This is thought to lead to the blocking of tissue B cell activation mediated by BAFF-R. .

[0013] Ianarumab targets human BAFF-R, and BAFF binds to BAFF-R. This competitively inhibits BAFF-R-mediated signaling in B cells. It is a human IgG1 / κ mAb designed to block it. In addition, ianarumab is Engineered to effectively remove B cells from circulation via ADCC in vivo. The ADCC activity of Ianarumab is derived from the carbohydrate portion bound to the Fc region of the antibody. It is significantly enhanced by removing the - residue. Accordingly, ianarumab is In vitro, it shows potent ADCC activity with an EC50 of 2.0 pM. Thus, ianarumab This is due to a dual mechanism, namely (1) antibody-dependent cell-mediated cytotoxicity (ADCC) and (2) in B cells. B cell apoptosis due to BAFF:BAFF-R interaction and blockade of downstream survival pathways Induction removes BAFF-R+ mature and immature B cells. BAFF-R expression is related to phosphorus. It is limited to immature and mature B cells up to the blastocyte stage, and therefore early-stage pro-B cells and Pre-B cells are not directly affected by ianarumab.

[0014] Therefore, the present inventors hereby discuss SjS patients treated with anti-BAFFR antibodies such as ianarumab. We devised a treatment regimen for this condition.

[0015] In one embodiment, an anti-BAFFR antibody is provided, wherein the antibody is the amino acid of SEQ ID NO: 9. An immunoglobulin VH domain containing an acid sequence and an immunoglobulin containing the amino acid sequence of SEQ ID NO: 10 The antibody comprises a robulin VL domain, and the antibody is used in a target that requires it. It will be administered in doses ranging from approximately 50 mg to 300 mg.

[0016] In a preferred embodiment, an anti-BAFFR called VAY736 (ianarumab) is used. It is provided. Specifically, VAY736 (ianarumab) is a heavy chain amino acid of SEQ ID NO: 9. The sequence and the light chain amino acid sequence of Sequence ID No. 10 are included, and the antibody requires them. The drug will be administered to the target population in doses ranging from approximately 50 mg to 300 mg.

[0017] In one embodiment, the route of administration of the antibody according to the embodiment described herein is subcutaneous or This is either intravenous or a combination of subcutaneous and intravenous administration.

[0018] Some patients may require a load regimen, for example, once a week for several weeks [for example, 1 to 5 weeks]. [Administer in weeks 0, 1, 2, 3 and / or 4] or once every two weeks for several weeks (for example, For 2 to 8 weeks, for example, administered at weeks 0, 2, 4, and / or 6, followed by a maintenance regimen. For example, a monthly maintenance regimen may be beneficial. For example, an appropriate regimen for anti-BAFFR antibodies Jimen is taken once a week or once every two weeks for several weeks [for example, 1 to 5 weeks, for example, 0, 1, 2 [Administered in weeks 3 and / or 4], followed by a monthly maintenance regimen.

[0019] In another example, the appropriate regimen for ianarumab is once every two weeks for several weeks (for example, Administered for 2-8 weeks (for example, at weeks 0, 2, 4, and / or 6), followed by monthly maintenance doses. It is a regimen.

[0020] In some embodiments, anti-BAFFR antibodies such as ianarumab are delivered via sc. The patient may be administered an initial dose of 300 mg, and this dose may be increased as needed. You may adjust it as the doctor decides.

[0021] In yet another specific embodiment, a dose of 150 mg ianarumab in 2 units is used The dosage is administered via SC every four weeks (q4w).

[0022] Ianarumab is administered subcutaneously, for example, four times a year, once a month, once a week, or once every two weeks, for approximately 50 ml. g to 500 mg, for example, about 150 to about 400 mg, for example, about 150 mg to about 300 mg, or For example, with a dosage setting of approximately 200mg to 300mg, administered by subcutaneous injection, approximately 50m It is administered in unit doses of approximately 100 mg, 150 mg, 200 mg, or 300 mg. That's fine.

[0023] Ianarumab is administered by subcutaneous injection every two weeks or once a month, at a dose of approximately 50 mg to 300 mg. It may be administered in doses of mg, preferably about 300 mg.

[0024] As defined herein, “unit dose” means approximately 50 mg to 500 mg, for example, approximately 15 0mg to approximately 400mg, for example, approximately 150mg to approximately 300mg, or for example, approximately 200mg to This refers to an SC dose that may contain approximately 300 mg. For example, a unit SC dose is approximately 50 mg. These amounts are approximately 150 mg, 150 mg, 200 mg, 250 mg, and 300 mg.

[0025] In one embodiment, the present invention provides ianarumab to SjS patients in a single treatment. A dose ranging from approximately 20 mg to approximately 500 mg, preferably 30 mg to 300 mg per treatment. The range is preferably 100 mg to 300 mg, preferably 150 mg to 300 mg. This includes administering. In one embodiment, the patient receives 20 mg to 300 mg per treatment. mg is administered. In one embodiment, the patient receives 150 mg to 300 mg per treatment. mg is administered. In one embodiment, the patient is given 20 mg or 30 mg per treatment. , 60mg, 90mg, 120mg, 150mg, 180mg, 200mg, 210mg 250 mg, 275 mg, or 300 mg is administered. In one embodiment, SjS Patients undergo each procedure every two weeks, every three weeks, once a month (every four weeks), every six weeks, and once every two months (2 The patient receives treatment every month, every nine weeks, or four times a year (every three months). In one embodiment, the patient receives each treatment The patient receives the treatment every three weeks. In one embodiment, the patient receives each treatment every four weeks.

[0026] If safety concerns arise, the dose may be adjusted, preferably by increasing the dosing interval. Preferably, the dose may be gradually reduced by doubling or tripling the administration interval. For example, 3 For regimens of 00mg once a month or every three weeks, double the dose and administer every two months or every six weeks. This can be done every other interval, or tripled to every three months or every nine weeks, respectively.

[0027] In some embodiments, an anti-BAFFR antibody such as ianarumab is used in the treatment of ianarumab. This can refer to an antibody that is an iosimilar or an antibody that has been proven to be replaceable by an iosimilar. These antibodies are embodiments referring to ianarumab administration as disclosed herein. It can be administered according to the following.

[0028] Definition: For the purposes of interpreting this specification, the following definitions apply, and terms used in the singular form are: Where appropriate, the plural form is also included, and vice versa.

