WO2024159715A1 - Method utilizing taci-fc fusion protein to treat igg4-related disease - Google Patents

Abstract

The present invention relates to a drug, a dosage regimen, a dosing interval, and an administration mode which use an effective amount of a drug targeting Blys and/or APRIL to treat an IgG4-related disease. The results demonstrate that the effective amount of the drug targeting Blys and/or APRIL provided in the present invention is clinically effective and safe in the process of treating patients with an IgG4-related disease.

Description

Method for treating IgG4-related diseases using TACI-Fc fusion protein Technical Field

The present invention relates to a TACI-Fc fusion protein drug for treating IgG4-related diseases, a dosage scheme, a dosing interval and an administration method.

Background Art

Immunoglobulin-G4 related disease (IgG4-RD) is an immune-mediated chronic inflammatory disease with fibrosis. The prominent pathological features of the disease are massive infiltration of IgG4 ⁺ plasma cells, occlusive phlebitis and storiform fibrosis (Reference 1: Kamisawa T, Zen Y, Pillai JH Stone (2015) IgG4-related disease. Lancet 385(9976):1460–1471). The disease can affect almost all organs in the body (Reference: 2: Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 2012; 22: 1-14.), and common affected tissues or organs are lymph nodes, submandibular glands, pancreas, kidneys, orbital accessory structures and retroperitoneum (Reference 3: Wallace ZS, Stone JH. An update on IgG4-related disease. Curr Opin Rheumatol. 2015 Jan; 27(1): 83-90). Since the clinical symptoms of the disease depend on the affected organs, its clinical manifestations are complex and varied. The most common clinical manifestations are mass-like lesions caused by persistent immune inflammation and fibrosis, or organ dysfunction caused by compression of surrounding organs. The severity of the disease is greater in patients with severe complications (such as obstruction or compression symptoms due to organ enlargement, or organ dysfunction due to cellular infiltration or fibrosis) (Reference 4: Stone JH, Zen Y, Deshpande V IgG4-related disease. N Engl J Med 2012; 366: 539-51.). It has also been reported that patients with IgG4-related diseases have a higher risk of malignancies (Reference 5: Yamamoto M, Takahashi H, Tabeya T, Suzuki C, Naishiro Y, Ishigami K, Yajima H, Shimizu Y, Obara M, Yamamoto H, Himi T, Imai K, Shinomura Y (2012) Risk of malignancies in IgG4-related disease. Mod Rheumatol 22(3):414–418.).

Due to the complex and diverse clinical symptoms of IgG4-related diseases and the lack of effective diagnostic methods, the exact prevalence of the disease is still unclear. The incidence of IgG4-related diseases reported in Japan is estimated to be 0.28-1.08/100,000 people, and 336-1300 new cases are diagnosed each year. Therefore, IgG4-RD seems to be a relatively rare disease (Reference 6: Masamune A, Kikuta K, Hamada S, Tsuji I, Takeyama Y, Shimosegawa T, Okazaki K; Collaborators. Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2016. J Gastroenterol. 2020 Apr; 55(4):462-470.).

Although an international consensus guideline statement on the management and treatment of IgG4-related diseases was proposed in 2015, there is currently no unified and clear international treatment guideline for this disease. In addition, in terms of clinical treatment, the treatment strategies for IgG4-related diseases in Asian and Western countries are different. Therefore, a clear treatment strategy for IgG4-related diseases remains to be established (Reference 7: Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, Chari ST, Della-Torre E, Frulloni L, Goto H, Hart PA, Kamisawa T, Kawa S, Kawano M, Kim MH, Kodama Y, Kubota K, Lerch MM, M, Masaki Y, Matsui S, Mimori T, Nakamura S, Nakazawa T, Ohara H, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Shimatsu A, Shimosegawa T, Takahashi H, Takahira M, Tanaka A, Topazian M, Umehara H, Webster GJ, Witzig TE, Yamamoto M, Zhang W, Chiba T, Stone JH; Second International Symposium on IgG4-Related Disease (2015) International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol 67(7): 1688–1699.). Systemic glucocorticoids are currently the first-line treatment for IgG4-related diseases. In addition, other reported treatments for the disease include immunosuppressive drugs and biological agents.

