Method for treating Sjogren's syndrome using TACI-Fc fusion protein

Abstract

The present invention relates to a therapeutic agent for Sjogren's syndrome using TACI-Fc fusion protein, its dosage scheme, administration interval and administration method. The results show that the TACI-Fc fusion protein provided by the present invention significantly improves the ESSDAI score and MF-20 score of patients with Sjogren's syndrome at 24 weeks, and shows better safety during treatment.

Description

[Technical Field]

[0001] The present invention relates to pharmaceuticals, dosage schemes, dosage intervals and methods of administration for treating Sjogren's syndrome. [Background technology]

[0002] Sjögren's syndrome (SS) is a chronic autoimmune disease that primarily affects exocrine glands, such as the lacrimal and salivary glands. It manifests as dry cornea, conjunctivitis, and xerostomia, and can affect other systems, including the respiratory, digestive, urinary, hematologic, nervous, muscle, and joint systems, potentially resulting in damage to multiple systems and organs. Sjögren's syndrome is a global disease with a high incidence rate, often occurring in middle-aged and elderly people between the ages of 40 and 60. More than 90% of patients are women, with few children. Due to the lack of uniform diagnostic criteria, the prevalence of this disease is generally estimated at 0.1% to 0.7%, although this is not accurate. In the United States, the incidence of Sjögren's syndrome is second only to rheumatoid arthritis. A survey of more than 10,000 people in China showed that the prevalence of this disease was 0.29% to 0.77%, not lower than the incidence of rheumatoid arthritis, which is 0.3% to 0.4%.

[0003] Currently, treatment for Sjögren's syndrome mainly involves using hormones to suppress the patient's abnormal immune response and protect the function of the exocrine glands and other vital organs. However, there are still no approved effective treatments or biological agents for Sjögren's syndrome worldwide. As of July 20, 2021, there are only five new biological agents targeting BAFF / BLyS / APRIL in clinical research for Sjögren's syndrome worldwide (see Table 1).

[0004] [Table 1] Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, there is a huge unmet clinical need in the field of Sjögren's syndrome treatment, whether in China or worldwide. [Means for solving the problem]

[0006] After detailed analysis of a large amount of clinical data, the present inventors have surprisingly discovered that the TACI-Fc fusion protein provided by the present invention produces an unexpected technical effect in treating cancer patients with Sjogren's syndrome. Specifically, the present invention provides a method for treating Sjogren's syndrome, comprising administering a therapeutically effective amount of a TACI-Fc fusion protein to a patient with Sjogren's syndrome. The TACI-Fc fusion protein: (i) a TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL; (ii) a fragment of a constant region of a human immunoglobulin.

[0007] In some preferred embodiments, the TACI-Fc fusion protein is administered in a single dose, preferably between about 0.1 and 10 mg / kg.

[0008] The present invention also relates to the use of a TACI-Fc fusion protein in the preparation of a medicament for treating Sjogren's syndrome.

[0009] In one embodiment, the TACI extracellular domain or fragment thereof comprises the amino acid sequence of SEQ ID NO:1. TIFF0007737468000002.tif22170

[0010] In one embodiment, the human immunoglobulin is an IgG1, or the fragment of the constant region of the human immunoglobulin comprises the amino acid sequence of SEQ ID NO:2 or an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, or at least 96% identical to SEQ ID NO:2. TIFF0007737468000003.tif37170

[0011] In a preferred embodiment, the fragment of a human immunoglobulin constant region comprises an amino acid modification corresponding to one or more of positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2. The modification is preferably an amino acid substitution, deletion or insertion.

[0012] In some particular embodiments, the substitutions are selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

[0013] In a specific embodiment, the fragment of a constant region of a human immunoglobulin comprises the amino acid sequence of SEQ ID NO:3. TIFF0007737468000004.tif38170

[0014] In one embodiment, the TACI-Fc fusion protein is telitacicept, the amino acid sequence of which is set forth in SEQ ID NO:4. TIFF0007737468000005.tif52170

[0015] In some preferred embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously at an administration site in the thigh, abdomen, or upper arm.

