Method for treating sjogren's syndrome with taci-fc fusion protein

Abstract

This invention relates to a drug, dosage regimen, dosing interval, and administration method for treating Sjögren's syndrome using TACI-Fc fusion protein. Results show that the TACI-Fc fusion protein provided by this invention significantly improves the ESSDAI and MF-20 scores of Sjögren's syndrome patients at week 24 and exhibits good safety during treatment.

Description

Treatment of Sjögren's syndrome with TACI-Fc fusion protein This invention relates to a drug, dosage regimen, dosing interval, and administration method for treating Sjögren's syndrome. Sjögren's syndrome (SS) is a chronic autoimmune disease that primarily affects exocrine glands such as the lacrimal and salivary glands. It is also known as an autoimmune exocrine gland disease. The main symptoms include dry keratitis, conjunctivitis, and xerostomia. It can also affect other systems such as the respiratory, digestive, urinary, hematologic, and nervous systems, as well as muscles and joints, causing damage to multiple systems and organs. Sjögren's syndrome is a global disease with a high incidence, primarily affecting middle-aged and elderly individuals between 40 and 60 years of age, with over 90% of cases occurring in women and fewer in children. Due to the lack of a unified diagnostic standard, the prevalence of this disease is highly inaccurate, generally estimated at 0.1% to 0.7%. In the United States, the incidence of Sjögren's syndrome is second only to rheumatoid arthritis. A survey of over 10,000 people in China found a prevalence of 0.29% to 0.77%, indicating that its prevalence in China is no less than the 0.3% to 0.4% incidence of rheumatoid arthritis. Currently, the main treatment for Sjögren's syndrome is to suppress the abnormal immune response in patients with hormones, thereby protecting the function of exocrine glands and other vital organs. However, there are currently no approved specific therapies or biologics for Sjögren's syndrome worldwide. As of July 20, 2021, only five novel biologics targeting BAFF / BLyS / APRIL were in clinical trials for Sjögren's syndrome globally (see Table 1). Therefore, there is a huge unmet clinical need in the treatment of Sjögren's syndrome, both in China and globally. Through in-depth analysis of a large amount of clinical data, this invention surprisingly discovered that the TACI-Fc fusion protein provided by this invention produces unexpected technical effects in treating cancer patients with Sjögren's syndrome. Specifically, this invention provides a method for treating Sjögren's syndrome, the method comprising administering a therapeutically effective amount of TACI-Fc fusion protein to a patient with Sjögren's syndrome, wherein the TACI-Fc fusion protein comprises: (i) the extracellular region of TACI or fragments thereof that bind Blys and / or APRIL; and (ii) Human immunoglobulin constant region fragment. In some preferred embodiments, the single dose of the TACI-Fc fusion protein is preferably about 0.1 to 10 mg / kg. The present invention also relates to the use of the TACI-Fc fusion protein in the preparation of a medicament for the treatment of Sjögren's syndrome. In one embodiment, the extracellular region of TACI or a fragment thereof comprises the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 1 In one embodiment, the human immunoglobulin is IgG1 or the human immunoglobulin constant region fragment contains the amino acid sequence of SEQ ID NO: 2 or contains 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. SEQ ID NO: 2 In a preferred embodiment, the human immunoglobulin constant region fragment comprises an amino acid modification at one or more sites corresponding to sites 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2, wherein the modification is preferably an amino acid substitution, deletion or insertion. In some specific embodiments, the substituted material is selected from the group consisting of: P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T. In one particular embodiment, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO: 3. SEQ ID NO: 3 In one embodiment, the TACI-Fc fusion protein is Telitacicept, whose amino acid sequence is shown in SEQ ID NO: 4. SEQ ID NO: 4 In some preferred embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously, or at the thigh, abdomen, or upper arm. In some preferred embodiments, the TACI-Fc fusion protein is used 2-4 times at monthly intervals. In some preferred embodiments, the TACI-Fc fusion protein is administered once a week. In some preferred embodiments, the treatment lasts for approximately 2-50 weeks. In some preferred embodiments, the Sjögren's syndrome is primary Sjögren's syndrome. In some preferred embodiments, the Sjögren's syndrome is secondary Sjögren's syndrome. In some preferred embodiments, the single dose of the TACI-Fc fusion protein is 160-240 mg, more preferably 160 mg or 240 mg. The present invention also includes the use of the above-mentioned TACI-Fc fusion protein