[0029] The term "antibody" as used herein includes all antibodies and any antigenic antibodies thereof. It contains a combined fragment (i.e., an "antigen-binding portion") or a single chain. Naturally occurring "antibodies" are di At least two heavy (H) chains and two light (L) chains are interconnected by sulfide bonds. It is a glycoprotein containing chains. Each heavy chain has a heavy chain variable region (V in this specification). H And abbreviated ) and the heavy chain steady region. The heavy chain steady region consists of 3 or 4 domains depending on the isotype. In, C H1. C H 2. C H 3 and C H 4 is included. Each light chain contains a light chain variable region (abbreviated as V in this specification) and a light chain constant region. The light chain constant region contains one domain, C is V L as omitted). L including V H and V L regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) with highly conserved regions called framework regions (FRs) placed in between It can be further divided. Each V and V H and V L consists of three CDRs arranged in the following order from the amino terminus to the carboxy terminus, namely FR 1, CDR1, FR2, CDR2, FR3, CDR3, FR4, and four FRs. The variable regions of the heavy and light chains contain binding domains that interact with antigens The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system The term "antigen-binding portion" (or simply "antigen portion") of an antibody, as used herein refers to the full length or one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a portion of BAFFR). It has been shown that the antigen-binding function of an antibody can be performed by fragments of the full-length antibody

[0030] Examples of binding fragments included within the scope of the term "antigen-binding portion" of an antibody include Fab fragments that are monovalent fragments consisting of one domain of V , V , C , and C ; Fab fragments containing two Fab fragments linked by a disulfide bridge in the hinge region L , V H , C L and C H is a monovalent fragment consisting of one domain The F(ab')2 fragment containing The bivalent fragment is the F(ab)2 fragment; V H and C H Fd fragment consisting of one domain; single-domain antibody One-arm V L and V H Fv fragment consisting of domains; V H dAb fragment consisting of domains ( Ward et al., 1989 Nature 341:544-546); and Single One example is the separated complementarity-determining region (CDR).

[0031] Furthermore, the two domains of the Fv fragment, V L and V H It is encoded by a separate gene. However, by using a recombination method, these can be joined together by a synthetic linker. , V L and V H A single protein chain (single chain Fv(s)) where regions pair up to form a monovalent molecule. Known as cFv); for example, Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc.N (See atl.Acad.Sci.85:5879-5883) This becomes possible. Such single-chain antibodies also fall within the scope of the term "antigen-binding region" of the antibody. They are intended to be included. These antigenic fragments are obtained using conventional techniques known to those skilled in the art. The fragments are then screened for usefulness in the same way as intact antibodies.

[0032] When used herein, "isolated antibody" refers to other antibodies with different antigen specificities. This refers to antibodies that do not contain B in a qualitative sense; for example, isolated antibodies that specifically bind to human BAFFR are B It contains virtually no antibodies that specifically bind to antigens other than AFFR. However, BAF Isolated antibodies that specifically bind to FR cross-react with other antigens, such as BAFFR molecules from other species. It may be reactive. Furthermore, the isolated antibody substantially contains other cellular material and / or chemical substances. It may not be possible.

[0033] The terms "monoclonal antibody" or "monoclonal antibody composition" are used herein. When used, it refers to a preparation of an antibody molecule with a single-molecule composition. Monoclonal antibody compositions are specific It exhibits a single binding specificity and affinity for the epitope.

[0034] The term "human antibody" as used herein refers to the framework region and the CDR region. The antibody contains a variable region in which both regions are derived from human sequences. Furthermore, the antibody If a constant region is included, that constant region is also such a human sequence, for example, a human germline sequence. Alternatively, a mutant version of the human germline sequence, or, for example, Knappik, et al. As described in al. (2000. J Mol Biol 296, 57-86) Antibodies containing consensus framework sequences derived from human framework sequence analysis. It originates from this.

[0035] The precise amino acid sequence boundaries of a given CDR are as follows: Kabat et al. (1991) "Sequences of immunologically beneficial proteins" of Immunological Interest)”, 5th Ed.Publi c Health Service,National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Laz ikani et al.,(1997)JMB 273,927-948(``Chot (hia) numbering scheme and ImMunoGenTics (IMGT) numbering (Lefra nc, M.-P., The Immunologist, 7, 132-136 (1999 );Lefranc,M.-P.et al.,Dev.Comp.Immunol., Including those listed in 27,55-77(2003) ("IMGT" numbering scheme), It can be determined using one of several well-known schemes. For example, classical formulas Regarding matte, according to Kabat, the CDR amino acid residue of the heavy chain variable domain (VH) The bases are 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCD). It is numbered R3; and the CDR amino acid residues of the light chain variable domain (VL) are 24-34. They are numbered as LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). According to Chothia, the CDR amino acids of VH are 26-32 (HCDR1), 52 They are numbered ~56 (HCDR2) and 95~102 (HCDR3); and VL amino The acid residues are 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR2). It is numbered DR3). It combines CDR definitions from both Kabat and Chothia. As a result, CDR is derived from amino acid residues 26-35 (HCDR1) and 50-6 of human VH. 5 (HCDR2), 95-102 (HCDR3), and 24 amino acid residues of human VL From ~34 (LCDR1), 50~56 (LCDR2), and 89~97 (LCDR3) Yes. Based on IMGT, the CDR amino acid residues of VH are approximately 26-35 (CDR1), 5 They are numbered 1-57 (CDR2) and 93-102 (CDR3), and are VL CDR amino acids. The residues are approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). ) is numbered (numbering related to "Kabat"). Based on IMGT, the CDR region of the antibody This can be determined using the program IMGT / DomainGap Align. Throughout this specification, the Complementarity Determination Region ("CDR") is defined as any of the schemes described above. Therefore, it is defined.

[0036] The human antibodies disclosed herein contain amino acid residues not encoded by human sequences (e.g., in vitro By random or site-directed mutagenesis, or by somatic mutation in vivo It may include (mutations introduced). However, the term "human antibody" is used in this specification. When used in books, CDR sequences derived from the germline of another mammalian species, such as mice, are used. Antibodies grafted onto human framework sequences are not intended to be included.

[0037] The term "human monoclonal antibody" refers to an antibody that exhibits single-combination specificity, and is frame This refers to antibodies in which both the work region and the CDR region have variable regions derived from human sequences.

[0038] The term "recombinant human antibody," as used herein, refers to a human immunoglobulin gene. Regarding transgenic or transchromosomal animals (e.g., mice) or Antibodies isolated from hybridomas prepared therefrom, for example, from transfectomas, Antibodies isolated from host cells transformed to express antibodies, recombinant combinatorial antibodies Antibodies isolated from a real human antibody library, and human immunoglobulins to other DNA sequences. All or part of the gene, prepared by any other means involving sequence splicing. Antibodies prepared by recombinant means, expressed, created or isolated, etc. This includes any human antibodies that have been synthesized or isolated. Such recombinant human antibodies are included in the framework and The CDR region has a variable region derived from a human germline immunoglobulin sequence. In certain embodiments, such recombinant human antibodies induce in vitro mutagenesis (or When transgenic animals are used with respect to human Ig sequences, in vivo somatic cell fusion It may also be used for natural mutagenesis, and consequently for recombinant antibody V H and V L amino acid sequence of the region However, human germline V H and V L It is derived from and related to the sequence, but in vivo This may be a sequence that does not naturally exist within the range of the human antibody germline repertoire. Yes.

[0039] As used herein, “isotype” refers to a gene provided by a heavy chain constant region. Antibody classes (e.g., IgM, IgA, IgD, IgE and IgG, e.g., IgG) 1. Refers to IgG2, IgG3, or IgG4, etc.

[0040] In this specification, the terms "antibody that recognizes an antigen" and "antibody that is specific to an antigen" are referred to as "antibody." It is used synonymously with "an antibody that specifically binds to the source."