[0016] In some preferred embodiments, the TACI-Fc fusion protein is administered 2-4 times at monthly intervals.

[0017] In some preferred embodiments, the TACI-Fc fusion protein is administered once a week.

[0018] In some preferred embodiments, the treatment lasts for about 2 to 50 weeks.

[0019] In some preferred embodiments, the Sjogren's syndrome is primary Sjogren's syndrome.

[0020] In some preferred embodiments, the Sjogren's syndrome is secondary Sjogren's syndrome.

[0021] In some preferred embodiments, the TACI-Fc fusion protein is administered in a single dose of 160-240 mg, more preferably 160 mg or 240 mg.

[0022] The present invention also includes the use of the TACI-Fc fusion protein in the preparation of a medicament for treating Sjogren's syndrome.

[0023] The results of a clinical study conducted by the present invention showed that treatment with telitacicept significantly improved the ESSDAI score and MF-20 score in patients with pSS at 24 weeks, and that telitacicept showed better safety in patients with pSS. [Brief explanation of the drawings]

[0024] [Figure 1] Figure 1 shows the percent change from baseline in IgG levels in the placebo, 160 mg, and 240 mg groups. [Figure 2] Figure 2 shows the percent change from baseline in IgA levels in the placebo, 160 mg, and 240 mg groups. [Figure 3] Figure 3 shows the percent change from baseline in IgM levels in the placebo, 160 mg, and 240 mg groups. [Figure 4]Figure 4 shows the percent change from baseline in CD19+ B cell counts in the placebo group, 160 mg group, and 240 mg group. [Figure 5] Figure 5 shows the percent change from baseline in CD4+ T cell counts in the placebo group, 160 mg group, and 240 mg group. [Figure 6] Figure 6 shows the rate of change from baseline in CD8+ T cell counts in the placebo group, 160 mg group, and 240 mg group. DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless otherwise defined, technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art. For definitions and terminology in this field, those skilled in the art can refer specifically to Current Protocols in Molecular Biology (Ausubel).

[0026] The three-letter and one-letter codes for amino acids used in the present invention are as described in J. Biol. Chem, 243, p. 3558 (1968).

[0027] The present invention provides the use of a transmembrane activator, calcium regulator and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., a TACI-Fc fusion protein) in the treatment of Sjogren's syndrome. The patient of the present invention is preferably a mammal, such as a human.

[0028] The term "TACI," i.e., transmembrane activator and calmodulin ligand interactor, as used herein refers to a member of the tumor necrosis factor receptor superfamily. The term "BLys," as used herein refers to B lymphocyte stimulator, a member of the TNF ligand superfamily that exists in two forms, membrane-bound and soluble. It is specifically expressed on the surface of myeloid cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production. The term "APRIL" (a proliferation-inducing ligand) as used herein refers to a tumor necrosis factor (TNF) analog that stimulates the proliferation of primitive B cells and T cells in the body, promoting the accumulation of B cells and increasing their content in the spleen. APRIL can specifically bind to TACI and BCMA, and upon binding, inhibits APRIL from binding to B cells and suppresses the proliferative response of primitive B cells stimulated by APRIL. Furthermore, APRIL can compete with BLys to bind to receptors (BCMA, TACI).

[0029] As used herein, the term "TACI-Fc fusion protein" refers to a transmembrane activator, calcium regulator, and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., a TACI-Fc fusion protein). The TACI-immunoglobulin fusion protein provided herein comprises (i) the TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL, and (ii) a fragment of a human immunoglobulin constant region.

[0030] The term "TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL" specifically refers to the extracellular domain of TACI and specific fragments of the TACI extracellular domain that can interact with TACI ligands disclosed in U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428, and U.S. patent applications 09 / 569,245 and 09 / 627,206 (the contents of which are incorporated herein by reference), or the amino acid fragment from amino acids 13 to 118 of the TACI extracellular domain disclosed in Chinese patent publication number CN101323643A.