Glucocorticoid therapy is effective for the vast majority of patients. It has the advantages of rapid onset and strong anti-inflammatory effects. For most patients who have just been treated, the condition can generally be effectively controlled after taking 30-40 mg/d of prednisone orally for 2-4 weeks. However, long-term use is still required in the later stage. Once discontinued, 50% of patients relapse within a median of 3 months (Reference 8: Kamisawa T, Okazaki K, Kawa S, Shimosegawa T, Tanaka M., Research Committee for Intractable Pancreatic Disease and Japan Pancreas Society. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol. 2010 May; 45(5): 471-7.). Even with long-term treatment, the relapse rate is still very high. According to statistics, the cumulative relapse rate (n=99) after long-term use of glucocorticoids for 1 year is 56%, 76% after 2 years, and 92% after 3 years. (Reference 9: Kamisawa T, Shimosegawa T, Okazaki K, Nishino T, Watanabe H, Kanno A, Okumura F, Nishikawa T, Kobayashi K, Ichiya T, Takatori H, Yamakita K, Kubota K, Hamano H, Okamura K, Hirano K, Ito T, Ko SB, Omata M (2009a) Standard steroid treatment for autoimmune pancreatitis. Gut 58: 1504–1507.) Long-term use of glucocorticoids can easily lead to hormone-related adverse reactions such as increased blood sugar, increased blood pressure, osteoporosis, and cataracts. In addition, due to the high incidence of IgG4-related diseases in the population, Most of the patients are elderly (62% to 83% of the patients are male and over 50 years old), so the adverse reactions will be more prominent. Therefore, when formulating a treatment strategy, it is necessary to minimize the dosage and duration of glucocorticoids while maintaining disease stability. If the patient has obvious adverse hormone reactions, hormones alone cannot fully control the disease, the disease persists and hormones cannot be reduced, or the disease recurs, other treatment options need to be considered.

Traditional immunosuppressants have a slow onset of effect and are usually not recommended alone for the treatment of patients in the acute active phase. However, their combination with hormones can effectively improve the remission rate and reduce relapses, and also help to reduce the dosage of hormones (Reference 10: Hong X, Zhang YY, Li W, et al. Treatment of immunoglobulin G4-related sialadenitis: outcomes of glucocorticoid therapy combined with steroid-sparing agents[J]. Arthritis Res Ther, 2018, 20(1):12.). Studies have shown that mycophenolate mofetil combined with hormone therapy is more effective than hormone monotherapy, especially for patients with IgG4-related pancreatitis or cholangitis (Reference 11: Fei YY, Peng Y, Zhang PP, et al. Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial [J]. Rheumatology, 2019, 58(1): 52-60.). In addition, cyclophosphamide (Reference 12: Fei YY, Chen Y, Zhang PP, et al. Efficacy of cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids[J]. Sci Rep-Uk, 2017, 7(1):6195.), leflunomide (Reference 13: Wang YW, Zhao Z, Gao D, et al. Additive effect of leflunomide and glucocorticoids compared with glucocorticoids monotherapy in preventing relapse) of IgG4-related disease: a randomized clinical trial[J]. Semin Arthritis Rheu, 2020, 50(6): 1513-1520.) and iguratimod (Liu YY, Zhang YX, Bian WJ, et al. Efficacy and safety of iguratimod on patients with relapsed or refractory IgG4-related disease[J]. Clin Rheumatol, 2020, 39(2): 491-497.) have also been shown to have a lower relapse rate and longer remission duration in combined hormone therapy than in single hormone therapy, and can even achieve remission in patients with relapsed or hormone-refractory IgG4-related diseases. Therefore, when hormone monotherapy cannot fully control the disease, the disease activity requires the continuous use of higher doses of hormones, the disease recurs during the reduction of hormones, and (or) the side effects of hormones are obvious, the combined use of hormones and traditional immunosuppressants can be considered. However, since most of the current studies on traditional immunosuppressants for the treatment of IgG4-related diseases are observational, their effectiveness and safety still need to be confirmed by more randomized controlled clinical trials.