[0041] When used herein, antibodies that "specifically bind to BAFFR polypeptides" or The "anti-BAFFR antibody" contains less than 100 nM of the human BAFFR polypeptide of SEQ ID NO: 13. , K below 10 nM, below 1 nM D This refers to antibodies that bind to antigens other than BAFFR. Antibodies that react to differential reactions are 0.5 × 10 -8 M or less, 5×10 -9 M or less, or 2 × 10 -9 K below M D This refers to an antibody that binds to the antigen in question. It is an antibody that "does not cross-react with a specific antigen." This involves 1.5 × 10⁶ of the antigen in question. -8 M or higher K D , or 5-10 x 10 -8 M or 1 ×10 -7 M or higher K D This is intended to refer to an antibody that binds to it. In a particular embodiment, Antibodies that do not cross-react with antigens can be bound to those proteins in standard binding assays. In contrast, it exhibits a binding that is essentially undetectable.

[0042] Where used herein, the phrase “pharmaceutically acceptable” means “appropriate medical judgment.” Within the range, in accordance with a reasonable benefit / risk ratio, excessive toxicity, irritation, and allergens are avoided. - Use in contact with human and animal tissues without reaction or other problems or complications. This refers to those compounds, substances, compositions, and / or dosage forms that are suitable for [the purpose].

[0043] The term “combination of drugs” as used herein refers to a combination of multiple active ingredients. This refers to products resulting from the use, mixing, or combination of drugs. When used in a pharmacopoeia, it is understood that this may include both immobilized and non-immobilized combinations of active ingredients. I want to.

[0044] Terms such as "simultaneous administration" or "combined administration" are used herein. , a combination of parts selected for a single subject (e.g., a patient or subject) that requires it. This includes administering one or more of the compounds described herein together with the toner. In the treatment, the compound is not necessarily administered via the same route and / or at the same time. It shall contain germanium.

[0045] The term "pharmaceutical composition" in this specification refers to a specific disease or condition affecting warm-blooded animals. For the prevention or treatment of, a small amount intended to be administered to warm-blooded animals, such as mammals or humans. This refers to a mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent. It is defined as something that...

[0046] The term “therapeutic effective dose” of the compound in this disclosure refers to the biological or Medical response, such as a decrease or inhibition of enzyme or protein activity, or remission of symptoms, The compounds disclosed herein elicit symptoms such as alleviation of symptoms, slowing or delaying disease progression, or prevention of disease. It refers to the quantity of a substance. The therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the patient's type. Depending on weight, age, sex and individual condition, the disability or disease being treated or its severity To exist. A skilled physician, clinician, or veterinarian may prevent, treat, or inhibit the progression of a disorder or disease. The effective amount of each active ingredient needed for this purpose can be easily determined.

[0047] The term "treatment regimen" refers to a regimen used to treat a disease, for example, pSS. This refers to the administration protocol used in the treatment. The treatment regimen includes an induction regimen. And maintenance regimens may be included.

[0048] The term "dosing," as used herein, refers to a therapeutic purpose (for example) This refers to the administration of a substance (for example, an anti-BAFFR antibody) to achieve the treatment of SjS.

[0049] The frequency of medication depends on the compound used and the specific condition being treated or prevented. It can vary. Generally, it is preferable to use the smallest dose that is sufficient to provide effective treatment. Patients generally use appropriate assays to assess the effectiveness of treatment for the condition being treated or prevented. It can be monitored, which should be obvious to those skilled in the art.

[0050] As used herein, the terms “carrier” or “pharmaceutically acceptable carrier” are used in this specification. all solvents, dispersions, coatings, and other materials known to those skilled in the art. Surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption retarders, salts Classes, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, Pigments, and combinations thereof (e.g., Remington's Pharm) aceutical Sciences,18th Ed.Mack Printing Company, 1990, pp. 1289-1329). All conventional carriers, Unless otherwise incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is intended.

[0051] As used herein, the term “subject” refers to an animal. Typically, an animal is It is a mammal. The subjects include, for example, primates (e.g., humans, male and female), cattle, sheep, goats, This also refers to horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, The subject is primates. In a preferred embodiment, the subject is human. The term "subject" is used. When it refers to a person, it is used interchangeably with "patient."

[0052] As used herein, a subject "requires" treatment if such subject Those who receive biological, medical, or quality-of-life benefits from such treatments This is the case.

[0053] As used herein, the phrase “patient population” is used to mean a group of patients. It is used.

[0054] The term "comprising" is the same as "including". "Consisting" is included in "complementary" (complementary) X, for example. The composition may consist exclusively of X, or may include some additional components. (For example, X + Y).

[0055] AUC0-t refers to the area under the plasma concentration-time curve from time 0 to time "t". Here, t is the defined time point after administration [mass × time / volume].

[0056] AUCtx-ty represents the area under the plasma concentration-time curve from time "x" to time "y". Here, "time x" and "time y" are defined points in time after administration.

[0057] Cmax is the highest plasma concentration observed after drug administration [mass / volume].

[0058] Cmin is the lowest plasma concentration observed after drug administration.

[0059] Ctrough is the plasma concentration observed immediately before the start of the dosing interval or at the end of the dosing interval. It is a degree.

[0060] Tmax is the time [hours] it takes for a drug to reach its peak concentration after administration.

[0061] The subscript ss indicates that the parameter is defined in a steady state.

[0062] The term "means of administration" is not limited to pre-filled syringes, vials, and syringes. This includes injection pens, automatic infusion devices, intravenous drip bags, pumps, patch pumps, etc. The term is used to refer to any available device for systemically administering a drug to a patient. The item allows patients to self-administer the medication (i.e., administer the medication themselves). Alternatively, a physician may administer the drug.

[0063] The term "approximately" in relation to a number x means, for example, + / - 10%. Numerical range or When used before a list of numbers, the term "approximately" applies sequentially to each number, for example. The phrase "approximately 1 to 5" should be interpreted as "approximately 1 to approximately 5," or, for example, "approximately 1, 2 The phrases ", 3, 4" should be interpreted as "approximately 1, approximately 2, approximately 3, approximately 4, etc."

[0064] The terms "treatment" or "treat" are originally intended to be used in the context of the original text. In the details, the subject or isolated tissue or cell line derived from the subject is subjected to the compound (formula (I)) according to the disclosure. Application or administration of a compound of ) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing said compound Defined as a given, the subject is a specific disease (e.g., SjS), or a disease (e.g., SjS) related to If you have a predisposition to the development of the symptoms or disease (e.g., SjS) that can be applied, then this item The target is the cure (if applicable), delayed onset, reduced severity, or relief of one or more symptoms of the disease. , remission, improvement of the disease, reduction or improvement of any symptoms related to the disease, or onset of the disease This refers to the reduction or improvement of the underlying cause. The term "(treat)" refers to patients suspected of having a disease, as well as patients who are ill or This includes treating patients who have been diagnosed with a disease or medical condition. This also includes suppressing clinical relapses.