[0031] The immunoglobulin portion of the TACI-immunoglobulin fusion proteins provided herein is preferably an IgG1, which may include a heavy chain constant region, such as a human heavy chain constant region. A preferred IgG1 heavy chain constant region of the present invention is an IgG1 Fc fragment containing the CH2 and CH3 regions, which may be a wild-type IgG1 Fc fragment or a mutated IgG1 Fc fragment.

[0032] In the term "fragment of a human immunoglobulin constant region," the immunoglobulin portion is preferably IgG1, which may include a heavy chain constant region, such as a human heavy chain constant region. A preferred "fragment of a human immunoglobulin constant region" of the present invention is an amino acid fragment comprising a portion of the hinge region domain, CH2 domain, and CH3 domain. In some more preferred embodiments, the amino acid sequence of the "fragment of a human immunoglobulin constant region" described in the present invention is set forth in SEQ ID NO:2, or comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2. In some more preferred embodiments, the amino acid sequence of the "fragment of a human immunoglobulin constant region" is set forth in SEQ ID NO:3.

[0033] The term "amino acid" in the present invention is understood in the broadest sense and is a general term for a type of organic compound containing an amino group and a carboxyl group. Preferably, the amino acid in the present invention is a main unit constituting proteins in living organisms, such as, but not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine.

[0034] The three-letter and one-letter amino acid codes used in the present invention are as described in J. Biol. Chem., 243, p. 3558 (1968). There are various methods for numbering amino acid positions, such as Kabat numbering, EU numbering, and ordinal numbering. In the present invention, the "ordinal numbering" method is used as the method for numbering amino acid positions. For example, "positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 2" in the present invention refers to the third amino acid, the eighth amino acid, etc. of SEQ ID NO: 2. In the present invention, "P3T" means that the third amino acid in the sequence of SEQ ID NO: 2 is mutated from "P" to "T," and "L8P" means that the eighth amino acid in the sequence of SEQ ID NO: 2 is mutated from "L" to "P," as in this example.

[0035] In another embodiment, the constant regions of the immunoglobulins provided herein can have one or more amino acid changes introduced, such as substitutions (i.e., mutations), additions (i.e., insertions), or deletions (i.e., deletions).

[0036] The term "telitacicept" (which can be used interchangeably in the present invention with its Chinese name "Tei Ai") is a TACI-Fc fusion protein, the INN name of which is Telitaccept, and the amino acid sequence of which is shown in SEQ ID NO: 4, or see https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932.

[0037] The TACI-Fc fusion proteins of the present invention can be administered via any route, including, but not limited to, oral administration, intravenous injection, intramuscular injection, intraarterial injection, intramedullary injection, intraperitoneal injection, intrathecal injection, intracardiac, transdermal, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal, and rectal routes.

[0038] The term "treatment" as used herein relates to a given disease or condition, and includes, but is not limited to, suppressing the disease or condition so as to prevent its progression, alleviating the disease or condition so as to cause regression of the disease or condition, or alleviating symptoms caused by the disease or condition so as to alleviate, prevent, or treat the symptoms of the disease or condition.

[0039] Hereinafter, embodiments of the present invention will be described in detail in conjunction with examples. However, it will be understood by those skilled in the art that the following examples are used to explain the present invention and should not be considered to limit the scope of the present invention.

[0040] Example 1 Clinical Trial to Treat Sjögren's Syndrome with Telitaccept

[0041] 1. Research method This was a multicenter, randomized, double-blind, placebo-controlled phase II clinical study. Participants were required to be anti-SSA antibody positive, diagnosed with primary Sjögren's syndrome (pSS), and had an ESSDAI score of ≥ 5 during the screening period. The study phase was divided into two parts: a screening period and a double-blind treatment period. The screening period ran from Day -28 to Day -1. Subjects who met the inclusion criteria but did not meet any exclusion criteria were randomly assigned in a 1:1:1 ratio to the placebo group, the telitacicept 160 mg group, or the telitacicept 240 mg group. The double-blind treatment period ran from Day 0 to Day 168 (Week 24), during which 24 doses were administered once weekly.