With the development of precision medicine, some biological agents have also been used to explore the treatment of IgG4-related diseases that have failed traditional treatments, have hormone resistance or intolerance, relapse during hormone reduction, or are refractory or severe. Currently, the more promising biological targeted therapies include inelizumab Inebilizumab (https://clinicaltrials.gov/：NCT04540497), Obexelimab (https://clinicaltrials.gov/：NCT0272547), Elotuzumab (https://clinicaltrials.gov/：NCT04918147), Zanubrutinib (https://clinicaltrials.gov/：NCT04602598), Rilzabrutinib (https://clinicaltrials.gov/：NCT04520451), Rituximab (https://clinicaltrials.gov/：NCT01584388), Abatacept (Reference 15: Matza MA, Perugino CA, Harvey L, Fernandes AD, Wallace ZS, Liu H, Allard-Chamard H, Pillai S, Stone JH. Abatacept in IgG4-related disease: a prospective, open-label, single-arm, single-centre, proof-of-concept study. Lancet Rheumatol. 2022Feb; 4(2):e105-e112.), Belimumab (Literature 16: Katayama Y, Katsuyama T, Shidahara K, Nawachi S ,Asano Y,Ohashi K,Miyawaki Y,Katsuyama E,Narazaki M,Matsumoto Y,Sada KE,Wada JA case of recurrent IgG4-related disease successfully treated with belimumab after remission of systemic lupus erythematosus.Rheumatology(Oxford).2022Oct 6; 61(10):e308-e310.), dupilumab (Reference 17: Isana Nakajima, Yoshinori Taniguchi, Hideki Tsuji, Tomoka Mizobuchi, Ken Fukuda, Therapeutic potential of the interleukin-4/interleukin-13 inhibitor dupilumab for treating IgG4-related disease, Rheumatology, Volume 61, Issue 6, June 2022, Pages e151–e153.). These studies are currently in the clinical research stage. The fastest progress is innerizumab and obelizumab, and their highest clinical research stage is clinical phase III.

Table 1 Biological agents with potential application prospects in the treatment of IgG4-related diseases

Obexelimab is a drug that targets B cells expressing CD19. CD19 is expressed on B cells and plasmablasts throughout their life cycle. Therefore, the range of cells targeted by CD19 monoclonal antibodies is wider than that of CD20 monoclonal antibodies. In addition to B cells, it can directly target plasma cells and plasmablasts that are closely related to the onset of IgG4-related diseases. Obexelimab is a new type of bispecific antibody that can simultaneously target CD19 and FcγRIIb, which inhibits B cell activity. When it binds to CD19 on the surface of B cells, its Fc segment automatically binds to the inhibitory receptor FcγRIIb on the same B cell, thereby inhibiting B cell receptor (BCR)-mediated B cell activation and proliferation. A phase II single-arm open-label study (https://clinicaltrials.gov/: NCT0272547) enrolled 20 patients with active IgG4-related diseases. Disease improvement was defined as a decrease of ≥2 points in the response index (RI) compared with baseline after 169 days of treatment. 80% of patients achieved disease improvement. However, 2 adverse reactions were reported, including 1 case of pneumonia and 1 case of chronic lymphocytic leukemia combined with chronic inflammatory demyelinating polyneuropathy.