[0065] As used herein, "selecting" in relation to a patient " and "selected" refer to specific patients who meet predetermined criteria. Based on (and resulting from) this, specific patients are selected from a larger group of patients. It is used to mean that. Similarly, "to treat selectively" means to treat patients with a particular disease. This refers to providing treatment to a person, and that patient is a specific patient who meets predetermined criteria. They are specifically selected from a larger patient group on which they are based. Similarly, "selective administration" means that A larger patient group based on (and resulting from) specific patients who meet predetermined criteria This refers to administering medication to patients who are specifically selected. "To administer" and "to administer selectively" refer only to patient membership in the larger group. Rather than providing a standard treatment regimen based on the patient's individual treatment history (for example, previously...) Therapeutic interventions (e.g., previous treatment with biological agents), biological factors (e.g., specific gene marketing) Individualized treatment based on the patient's condition and / or symptoms (e.g., those that do not meet specific diagnostic criteria). This means providing to the patient. In relation to the treatment methods used herein, To select does not refer to incidental treatment of patients who meet certain criteria, but rather to treatment of patients who meet certain criteria. It refers to the intentional selection of treatment for a patient based on the patient's condition. Therefore, selective treatment / administration is Unlike standard treatment / administration, this may be related to the individual's medical history, disease findings, and / or biology. In addition, specific drugs are delivered to patients with specific diseases. In some embodiments, Sj Patients were selected for treatment based on having S.

[0066] Sjögren's syndrome and the effectiveness of treatment according to the present invention The disclosed anti-BAFF antibody, ianarumab, is used to treat SjS patients (e.g., human patients). For placement, it can be used in vitro, ex vivo, or incorporated into pharmaceutical compositions. It is administered in vivo.

[0067] The effectiveness of treatment for Sjögren's syndrome depends on the condition of Sjögren's syndrome and / or the Sjögren's condition. Clinical responses can be evaluated using various known methods and tools. Some examples include: For example, EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI), Physician Globa l Assessment Scale (PhGA), EULAR Sjogren' s Syndrome Patient Reported Index (ESSPRI) ), The Functional Assessment of Chronic I llness Therapy-Fatigue Scale(FACIT-Fatigue Examples include the UE and EQ5D.

[0068] Effectiveness The clinical effectiveness measurements for the primary and secondary objectives are outlined below.

[0069] EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ESSDAI is a validated disease outcome measure for Sjögren's syndrome. Applicable to the subjects of the study (Seror R, et al (2015) Validation n of EULAR primary Sjogren's syndrome di sease activity(ESSDAI) and patient index es(ESSPRI).Ann.Rheum.Dis.p.859-66). This method is It contains 12 organ-specific regions that contribute to disease activity. The characteristics of disease activity are scored on a 3 or 4-point scale according to the severity of the disease. Next, the weighting method The formula sums these scores across 12 different areas to provide the total score. The symptoms are as follows: constitution (3), lymph node swelling (4), glandular symptoms (2), joints (2 ), skin (3), lungs (5), kidneys (5), muscles (6), PNS (5), CNS (5), blood Fluid (2) and biological findings (1). The maximum possible score is 123.

[0070] To calculate ESSDAI, all 12 organ regions were individually evaluated at all planned time points. It must be evaluated (from screening visit to end of trial). Subject evaluation on a tablet. (Provided by the central vendor) Fill in the information in the software. Calculate the ESSDAI score.

[0071] X-ray examination, high-resolution computed tomography (HRCT), pulmonary function test (DLCO, FVC), estimated glomerular filtration rate (eGFR), electromyography (EMG), muscle (or any ESSDAI is suspected to be a necessary test, even though it is not listed in the protocol as a required test, including other biopsies. Regarding the evaluations that may be necessary to correctly interpret the ESSDAI, the clinical trial physician may decide at their discretion. To provide information, these should be evaluated based on the patient's signs and symptoms. The definitions and weights of the Glenn Syndrome Disease Index (ESSDAI), domains, and items are summarized in the table below. Meru:

[0072] [Table 1]

[0073] [Table 2]

[0074] [Table 3]

[0075] [Table 4]

[0076] [Table 5]

[0077] Comprehensive Physician Assessment Scale (PhGA) 100 mm VA in the range of "no disease activity" (0) to "maximum disease activity" (100) To assess the patient's disease activity using S, the attending physician will perform a comprehensive physician assessment schedule. A ru is used.

[0078] To promote objectivity, when a physician evaluates a patient, they should identify The reported treatment outcomes of the patients should not be known. Therefore, the overall disease activity score This assessment must be performed before reviewing the overall assessment of patient A.

[0079] EULAR Sjogren's Syndrome Patient Report dIndex (ESSPRI) ESSPRI is an established disease outcome measure for Sjögren's syndrome. (Seror R,et al(2011)EULAR Sjogren's Synd rome Patient Reported Index(ESSPRI):deve lopment of a consensus patient index for primary Sjogren's syndrome.Ann.Rheum.Di (sp968-72). This consists of three areas: dryness, pain, and fatigue. The subjects are: For each of the three domains, the symptoms experienced by the subject are represented on a single numerical scale from 0 to 10. Severity can be assessed. The ESSPRI score is the average of scores from three scales. Determined: (dryness + pain + fatigue) / 3.

[0080] FACIT - Fatigue The Functional Assessment of Chronic Il The Inner Resilience Therapy-Fatigue Scale (FACIT-F v4) is This involves measuring the individual's fatigue level during their typical daily activities over the past week. It is an easy-to-manage tool with 13 items. Fatigue levels are measured on a 5-point Likert scale. Evaluate Bell (0=not at all, 1=a little, 2=some, 3=quite a bit, 4=very) (Webster K, et al. (2003) The Functional Assessment of Chronic Illness Therapy(F ACIT)Measurement System:properties,appli cations,and interpretation.Health Qual L (ife Outcomes p.79)

[0081] EQ5D EQ-5D is a standardized method for measuring health-related quality of life. -5D consists of a description system and an EQ VAS scale.

[0082] This description system includes five aspects: mobility, self-care, usual activity, and pain / incontinence. Pleasure and anxiety / depression. This is a quantitative measure of health outcomes that reflects the patient's own judgment. These can be used as a health profile. The scores from these five aspects are presented as a health profile. A single aggregate that reflects the possibility of or being more favorable compared to other health profiles. This can be converted into the number of indicators (usefulness).

[0083] EQ VAS uses a scale where 0 represents the "worst imaginable health state" and 100 represents the "best imaginable health state." A "healthy state" is a self-assessed health state by the patient on a vertical visual analog scale. Record it.

[0084] Appropriateness of effectiveness evaluation The primary measure of effectiveness in this trial is the ESSDAI, which measures organ-specific disease criteria. (EULAR SS Disease Activity Index) and patient subjective assessment ESSPRI (European League Against the Critical Diseases) st Rheumatism[EULAR]Sjogren Syndrome[SS] Based on the Patient Reported Index. Both methods are widely accepted. These are the gold standard findings for systemic and symptomatic findings of SjS, respectively. This is a guideline. ESSDAI is a 12-type region (biological findings) that is weighted differently. Blood, joints, glandular symptoms, skin, constitution, lymph node swelling, kidneys, lungs, PNS, CNS and muscles Systemic disease activity index classifies disease activity at 3-4 levels across each of the following categories. This is the target. When the composite weighted score is validated across multiple cohort studies, it shows a change in response to the changes. It provides a highly sensitive and accurate assessment of disease activity (Seror R et al (2 015)Validation of EULAR primary Sjogren' s syndrome disease activity(ESSDAI)and p patient indexes(ESSPRI).Ann.Rheum.Dis.p.8 59-66). On the other hand, the ESSPRI tool showed 0-10 visual analysis results in the preceding two weeks. A composite of symptoms reported by the patient, including dryness, limb pain, and fatigue, as assessed on a log-scale. The core is (Seror R et al (2011) EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) :development of a consensus patient inde x for primary Sjogren's syndrome.Ann.Rhe (um.Dis.p.968-72). The scores reported by patients reflect changes in disease activity. Although its sensitivity is low, among the available tools, ESSPRI has remarkably good sensitivity. It has been reported that the correlation between systematic scores and patient scores is The report indicates low levels, suggesting that the two indicators assess complementary components of disease activity. This suggests that both parameters are necessary to arrive at a correct assessment of disease activity and its changes. The importance of meter evaluation is emphasized (Seror R et al (2015) Vali dation of EULAR primary Sjogren's syndrome me disease activity(ESSDAI)and patient i ndexes(ESSPRI).Ann.Rheum.Dis.p.859-66).