[0042] [Table 2]

[0043] 2. Selected patients Patients who fulfill the 2016 ACR / EULAR classification criteria for primary Sjögren's syndrome and have at least one symptom of dry eye and dry mouth, i.e., at least one of the following is positive: - Having experienced unbearable dry eyes every day for more than three months · Recurring grittiness in the eyes, The need to use artificial tears three or more times a day; - Have had dry mouth every day for more than three months - Frequent need for water assistance when swallowing dry food; positive anti-SSA antibodies; and ESSDAI score ≥ 5 points.

[0044] 3. Evaluation criteria 3.1 Treatment effect index 3.1.1 Primary treatment effect index Change in ESSDAI score from baseline to week 24

[0045] 3.1.2 Secondary treatment effect indicators Change in ESSDAI score from baseline to week 12, Change in ESSPRI score from baseline at weeks 12 and 24 Physician's Global Assessment of change in disease activity from baseline at weeks 12 and 24; Patient Global Assessment of Disease Activity at Weeks 12 and 24 compared to baseline; Changes in SF-36 scores at 12 and 24 weeks from baseline Change in MFI-20 from baseline at weeks 12 and 24, · Unirritating whole saliva (UWS) flow rate; A scale mark corresponding to the leading edge of the wetted area of ​​the filter paper strip at 5 minutes, · Immunological indicators: IgG, IgA, IgM, complement (C3, C4), total number of B lymphocytes (CD19+), number of CD4+ T cells, number of CD8+ T cells.

[0046] 3.2 Safety assessment Adverse events, Laboratory testing, Vital signs, · Chest X-ray; electrocardiogram, · Immunogenicity.

[0047] 4. Statistical methods In this study, SAS 9.4 software was used for analysis, and two-sided tests were used for all statistical tests, and the differences tested were considered statistically significant when P values ​​were ≤ 0.05. Continuous variables were described by means, standard deviations, medians, minimum and maximum values, and count and graded data were described by frequency counts and percentages.

[0048] The study had three analysis populations: Full Analysis Set (FAS): The full analysis set refers to the set of all patients who were randomized and received at least one dose of the investigational drug. Per Protocol Set (PPS): The per protocol set is a data set generated by subjects who are fully compliant with the protocol, including exposure to treatment, availability of primary endpoint measures, and absence of major protocol violations. Safety analysis set (SS): This is the actual data for which at least one treatment was administered and safety endpoints were recorded. The incidence of adverse reactions is calculated using the number of cases in the safety analysis set as the denominator.

[0049] 5. Demographics and baseline characteristics In this study, 57 patients were screened, 42 were randomly assigned, 30 completed the 24-week observation period, and 12 discontinued the study early. Finally, 42 patients were included in the full analysis set (FAS), 30 in the per protocol set (PPS), and 42 in the safety analysis set (SS). In the placebo group, there were 14 patients in the FAS, 10 in the PPS, and 14 in the SS. In the 160 mg group, there were 14 patients in the FAS, 12 in the PPS, and 14 in the SS. In the 240 mg group, there were 14 patients in the FAS, 8 in the PPS, and 14 in the SS.

[0050] At baseline, the 240 mg group (N=14), 160 mg group (N=14), and placebo group (N=14) were comparable in terms of subjects' age, height, weight, BMI, sex, ethnicity, occupation, marital status, upbringing, smoking history, history of drug allergies, course of primary Sjögren's syndrome, primary Sjögren's syndrome diagnostic score, onset of primary Sjögren's syndrome, history of treatment for primary Sjögren's syndrome, vital signs, virological tests, thyroid function tests, immunological indicators, ESSDAI total score, investigator's global assessment of disease, ESSPRI total score and each dimension score, subject's global assessment of disease, SF-36 total score and each dimension score, MFI-20 total score and each dimension score, autoantibody tests, BLyS concentration, and APRIL concentration (P>0.05).