in the preparation of a medicament for treating Sjögren's syndrome. In a clinical study conducted under this invention, the results showed that teltasicip treatment significantly improved the ESSDAI and MF-20 scores of pSS patients at week 24; teltasicip also demonstrated good safety in pSS patients. Figure 1 shows the rate of change in IgG levels from baseline in the placebo group, 160 mg group, and 240 mg group; Figure 2 shows the rate of change of IgA levels from baseline in the placebo group, 160 mg group, and 240 mg group; Figure 3 shows the rate of change of IgM levels from baseline in the placebo group, 160 mg group, and 240 mg group; Figure 4 shows the rate of change in CD19+ B cell count from baseline in the placebo group, 160 mg group, and 240 mg group. Figure 5 shows the rate of change in CD4+ T cell count from baseline in the placebo group, 160mg group, and 240mg group. Figure 6 shows the rate of change in CD8+ T cell count from baseline in the placebo group, 160mg group, and 240mg group. Unless otherwise defined, all technical terms used herein have the same meaning as understood by one of ordinary skill in the art. For definitions and terminology in this field, professionals may refer to Current Protocols in Molecular Biology (Ausubel). The amino acid three-letter codes and single-letter codes used in this invention are as described in J. biol. chem, 243, p3558 (1968). This invention provides the application of a transmembrane initiator, calcium regulator, and cyclic ligand interactor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein) in the treatment of Sjögren's syndrome. The patients involved in this invention are preferably mammals, such as humans. In this invention, the term "TACI" stands for transmembrane activator and CAML interactor, a member of the tumor necrosis factor receptor superfamily. The term "BLys" refers to B lymphocyte stimulator, a member of the TNF ligand superfamily existing in both membrane-bound and soluble forms. It is specifically expressed on the surface of bone marrow cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production. The term "APRIL" (a proliferation-inducing ligand) is a tumor necrosis factor (TNF) analog that stimulates the proliferation of primitive B cells and T cells in vivo, promotes B cell accumulation, and increases spleen content. APRIL specifically binds to TACI and BCMA, preventing APRIL from binding to B cells and inhibiting the APRIL-induced primitive B cell proliferation response. Furthermore, APRIL competitively binds to receptors (BCMA and TACI) with BLys. The term "TACI-Fc fusion protein" as used in this invention refers to a transmembrane initiator, calcium regulator and cyclic protein ligand interactor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein). The TACI-immunoglobulin fusion protein provided by this invention comprises: (i) the extracellular region of TACI or a fragment thereof binding to Blys and / or APRIL; and (ii) a fragment of the human immunoglobulin constant region. The term “TACI extracellular domain or a fragment thereof binding to Blys and / or APRIL” can be specifically referred to in U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428 and U.S. Patent Applications Nos. 09 / 569,245 and 09 / 627,206 (the contents of which are incorporated herein by reference) as the extracellular domain of TACI and specific fragments of the extracellular domain of TACI that can interact with TACI ligands, or the amino acid fragment of the extracellular domain of TACI disclosed in Chinese Patent Publication No. CN101323643A, which consists of amino acids 13-118 of the extracellular domain of TACI. The immunoglobulin portion of the TACI-immunoglobulin fusion protein provided by this invention is preferably IgG1, which may include a heavy chain constant region, such as the human heavy chain constant region. The preferred IgG1 heavy chain constant region of this invention is an IgG1Fc fragment containing CH2 and CH3 regions, which may be a wild-type IgG1Fc fragment or a mutated IgG1Fc fragment. In the term "human immunoglobulin constant region fragment," the immunoglobulin portion is preferably IgG1, which may include a heavy chain constant region, such as the human heavy chain constant region. The preferred "human immunoglobulin constant region fragment" of this invention is an amino acid fragment containing a partial hinge region domain, a CH2 domain, and a CH3 domain. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" of this invention is as shown in SEQ ID NO: 2, or contains 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 "human immunoglobulin constant region fragment" is as shown in SEQ ID NO: 3. The term "amino acid" in this invention is understood in the broadest sense as a general term for a class of organic compounds containing amino and carboxyl groups. Preferably, the amino acids involved in this invention are the main building blocks of proteins in living organisms, including but not limited to: glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, aspartamine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine. The amino acid three-letter codes and single-letter codes used in this invention are as described in J. Biol. Chem., 243, p3558 (1968). There are various methods for numbering amino acid positions, such as the Kabat numbering system, the EU numbering system, and sequential numbering. In this invention, the amino acid positions are numbered sequentially. For example, "positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 2" refers to the 3rd amino acid, the 8th amino acid of SEQ ID NO: 2, and so on. Similarly, "P3T" refers to changing the 3rd amino acid sequence of SEQ ID NO: 2 from "P" to "T," and "L8P" refers to changing the 8th amino acid sequence of SEQ ID NO: 2 from "L" to "P," and so on. As an alternative implementation, the constant region of the immunoglobulin provided by the present invention can be modified by one or more amino acid changes, such as substitution (i.e., mutation), addition (i.e., insertion), or deletion (i.e., deletion). The term "telitacicept" (or "Telitacicept", which can be used interchangeably in this invention) is a TACI-Fc fusion protein with the INN name Telitacicept and its amino acid sequence as shown in SEQ ID NO: 4, or see https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932. The TACI-Fc fusion protein of the present invention can be administered via any and many routes, including but not limited to: oral, intravenous, intramuscular, intra-arterial, intramedullary, intraperitoneal, intrathecal, intracardiac, transdermal, transdermal, topical, subcutaneous, intranasal, intraenteral, sublingual, vaginal, or rectal routes. The term "treatment" as used in this invention relates to a given disease or condition, including but not limited to: suppressing the disease or condition, such as preventing the development of the disease or condition; alleviating the disease or condition, such as causing the disease or condition to subside; or reducing the symptoms caused by the disease or condition, such as reducing, preventing or treating the symptoms of the disease or condition. The embodiments of the present invention will be described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Example 1: Clinical trial of telitapril for the treatment of Sjögren's syndrome 1. Research Methods This study is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. Participants were diagnosed patients with primary Sjögren's syndrome (pSS) who were positive for anti-SSA antibodies and required ESSDAI screening. 5 points. The trial was divided into two phases: a screening period and a double-blind treatment period. During the screening period, from day -28 to day -1, subjects meeting the inclusion criteria but not the exclusion criteria were randomly assigned in a 1:1:1 ratio to the placebo group, the telitacicept 160 mg group, and the telitacicept 240 mg group. The double-blind treatment period ran from day 0 to day 168 (week 24), with medication administered once weekly for a total of 24 doses. 2. Enrolled patients Patients who meet the 2016 ACR / EULAR classification criteria for primary Sjögren's syndrome and have at least one of the following symptoms: dry eyes or dry mouth, i.e., at least one of the following criteria is positive: • Unbearable dryness of the eyes every day for more than 3 months; • A persistent gritty sensation in the eyes; • Artificial tears need to be used 3 or more times daily; • Experiencing daily dry mouth for more than 3 months; • Instructions for frequent hydration when swallowing dry foods; positive anti-SSA antibody; and ESSDAI. 4 points. 3. Evaluation Criteria 3.1 Therapeutic Indicators 3.1.1 Main therapeutic indicators • Change in ESSDAI score from baseline at week 24. 3.1.2 Secondary efficacy indicators • The change in ESSDAI score from baseline at week 12; • The change in ESSPRI score from baseline at weeks 12 and 24; • At weeks 12 and 24, the physician assesses the overall change in disease activity compared to baseline; • At weeks 12 and 24, assess the change in overall disease activity compared to baseline; • Changes in SF-36 levels compared to baseline at weeks 12 and 24; • The change in MFI-20 from baseline at weeks 12 and 24; • Non-irritating whole saliva (UWS) flow rate; • The graduation marked on the leading edge of the wetted portion 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. 3.2 Safety Evaluation • Adverse events; • Laboratory tests; • Vital signs; Chest X-ray; Electrocardiogram (ECG); • Immunogenicity. 