[0085] Pharmaceutical composition The pharmaceutical composition used in the method disclosed herein may be manufactured by conventional methods. Exemplary pharmaceutical compositions containing anti-BAFFR antibodies such as B are described in International Publication No. 2012 / 07667. Pamphlet No. 0 and International Publication No. 2013 / 186700 (see reference to this book) Disclosed (as incorporated by the specification). In one embodiment, the pharmaceutical composition is typically The pharmaceutical composition of the present invention is delivered by injection or by a delivery device (e.g., a syringe). It is provided to be administered in a container (e.g., a pre-filled syringe).

[0086] combination: When performing any of the treatments or methods of use described herein, a therapeutically effective amount of the compound of formula (I) Alternatively, a pharmaceutically acceptable salt thereof is administered to a patient, for example, a mammal (e.g., a human). While it is understood that the disclosed method provides treatment for Sjögren's syndrome patients, this treatment Treatment is not always monotherapy. In reality, patients may receive anti-BAFFR therapies such as ianarumab. When chosen for antibody treatment, anti-BAFFR antibodies such as ianarumab are used alone. or in combination with other drugs and treatments for Sjögren's syndrome patients, for example, less In combination with at least one further Sjögren's drug, or in any of the manner described herein. It can be administered.

[0087] Various therapeutic agents are used during the treatment of SjS, along with anti-BAFFR antibodies such as ianarumab, which are disclosed. They can be beneficially combined. Such therapeutic agents include steroids (corticosterone). For example, prednisone or equivalent); DMARDs, for example, hydroxychloroquine (P Laquenil, methotrexate (Trexall), sulfasalazine (Azu) lfidine, minocycline (Minocin), or leflunomide (Arava) ); or B-cell scavenging agents, such as rituximab.

[0088] Those skilled in the art will know the above for co-delivery with anti-BAFFR antibodies such as ianarumab disclosed. It is possible to determine the appropriate dosage of SjS agents.

[0089] Embodiment Treatment method A1. Treat the Sjögren's syndrome that is in need, for example, primary Sjögren's syndrome. A method of administering or preventing the use of a therapeutically effective amount of anti-BAFFR antibody or its functional properties to the target. A method involving the administration of a fragment. A2. Treat the Sjögren's syndrome that is in need, for example, primary Sjögren's syndrome. A method of administering or preventing the use of a therapeutically effective amount of anti-BAFFR antibody or its functional properties to the target. The procedure involves administering a fragment, wherein the anti-BAFFR antibody or its functional fragment is, respectively, SEQ ID NO: Heavy chains CDR1, CDR2, and CDR3 of sequences 3, 4, and 5, and light chain C of sequences 6, 7, and 8. A method comprising DR1, CDR2, and CDR3. A3. The anti-BAFFR antibody or its functional fragment contains the heavy chain sequence of SEQ ID NO: 9 and SEQ ID NO: 10 The method according to Embodiment A1 or A2, comprising a light chain sequence. A4. In the embodiments described above, the anti-BAFFR antibody or its functional fragment is ianarumab. The method described in one of the following options. A5. Anti-BAFFR antibody or its functional fragment, in doses of approximately 50 mg to approximately 300 mg The method according to one of the embodiments described above, which will be administered. A6. The anti-BAFFR antibody or its functional fragment is administered in doses of approximately 150 mg to approximately 300 mg. The method according to any one of the embodiments described above, administered as follows. A7. Embodiment A, in which an anti-BAFFR antibody or a functional fragment thereof is administered at a dose of approximately 300 mg. The method described in 6. A8. Embodiment A, in which an anti-BAFFR antibody or a functional fragment thereof is administered at a dose of approximately 200 mg. The method described in 6. A9. Embodiment A, in which an anti-BAFFR antibody or a functional fragment thereof is administered at a dose of approximately 150 mg. The method described in 6. A10. The aforementioned practice involves subcutaneous administration of an anti-BAFFR antibody or its functional fragment. A method according to any one of the application forms. A11. The anti-BAFFR antibody or its functional fragment is administered in a monthly dosing regimen. The method according to any one of the embodiments described above. A12. Anti-BAFFR antibody or its functional fragment, 150 mg ianarumab in 2-unit doses. It will be administered in a dose containing [the substance], and this will be administered via SC every four weeks (q4w). or the method according to any one of the embodiments described above. A13. Anti-BAFFR antibody or its functional fragment is administered in combination with an additional therapeutic agent. The method described in any one of the embodiments described above. A14. The aforementioned embodiment in which the additional therapeutic agent is a steroid, such as a corticosteroid. The method described in any one of the following. A15. The method according to embodiment A14, wherein the additional therapeutic agent is prednisone. A16. Anti-BAFFR antibody or its functional fragment in combination with 50 mg prednisone It will be administered in this way, for example, prednisone will be administered orally here, before A method according to any one of the embodiments described above. A17. The subject, after treatment with an anti-BAFFR antibody or a functional fragment thereof, exhibits ESSPR Embodiments A11-A1 that achieve a sustained reaction when measured by I or ESSDAI The method described in any one of the six methods. A18. The antibody is a biosimilar of ianarumab or is replaceable therewith. A method according to any one of the embodiments described above, wherein the antibody has been proven to be effective.