[0051] 6. Treatment Effect Results 6.1 Primary Treatment Effect Endpoint The primary treatment efficacy endpoint in this study was the change from baseline in the ESSDAI score at week 24. Analysis was performed using a mixed-effects model with repeated measures (MMRM) without deletion or imputation of missing data. The change from baseline in the ESSDAI score at week 24 and its 95% CI were -0.3 [95% CI: -2.1 to 1.6] in the placebo group (N = 14), -4.0 [95% CI: -5.7 to -2.3] in the 160 mg group (N = 14), and -3.1 [95% CI: -5.2 to -1.0] in the 240 mg group (N = 14). Comparison of the MMRM revealed statistically significant differences between the 160 mg and placebo groups (P = 0.004) and between the 240 mg and placebo groups (P = 0.044). According to the analysis results for PPS, the change from baseline in ESSDAI score at 24 weeks after treatment and its 95% CI were -0.2 [95% CI: -1.8 to 1.4] in the placebo group (N = 10), -3.9 [95% CI: -5.4 to -2.5] in the 160 mg group (N = 12), and -3.1 [95% CI: -4.8 to -1.3] in the 240 mg group (N = 8). Furthermore, a comparison of MMRM showed that the difference between the 160 mg group and the placebo group was statistically significant (P < 0.001), and the difference between the 240 mg group and the placebo group was statistically significant (P = 0.019).

[0052] 6.2 Secondary Treatment Efficacy Endpoints 6.2.1. Change in ESSDAI score from baseline to week 12 The change from baseline in the ESSDAI score at week 12 was one of the secondary efficacy endpoints in this study. A mixed-effects model for repeated measures (MMRM) was used to compare differences between groups without removing or imputing missing data. The FAS analysis revealed that the change from baseline in the ESSDAI score at week 12 was 0.7 [95% CI: -1.0 to 2.4] in the placebo group (N = 14), -3.8 [95% CI: -5.5 to -2.1] in the 160 mg group (N = 14), and -2.5 [95% CI: -4.3 to -0.6] in the 240 mg group (N = 14). Comparison of the MMRM revealed statistically significant differences between the 160 mg and placebo groups (P < 0.001), and between the 240 mg and placebo groups (P = 0.013). According to the PPS analysis results, the change from baseline in ESSDAI score at 12 weeks after treatment and its 95% CI were -0.5 [95% CI: -2.1 to 1.1] in the placebo group (N = 10), -3.8 [95% CI: -5.2 to -2.3] in the 160 mg group (N = 12), and -2.9 [95% CI: -4.7 to -1.2] in the 240 mg group (N = 8). Furthermore, a comparison of MMRM showed that the difference between the 160 mg group and the placebo group was statistically significant (P = 0.003), and the difference between the 240 mg group and the placebo group was statistically significant (P = 0.045).

[0053] 6.2.9. Immunological indicators Immunological indices included IgG, IgA, IgM, complement (C3, C4), total B lymphocyte count (CD19+), CD4+ T cell count, and CD8+ T cell count. The changes in immunological indices after treatment compared to baseline were compared between groups using analysis of variance. When P ≤ 0.05 in the analysis of variance, pairwise comparisons between groups were performed using the LSD t-test. Analysis was performed using the actual data from the FAS.

[0054] Compared with the placebo group, the telitacicept treatment group showed significant decreases in IgG, IgA, and IgM levels from week 4 to week 24. At week 24, the percent changes in IgG levels from baseline in the placebo, 160 mg, and 240 mg groups were 1.02 ± 21.855, -23.91 ± 10.199, and -28.40 ± 11.219, respectively; the difference between the 160 mg and placebo groups was statistically significant (P < 0.001), and the difference between the 240 mg and placebo groups was statistically significant (P < 0.001). At week 24, the percent changes in IgA levels from baseline in the placebo, 160 mg, and 240 mg groups were -1.29±14.749, -47.55±8.790, and -49.18±11.294, respectively. The difference between the 160 mg and placebo groups was statistically significant (P<0.001), and the difference between the 240 mg and placebo groups was statistically significant (P<0.001). At week 24, the percent change in IgM levels from baseline in the placebo, 160 mg, and 240 mg groups was -7.87 ± 19.062, -55.74 ± 11.010, and -61.61 ± 8.692, respectively. The difference between the 160 mg group and the placebo group was statistically significant (P < 0.001), and the difference between the 240 mg group and the placebo group was statistically significant (P < 0.001). A time-course analysis of the percent change in IgG, IgA, and IgM levels from baseline in each group is shown in Figures 1 to 3.