4. Statistical methods This study used SAS 9.4 software for analysis. All statistical tests were two-tailed, and the p-value was calculated. A difference of 0.05 was considered statistically significant. Continuous variables were described using the mean, standard deviation, median, minimum, and maximum values, while count and ordinal data were described using frequency and percentage. This study has 3 analysis sets: • Full Analysis Set (FAS): The full analysis set refers to the collection of all cases that have been randomized and have used the investigational drug at least once. • Compliance Set (PPS): A compliance set is a data set generated by subjects who fully comply with the trial protocol. Compliance includes the treatment received, the availability of the primary endpoint measurement, and no major deviations from the trial protocol. • Safety Data Set (SS): Actual data from patients who received at least one treatment and whose safety indicators were recorded. The incidence of adverse reactions is calculated using the number of cases in the safety set as the denominator. 5. Demographic and baseline characteristics This trial screened 57 patients, randomly assigned 42 to the study, and 30 completed the 24-week trial observation. 12 patients withdrew early, resulting in 42 patients included in the full analysis set (FAS); 30 patients were included in the protocol compliance set (PPS); and 42 patients were included in the safety data set (SS). Specifically, in the placebo group, there were 14 patients in the FAS, 10 in the PPS, and 14 in the SS; in the 160mg group, there were 14 patients in the FAS, 12 in the PPS, and 14 in the SS; and in the 240mg group, there were 14 patients in the FAS, 8 in the PPS, and 14 in the SS. At baseline, the age, height, weight, BMI, sex, ethnicity, occupation, marital status, fertility status, smoking history, drug allergy history, duration of primary Sjögren's syndrome, diagnostic score of primary Sjögren's syndrome, manifestations of primary Sjögren's syndrome, history of treatment for primary Sjögren's syndrome, vital signs, virological examination, thyroid function examination, immunological indicators, ESSDAI total score, investigator's overall assessment of the disease, ESSPRI total score and scores of each dimension, subject's overall assessment of the disease, SF-36 total score and scores of each dimension, MFI-20 total score and scores of each dimension, autoantibody examination, BLyS concentration, and APRIL concentration were all comparable (P>0.05). 6. Treatment Results 6.1 Primary therapeutic endpoint The primary efficacy endpoint of this study was the change in ESSDAI score from baseline at week 24. A repeated measures mixed-effects model (MMRM) was used to compare differences between groups, and missing data were not filled. Analysis of the FAS showed that the changes in ESSDAI score from baseline at week 24 after treatment and their 95% CIs were as follows: placebo group (N=14), -0.3 [95% CI: -2.1 to 1.6]; 160mg group (N=14), -4.0 [95% CI: -5.7 to -2.3]; 240mg group (N=14), -3.1 [95% CI: -5.2 to -1.0]. The MMRM comparisons between the 160mg and placebo groups showed statistically significant differences (P=0.004), and between the 240mg and placebo groups also showed statistically significant differences (P=0.044). Analysis of PPS showed that the changes in ESSDAI scores from baseline at week 24 after treatment and their 95% CIs were as follows: placebo group (N=10), -0.2 [95% CI: -1.8 to -1.4]; 160mg group (N=12), -3.9 [95% CI: -5.4 to -2.5]; 240mg group (N=8), -3.1 [95% CI: -4.8 to -1.3]. The MMRM comparison showed statistically significant differences between the 160mg group and the placebo group (P<0.001), and between the 240mg group and the placebo group (P=0.019). 6.2 Secondary therapeutic endpoints 6.2.1. Change in ESSDAI score from baseline at week 12 The change in ESSDAI score from baseline at week 12 was one of the secondary efficacy endpoints in this study. A repeated measures mixed-effects model (MMRM) was used to compare differences between groups, and missing data were not filled. Analysis of the FAS showed that the changes in ESSDAI score from baseline at week 12 after treatment and their 95% CIs were as follows: placebo group (N=14), 0.7 [95% CI: -1.0 to 2.4]; 160mg group (N=14), -3.8 [95% CI: -5.5 to -2.1]; 240mg group (N=14), -2.5 [95% CI: -4.3 to -0.6]. The MMRM comparisons between the 160mg and placebo groups showed statistically significant differences (P<0.001), and between the 240mg and placebo groups also showed statistically significant differences (P=0.013). Analysis of PPS showed that the changes in ESSDAI scores from baseline at week 12 after treatment and their 95% CIs were as follows: placebo group (N=10), -0.5 [95% CI: -2.1 to -1.1]; 160mg group (N=12), -3.8 [95% CI: -5.2 to -2.3]; 240mg group (N=8), -2.9 [95% CI: -4.7 to -1.2]. The MMRM comparison showed statistically significant differences between the 160mg group and the placebo group (P=0.003), and between the 240mg group and the placebo group (P=0.045). 