[0090] Isolated human anti-BAFFR antibody B1: Use in the treatment or prevention of Sjögren's syndrome (SjS) in the target population. An isolated human anti-BAFFR antibody for the purpose of providing approximately 50 mg of the anti-BAFFR antibody to the subject. This is an isolated human anti-BAFFR antibody that will be administered in doses of approximately 300 mg. B2. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. Isolated human anti-BAFFR antibody for the purpose of, wherein the antibody is present in an amount of approximately 50 mg to approximately 300 mg The isolated human anti-BAFFR antibody will be administered subcutaneously to the subject as a dosage. B4. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. Isolated human anti-BAFFR antibody for the purpose, where anti-BAFFR antibody, here antibody, The drug is administered subcutaneously to the aforementioned subjects every four weeks in a monthly regimen of approximately 50 mg to 300 mg. As a result, the antibodies are the heavy chain CDR1, CDR2 and of SEQ ID NOs. 3, 4, and 5, respectively. A single CDR3 comprising CDR1, CDR2, and CDR3 of sequence numbers 6, 7, and 8. Human anti-BAFFR antibody. B5. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. For the purpose of is an isolated human anti-BAFFR antibody, wherein the antibody is administered once a month in a regimen of 150 mg. The vaccine will be administered subcutaneously to the target every four weeks, and the antibodies will be SEQ ID NOs: 3 and 4, respectively. and heavy chain CDR1, CDR2 and CDR3 of sequence 5, and light chain CDR1 of sequence numbers 6, 7 and 8 Isolated human anti-BAFFR antibody containing CDR2 and CDR3. B6. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. Isolated human anti-BAFFR antibody for use in a regimen of 300 mg once monthly. The antibodies will be administered subcutaneously to the target every four weeks, and the antibodies will be SEQ ID NOs: 3, 4 and 4 respectively. The heavy chains CDR1, CDR2 and CDR3 of sequence 5, and the light chains CDR1 and CDR3 of sequence numbers 6, 7 and 8. It includes DR2 and CDR3, and the antibody is a steroid drug, such as a corticosteroid drug. This is an isolated human anti-BAFFR antibody that will be administered in combination with the other antibody. B7. Embodiment B1, in which the antibody comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10. Alternatively, the isolated antibody described in B2. B8. The antibody is ianarumab, or a biosimilar of ianarumab, or The antibody shown to be replaceable is the antibody described in Embodiments B1 to B7 above. The isolated antibody described in any one of the following documents. B9. The antibody will be administered in combination with 50 mg of prednisone, and this is optional. The isolated anti-BAFFR described in Embodiment B8 is administered orally, with prednisone being given.

[0091] Antibodies for use C1. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. An anti-BAFFR antibody or a functional fragment thereof for which the anti-BAFFR antibody is effective in therapeutic amounts An anti-BAFFR antibody or a functional fragment thereof, which will be administered to the subject. C2. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. An anti-BAFFR antibody or a functional fragment thereof for which the anti-BAFFR antibody is Ianurma ianarumab is administered to the subject in a therapeutically effective dose, anti-BAF FR antibody or its functional fragment. C3. Use in the treatment or prevention of Sjögren's syndrome (SjS) in individuals in need. An anti-BAFFR antibody or a functional fragment thereof for the purpose of an anti-BAFFR antibody or its function The sexual fragment is ianarumab, and ianarumab is administered in doses of approximately 50 mg to approximately 300 mg. The anti-BAFFR antibody or its functional fragment to be administered to the subject. C4. Use in the treatment of Sjögren's syndrome (SjS) in patients requiring treatment. An anti-BAFFR antibody or a functional fragment thereof for which the anti-BAFFR antibody is ianarumab The therapeutic effective dose of ianarumab is approximately 300 mg, and the anti-BAFFR antibody or so Functional fragments. C5. The dose of the antibody is approximately 150 mg, as described in any one of Embodiments C1 to C3. Anti-BAFFR antibody or its functional fragment for use. C6. The dose of the antibody is approximately 200 mg, as described in any one of Embodiments C1 to C3. Anti-BAFFR antibody or its functional fragment for use. C7. The dose of the antibody is approximately 300 mg, as described in any one of Embodiments C1 to C3. Anti-BAFFR antibody or its functional fragment for use. C8. The antibody or its functional fragment is administered to the subject every four weeks (q4w). or an anti-BAFFR antibody or the apparatus thereof for use as described in any one of Embodiments C1 to C7 functional fragment. C9. The antibody or its functional fragment is administered to the subject every two weeks (q2w). or an anti-BAFFR antibody or the apparatus thereof for use as described in any one of Embodiments C1 to C7 functional fragment. C10. Anti-BAFFR antibody or its functional fragment is administered in a monthly dosing regimen. The anti-BAFFR antibody for use described in any one of Embodiments C1 to C7 or Its functional fragments. C11. Embodiment C, in which the antibody or a functional fragment thereof is administered subcutaneously to the subject. An anti-BAFFR antibody or a functional fragment thereof for use as described in any one of 1 to C10. C12. Anti-BAFFR antibody or its functional fragment, 150 mg anti-BAFFR in 2 unit doses. The drug will be administered in a dose containing the antibody or its functional fragment, and this will be done every four weeks (q4 The antimicrobial agent for use according to any one of embodiments C1 to C11 is administered to w) via sc. BAFFR antibody or its functional fragment. C13. Anti-BAFFR antibodies or their functional fragments are administered in combination with additional therapeutic agents. This will result in the use of anti-BAFFR according to any one of embodiments C1 to C12. Antibodies or their functional fragments. C14. Embodiment C13, in which the additional therapeutic agent is a steroid, for example, a corticosteroid. An anti-BAFFR antibody or a functional fragment thereof for use as described above. C15. Anti-B for use as described in Embodiment C14, wherein the additional therapeutic agent is prednisone. AFFR antibody or its functional fragment. Embodiment C14 or an anti - BAFFR antibody or a functional fragment thereof for use in the use described in C15, wherein prednisone is to be administered orally in an amount of about 50 mg. C17. An anti - BAFFR antibody or a functional fragment thereof for use in the use described in any one of embodiments C14 - C16, wherein an additional therapeutic agent is to be administered before the administration of the first dose of the anti - BAFFR antibody or functional fragment. C18. An anti - BAFFR antibody or a functional fragment thereof for use in the use described in any one of embodiments C14 - C17, wherein an additional therapeutic agent is to be administered before the administration of the first dose of the anti - BAFFR antibody or functional fragment and is not to be administered in combination with subsequent doses of the anti - BAFFR antibody or functional fragment. C19. An anti - BAFFR antibody or a functional fragment thereof for use in the use described in any one of embodiments C1 - C18, wherein the subject achieves a sustained response when measured by ESSPRI or ESSDAI after treatment with the anti - BAFFR antibody or functional fragment. C20. The method according to any one of the preceding embodiments C1 - C19, wherein the antibody is a biosimilar of epratuzumab or an antibody that has been demonstrated to be replaceable with it.