[0055] Compared with the placebo group, the telitacicept treatment group demonstrated a trend toward a significant decrease in CD19+ B cell counts. At week 24, the percent change in CD19+ B cell counts from baseline in the placebo, 160 mg, and 240 mg groups was 6.31 ± 32.826, -29.26 ± 44.698, and -39.36 ± 37.836, respectively. The difference between the 160 mg and placebo groups was statistically significant (P = 0.044), and the difference between the 240 mg and placebo groups was statistically significant (P = 0.021). A time-course analysis of the percent change in CD19+ B cell counts from baseline in each group is shown in Figures 4–6.

[0056] 6.3 Safety results Only one subject in the placebo group experienced serious adverse events, including hypoalbuminemia, herpes zoster, pulmonary tuberculosis, infectious pneumonia, and exacerbation of Sjogren's syndrome, which were alleviated after treatment. Only two subjects in the 240 mg group experienced severe or more severe (CTCAE grade 3-5) adverse events: acute pyelonephritis and leukopenia, respectively.

[0057] 6.4 Conclusion Compared with the placebo group, treatment with telitacicept significantly improved ESSDAI and MF-20 scores in patients with pSS at week 24. Telitacic met the safety criteria for pSS patients.

[0058] The above description is merely a preferred embodiment and is used for illustration only, and does not limit the combination of features necessary to implement the present invention. The titles provided are not meant to limit the various embodiments of the present invention. Terms such as "comprises," "includes," and "included" are not meant to limit. Furthermore, unless otherwise specified, when not modified by a number, plural forms are included, and "or" means "and / or." Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0059] All publications and patents mentioned in this application are incorporated herein by reference. Various modifications and variations made to the methods and combinations described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in terms of specific preferred embodiments, it should be understood that the invention for which protection is sought should not be unduly limited to these specific embodiments. Indeed, various variations of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be encompassed within the scope of the following claims.

Claims

1. A pharmaceutical composition for treating Sjogren's syndrome, comprising a TACI-Fc fusion protein having the amino acid sequence shown in SEQ ID NO:

4.

2. The pharmaceutical composition for treatment according to claim 1, wherein the TACI-Fc fusion protein is telitacicept.

3. The pharmaceutical composition for treatment according to claim 1 or 2, characterized in that the Sjogren's syndrome is primary Sjogren's syndrome or secondary Sjogren's syndrome.

4. The pharmaceutical composition for treatment according to claim 1 or 2, characterized in that the TACI-Fc fusion protein is administered in a single dose of about 0.1 to 10 mg / kg.

5. The pharmaceutical composition for treatment according to claim 1 or 2, characterized in that the TACI-Fc fusion protein is administered in a single dose of 160 to 240 mg.

6. The pharmaceutical composition for treatment according to claim 1 or 2, characterized in that the TACI-Fc fusion protein is administered in a single dose of 160 mg or 240 mg.

7. The pharmaceutical composition for treatment according to claim 5, wherein the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously at an administration site in the thigh, abdomen or upper arm.

8. The pharmaceutical composition for treatment according to claim 1, wherein the TACI-Fc fusion protein is used 2 to 4 times a month.

9. The pharmaceutical composition for treatment according to claim 8, wherein the TACI-Fc fusion protein is administered once a week.

10. The pharmaceutical composition for treatment according to claim 8, characterized in that the treatment is continued for about 2 to 50 weeks.

Images