6.2.9. Immunological Indicators Immunological markers included: IgG, IgA, IgM, complement (C3, C4), total B lymphocyte count (CD19+), CD4+ T cell count, and CD8+ T cell count. Changes in immunological markers after treatment compared to baseline were compared between groups using analysis of variance (ANOVA). When the P-value of the ANOVA was less than or equal to 0.5%, the difference was considered statistically significant. When the threshold is 0.05, the LSD-t test is used for pairwise comparisons between groups. Actual data from the FAS are used for analysis. Compared with the placebo group, from week 4, the telitacicept treatment group showed a significant decrease in IgG, IgA, and IgM levels, which persisted until week 24. At week 24, the rates of change from baseline in IgG levels 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 differences between the 160 mg and placebo groups were statistically significant (P<0.001), and the differences between the 240 mg and placebo groups were also statistically significant (P<0.001). At week 24, the rates of change from baseline for IgA levels in the placebo, 160mg, and 240mg groups were -1.29±14.749, -47.55±8.790, and -49.18±11.294, respectively. The differences between the 160mg and placebo groups were statistically significant (P<0.001), and the differences between the 240mg and placebo groups were also statistically significant (P<0.001). At week 24, the rates of change from baseline for IgM levels in the placebo, 160mg, and 240mg groups were -7.87±19.062, -55.74±11.010, and -61.61±8.692, respectively. The differences between the 160mg and placebo groups were also statistically significant (P<0.001), and the differences between the 240mg and placebo groups were also statistically significant (P<0.001). The time-dependent analysis of the rate of change of IgG, IgA, and IgM levels from baseline in each group is shown in Figures 1-3. Compared with the placebo group, the telitacicept treatment group showed a significant decreasing trend in CD19+ B cell count. At week 24, the rates of change from baseline in CD19+ B cell count in the placebo group, 160 mg group, and 240 mg group were 6.31±32.826, -29.26±44.698, and -39.36±37.836, respectively. The difference between the 160 mg group and the placebo group was statistically significant (P=0.044), and the difference between the 240 mg group and the placebo group was statistically significant (P=0.021). The diachronic analysis of the rate of change from baseline in CD19+ B cell count in each group is shown in Figures 4-6. 6.3 Security Results Only one subject in the placebo group experienced a serious adverse event, which manifested as hypoproteinemia, herpes zoster, pulmonary tuberculosis, infectious pneumonia, and exacerbation of Sjögren's syndrome, which were relieved after treatment. Two subjects in the 240mg group experienced severe or worse (CTCAE grade 3-5) adverse events, namely acute pyelonephritis and leukopenia. 6.4 Conclusion Compared with the placebo group, telitacicept treatment significantly improved ESSDAI and MF-20 scores in patients with pSS at week 24; telitacicept demonstrated a good safety profile in patients with pSS. The above description represents only preferred embodiments and is provided as an example only, not as a limitation on the combination of features necessary for carrying out the invention. The provided headings are not intended to limit the various embodiments of the invention. Terms such as “comprising,” “including,” and “including” are not intended to be limiting. Furthermore, unless otherwise stated, the plural form is included when not modified by a numeral, and “or” or “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. All disclosures and patents mentioned in this application are incorporated herein by reference without departing from the scope and spirit of the invention. Various modifications and variations of the methods and compositions described herein will be apparent to those skilled in the art. While the invention has been described through specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, various variations of the described modes for carrying out the invention that will be apparent to those skilled in the art are intended to be included within the scope of the appended claims.

Claims

1. Use of a fusion protein in the preparation of a medicament for treating Sjögren's syndrome, wherein the medicament comprises a therapeutically effective amount of the TACI-Fc fusion protein, characterized in that the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO: 4, wherein a single dose of the TACI-Fc fusion protein is 160-240 mg.

2. As described in claim 1, the TACI-Fc fusion protein therein is Telitacicept.

3. The use according to claim 1 or 2, wherein the dry syndrome includes primary dry syndrome or secondary dry syndrome.

4. The use as described in claim 1 or 2, wherein, The single-dose dose of the TACI-Fc fusion protein is 0.1 to 10 mg / kg.

5. The use as described in claim 1 or 2, wherein the single dose of the TACI-Fc fusion protein is 160 mg or 240 mg.

6. The use according to claim 5, wherein the method of administration of the drug is subcutaneous, intramuscular or intravenous, or the site of administration is the thigh, abdomen or upper arm.

7. As described in claim 1, the drug is used 2-4 times at monthly intervals.

8. The use as described in claim 7, wherein the drug is administered once a week.

9. The use as described in claim 7, wherein the treatment lasts for 2-50 weeks.

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