[0092] Further enumerated embodiments D1. A pharmaceutical for treating or preventing Sjögren's syndrome (SjS) in a subject in need of treatment, wherein the pharmaceutical comprises an anti - BAFFR antibody and the dose of the anti - BAFFR antibody is about 100 mg to about 300 mg. D2. The pharmaceutical according to embodiment D1, wherein the dose of the anti - BAFFR antibody is about 150 mg to about 300 mg. D3. The anti - BAFFR antibody has heavy - chain CDR1, CDR comprising the heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 6, 7 and 8, and the light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 6, 7 and 8 wherein the antibody is administered to a subject in need thereof at a dose of about 50 mg to about 300 mg of active ingredient The pharmaceutical product according to embodiment D1 or D2 D4. The anti-BAFFR antibody comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10 The pharmaceutical product according to embodiment D1 or D2 D5. The dose of the antibody is about 150 mg to about 300 mg, the pharmaceutical product according to embodiment D1 or D2 described D6. The dose of the antibody is about 150 mg of active ingredient, the pharmaceutical product according to any one of the above embodiments described D... The dose of the antibody is about 300 mg of active ingredient, the pharmaceutical product according to any one of the above embodiments described D8. The antibody is to be administered to a subject in need thereof every 4 weeks (q4w), the pharmaceutical product according to any one of embodiments D1 to D7 described D9. The antibody is to be administered to a subject in need thereof every 2 weeks (q2w), the pharmaceutical product according to any one of embodiments D1 to D7 described D10. The antibody is to be administered subcutaneously to a subject in need thereof, the pharmaceutical product according to any one of the above embodiments described D11. Use of an anti-BAFFR antibody for the treatment or prevention of Sjögren's syndrome in a subject in need thereof, wherein the anti-BAFFR antibody comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10 light chain sequence D12. Use of an anti-BAFFR antibody for the treatment or prevention of Sjögren's syndrome, wherein the anti-BAFFR antibody is belimumab D13. For the manufacture of a pharmaceutical product for the treatment of Sjögren's syndrome, an anti-BAFFR antibody, a buffer ​A liquid pharmaceutical composition containing a stabilizer and a solubilizer, and an anti-Sjögren's syndrome agent for subjects with Sjögren's syndrome. The use of a means for subcutaneous administration of BAFFR antibodies, wherein the anti-BAFFR antibodies are, The heavy chains CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, and the light chains of SEQ ID NOs: 6 and 7 Use including CDR1, CDR2, and CDR3. D14. Anti-BAFFR antibody, buffer for the manufacture of pharmaceuticals for the treatment of Sjögren's syndrome A liquid pharmaceutical composition containing a stabilizer and a solubilizer, and an anti-Sjögren's syndrome agent for subjects with Sjögren's syndrome. The use of a means for subcutaneous administration of a BAFFR antibody, wherein the anti-BAFFR antibody is SEQ ID NO Uses include the heavy chain sequence of sequence number 9 and the light chain sequence of sequence number 10. D15. Anti-BAFFR antibody for the manufacture of a drug for the treatment of primary Sjögren's syndrome. A liquid pharmaceutical composition comprising a buffer, stabilizer and solubilizer, and a treatment for Sjögren's syndrome The use of a means for subcutaneously administering an anti-BAFFR antibody to an elephant, wherein the anti-BAFFR antibody is It is narumab, to use. D16. Embodiments D11 to D15, in which the antibody is administered in doses of approximately 50 mg to approximately 300 mg. Use as described in any one of the following. D17. The use described in Embodiment D16, wherein the antibody is administered in a dose of approximately 300 mg. D18. The antibody is a biosimilar of ianarumab or is replaceable therewith. The drug described in any one of the embodiments above is an antibody that has been proven to be, or The use described in any one of the embodiments described above.

[0093] The attached description above provides details of one or more embodiments of this disclosure. Or, in the test, any method and material that is the same as or equivalent to those described herein. may be used, but the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference. The following examples are provided to further illustrate preferred embodiments of the present disclosure. These examples should in no way be construed as limiting the scope of the disclosed subject matter as defined by the appended claims.

[0094] Abbreviations AE Adverse event bid Twice a day (in Latin: “bis in die”) BMI Body mass index CBC Complete blood count cm Centimeter CL / F Apparent systemic (or total) clearance from plasma (or serum or blood) after dosing lance (mass / volume) CNS Central nervous system CV Coefficient of variation DMARD Disease-modifying antirheumatic drug ECG Electrocardiogram eGFR Estimated glomerular filtration rate ELISA Enzyme-linked immunosorbent assay EMG Electromyogram EQ-5D EuroQual 5 dimensions (standard means for measuring health-related quality of life) ESSDAI EULAR Sjogren’s Syndrome Disease ​Activity Index ESSPRI EULAR Sjogren's Syndrome Patient Reported Index EULAR European League against Rheumatism FACIT-F Functional Assessment of Chronic Illness Therapy - Fatigue FIH First in Human h time HRCT (High-Resolution Computed Tomography) iv intravenous IA interim analysis INR International Standardization Ratio kg (kilogram) LC-MS / MS Liquid Chromatography / Mass Spectrometry - Mass Spectrometry mAb monoclonal antibody MCP-Mod Multiple Comparison Procedure - Modeling MMRM (Mixed-Effects Model) Repeated Measures MRT average residence time Novel oral anticoagulants (NOACs) NSAIDs (non-steroidal anti-inflammatory drugs) PD Pharmacodynamics PhGA (Physician Assessment Scale) PK (Pharmacokinetics) PNS Peripheral Nervous System PT Prothrombin Time PTT (Partial Thromboplastin Time) qd Once a day (Latin for "quaque die") QT interval corrected by the QTcF Fridericia formula Racc cumulative coefficient of drugs SAE (Serious Adverse Event) Sjögren's syndrome (SjS) SOM Field Operation Manual SPT Skin Prick Test SS Safety Set TEC tyrosine protein kinase Apparent volume of distribution (volume) during the terminal elimination phase after Vz / F administration. [Examples]

[0095] Example 1: Preparation of anti-BAFFR antibody To enable those skilled in the art to implement the present invention, the amino acids of ianarumab are described below. Provides a nucleotide sequence.

[0096] The antibody ianarumab (MOR6654, or VAY736) specifically binds to BAFFR. This is also mentioned in the international publication pamphlet No. 2010 / 007082. This is a human IgG1κ antibody obtained by phage display. Its heavy and light chains are This consists of sequence numbers 9 and 10. The sequence characteristics of ianarumab are summarized in Tables 1 and 2 below. ru.

[0097] [Table 6]

[0098] [Table 7]

[0099] [Table 8]

[0100] [Table 9]

[0101] [Table 10]

[0102] [Table 11]

[0103] Example 2: Single-dose study in patients with primary Sjögren's syndrome CVAY736X2201 is a randomized, placebo-controlled, single-center, double-blind clinical trial. That is the case.

[0104] This study enrolled 27 patients with moderate to severe active Sjögren's syndrome. At baseline, six patients received a single intravenous dose of 3 mg / kg of VAY736. It was administered as such, and 12 patients received a single intravenous dose of 10 mg / kg of VAY736. And 9 patients received a single placebo infusion. Within 12 weeks, the primary ESSDAI Although the endpoint was reduced, the improvement did not reach clinical or statistical significance.

[0105] In patients with pSS, non-invasive and comprehensive ultrasound-based approaches are effective in responding to interventions. Early signs of salivary gland improvement can be detected at multiple time points. This single-dose ianarumab study Based on the combined findings of salivary gland ultrasound (SGUS) in this study, improvement in the echogenic structure (see Figure 1) Evidence has been shown suggesting a reduction in inflammation and swelling (echo-structure of the parotid / submandibular gland). .

[0106] Between the two ianarumab dose groups, ESSDAI, ESSPRI, MFI, and patient and There was variability in the overall clinical outcomes assessed by physicians. For some outcomes, The effect of 3 mg / kg ianarumab appears to be transient, with initial improvement observed at week 6. The symptoms reverted towards baseline by 12 or 24 weeks. In contrast, 10 months Patients who received g / kg ianarumab showed sustained effects up to week 24. Their observations were based on observed ianarumab exposure, i.e., at doses of 3 mg / kg and 10 mg / kg. For each group, ianarumab can be quantified up to approximately 8-12 weeks and 12-16 weeks, respectively. This was consistent with the detection level.

[0107] Example 3: PK PD data Receptor occupancy level (RO) data were evaluated. Patients with RA and Sjögren's syndrome showed PK and Using PD data, we established a dose-exposure-response relationship for circulating B cells in the blood. Applying Rearance's two-compartment population PK model to the iv and sc data. I fitted it in. Next, I used a sequential method (that is, I fixed the PK parameters from the population PK model) By determining the PK / PD (B cell) model in the pooled RA / Sjögren dataset, Dell was applied. Furthermore, a hypothesis-driven organizational RO model was developed. This model is BA We consider the competitive binding between VAY736 and soluble BAFF (sBAFF) to FF-R. I understand.

[0108] Based on the above, complete occupancy (i.e., ≥90%) of BAFF-R in the tissue with a monthly administration interval. To achieve this, 300mg sc is needed, and at least 50% of patients will achieve approximately 80% tissue RO. For this purpose, 50 mg and 150 mg scq4w were proposed. SC administration with q4w. The doses of ianarumab administered at 50 mg, 150 mg, and 300 mg are used to completely eliminate circulating B cells. In addition to the expected clinical benefits of depletion, targeting the BAFF-R pathway This provides evidence of increased effectiveness.

[0109] Example 3: Subcutaneous administration to patients with moderate to severe primary Sjögren's syndrome. To determine the safety and efficacy of multiple doses of ianarumab, a randomized, double-blind, Placebo-controlled, multicenter, phase 2 dose-range exploratory study Method: 190 patients with pSS were given either placebo or three doses of ianarumab: 5 mg, 50 mg, or 50 mg. Randomly administered either g or 300 mg once a month in a 1:1:1:1 ratio. The initial dose premedication was 250 mg IV methylprednisolone. To be eligible, one must be a member of the American-European Joint Research Group (American Europ Meets the pSS standards of the EAN Consensus Group (AECG) and is anti-Ro / SSA positive, ESSDAI ≥ 6 (7 out of 12 domains: glands, joints, lymph nodes, health) (Condition, skin, blood and biological) and the European Sjögren's Syndrome Patient Reporting Index (European Sjogren's Syndrome Patient Rep The orted Index (ESSPRI) had to be ≥ 5. This relates to the change from baseline of ESSDAI (12 domains), including MCP-Mod. The dose-response was determined, and as a secondary analysis, responder analysis was included, scoring 3 points on ESSDAI. The percentage of patients who showed the above improvements was calculated. Secondary endpoints included ESSPRI. Functional assessment of chronic disease treatment - Fatigue (FACIT-F), physician (PhGA), and patient overall The assessment includes PaGA, SF-36, stimulated salivary secretion (sSF), and Schirmer test. It was done.

[0110] Results: The primary objective of this study was achieved. Regarding ESSDAI as the primary endpoint... A statistically significant dose-response was observed (Figure 2). The largest decrease in ESSDAI was observed at: The score for ianarumab 300mg compared to placebo at week 24 was 1.92. A secondary analysis of ESSDAI showed that the 300mg vs. placebo responder ratio was 42%. / 47 (89.4%) versus 30 / 49 (61.2%), a difference of 28.1% (p=0.001). 9) On the other hand, it was revealed that there was no difference between 5 mg and 50 mg and placebo. This was the result. In line with this finding, regarding the change from baseline in PhGA, Iana There was a significant difference between lumab 300 mg and placebo (p=0.022). The numerical improvement trend in sSF for ianarumab 300mg, which was used for comparison, was evident at week 24. The author was (p=0.092). However, the secondary efficacy endpoint ESSPR I and FACIT-F showed no benefit compared to placebo in terms of improving disease burden. The placebo response was generally high. The incidence of adverse events that occurred during treatment was higher with placebo. The results were similar in the volcanic group and the active drug group, and according to these results, local injection reactions were the most frequent, with almost no side effects. However, the symptoms were mild and showed a dose-response.

[0111] The mean change in ESSDAI over time from week 4 to week 24, including placebo, is shown below. A decrease was observed in all groups. The mean change with ianarumab 5 and 50 mg was compared to placebo. There was almost no difference, but with 300mg, clear separation was observed from week 8 onwards. Signs of efficacy were observed. Stimulated saliva secretion increased significantly at 300 mg at 24 weeks. In addition, there was an increase of 0.22 mL / min compared to placebo (0.01, 0.38, 95%). (CI, p=0.037), changes were visible at week 12, but unstimulated secretion levels did not change. Tear secretion (in both the right and left eyes) showed an increasing trend.

[0112] Sjögren's syndrome, as evidenced by the legacy of undesirable consequences resulting from B cell depletion. Planning a reliable clinical trial in a group presents many challenges (appropriate patients and endpoints). (Examples include the selection of indicators, reliance on reported outcomes, and a lack of methods for evaluating tear and saliva production.) Nevertheless, this clinical trial was successful and showed several dose-dependent responses.

[0113] This study demonstrates that 300 mg ianarumab is a safe and effective dose, and that BAF Studies have shown that depleting F-positive B cells can reduce disease activity and increase saliva production. Ta.

[0114] This study focuses on effective exposure, regimens to achieve that exposure, and the specific dose ranges for the study. This clearly demonstrates how pharmacokinetic / pharmacodynamic modeling can be helpful.

Claims

1. A method for treating or preventing Sjögren's syndrome in the target population, the target population A method comprising administering a therapeutically effective amount of anti-BAFFR antibody or a functional fragment thereof to a patient.

2. The method according to claim 1, wherein the anti-BAFFR antibody or its functional fragment is ianarumab. Law.

3. The anti-BAFFR antibody or its functional fragment is administered in doses of approximately 50 mg to approximately 300 mg. The method according to claim 1 or 2.

4. The anti-BAFFR antibody or its functional fragment is administered in doses of approximately 150 mg to approximately 300 mg. The method according to any one of claims 1 to 3.

5. Claim 4, wherein the anti-BAFFR antibody or its functional fragment is administered in an amount of approximately 300 mg. Method of description.

6. Claim 4, wherein the anti-BAFFR antibody or its functional fragment is administered in an amount of approximately 200 mg. Method of description.

7. Claim 4, wherein the anti-BAFFR antibody or its functional fragment is administered in an amount of approximately 150 mg. Method of description.

8. Claims 1 to 1, wherein the anti-BAFFR antibody or a functional fragment thereof is administered subcutaneously. The method described in any one of item 7.

9. The anti-BAFFR antibody or its functional fragment is administered in a monthly dosing regimen. The method according to any one of claims 1 to 8.

10. The aforementioned anti-BAFFR antibody or its functional fragment is 150 mg ianarumab in a 2-unit dose. It will be administered in the prescribed dose, and this will be administered every four weeks (q4w). or the method according to any one of claims 2 to 9.

11. The anti-BAFFR antibody or its functional fragment is administered in combination with an additional therapeutic agent. The method according to any one of claims 1 to 10.

12. Claim 11 states that the additional therapeutic agent is a steroid, for example, a corticosteroid. The method.

13. The method according to claim 12, wherein the additional therapeutic agent is prednisone.

14. The aforementioned anti-BAFFR antibody or its functional fragment is used in combination with approximately 50 mg of prednisone. The drug will be administered by means of, for example, prednisone will be administered orally, claims 1 to The method described in any one of the 13 items.

15. The subject, after treatment with the anti-BAFFR antibody or its functional fragment, ESSPRI Or, any one of claims 1 to 14, which achieves a sustained reaction when measured by ESSDAI. The method described in item 1.

16. The antibody is either a biosimilar of ianarumab or is replaceable therewith. The method according to any one of claims 1 to 15, wherein the antibody is proven to be effective.

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