[09] Inebilizumab is a humanized anti-CD19 IgG1κ monoclonal antibody that eliminates CD19-expressing B cells through ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) (Reference 18: Agius MA, Klodowska-Duda G, Maciejowski M, Potemkowski A, Li J, Patra K, Wesley J, Madani S, Barron G, Katz E, Flor A. Safety and tolerability A phase III multicenter, randomized, double-blind, placebo-controlled study (https://clinicaltrials.gov/: NCT04540497) is currently recruiting patients to explore the efficacy and safety of inebilizumab in patients with IgG4-related disease.

Rituximab (RTX) is the earliest and most widely used biological agent in patients with IgG4-related diseases. A prospective study in 2015 confirmed the effectiveness of rituximab monotherapy in the treatment of IgG4-related diseases (Reference 19: Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial [J]. Ann Rheum Dis, 2015, 74(6): 1171-1177.). Rituximab is an anti-CD20 monoclonal antibody that can effectively eliminate B cells. It is reported that patients can achieve rapid relief of their condition after taking rituximab, and their blood Serum IgG4 levels, peripheral plasma cells, and IgG4 ⁺ plasma cell levels were significantly decreased (Reference 20: Della-Torre E, Feeney E, Deshpande V, et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease[J]. Ann Rheum Dis, 2015, 74(12): 2236-2243.). Studies have shown that during the hormone reduction and maintenance stages, patients can achieve higher remission rates and lower relapse rates with combined hormone and traditional immunosuppressant therapy compared with hormone monotherapy, while rituximab maintenance therapy has a lower relapse rate than combined hormone and traditional immunosuppressant therapy (Reference 21: Omar D, Chen Y, Cong Y, et al. Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta-analysis [J]. Rheumatology, 2020, 59(4): 718-726.). Therefore, when patients find that hormone monotherapy cannot fully control the disease, disease activity requires continuous use of higher doses of hormones, the disease recurs during hormone reduction, hormone side effects are obvious, or the combined use of traditional immunosuppressants is still not ideal, rituximab can be considered for treatment. However, studies have found that rituximab has serious infusion reactions. Various studies have reported that the incidence of rituximab-related infusion-related reactions is 26% to 85%. In patients with hematological tumors, rituximab has also been reported to cause rare adverse events such as hepatitis B virus reactivation and severe skin reactions (such as toxic epidermal necrolysis and Stevens-Johnson syndrome) (Reference 22: Alsharhan L, Beck LH Jr. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021 Mar; 77(3): 440-453.). In addition, rituximab also has serious side effects, including fulminant myocarditis (Reference 23: Sellier-Leclerc A L, Belli E, Guerin V, et al. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome[J]. Pediatr Nephrol, 2013, 28(9): 1875-1879.), fatal pulmonary fibrosis (Reference 24: Chaumais MC, Garnier A, Chalard F, et al. Fatal pulmonary fibrosis after rituximab administration[J]. Pediatr Nephrol, 2009, 24(9): 1753-1755.), etc. Currently, related research is still in the clinical phase I/II stage, but its effectiveness and safety still need to be further confirmed by clinical trials.

Therefore, whether in China or around the world, there is still a real unmet clinical need for the treatment of IgG4-related diseases, especially for patients who are unable or unwilling to use long-term glucocorticoid treatment due to various diseases. There is a lack of safe and effective clinical treatment drugs.

Summary of the invention

The present invention surprisingly found that TACI-Fc fusion protein produced significant therapeutic effects when treating patients with IgG4-related diseases.

Specifically, the present invention provides a method for treating an IgG4-related disease, comprising administering a therapeutically effective amount of a drug targeting Blys and/or APRIL to a patient having the IgG4-related disease.

Furthermore, the drug targeting Blys and/or APRIL is a TACI-Fc fusion protein.

Specifically, the present invention also provides a method for treating a patient with an IgG4-related disease who has received a treatment regimen for an IgG4-related disease, the method comprising (1) determining whether the patient has received a treatment regimen for an IgG4-related disease, and (2) if the patient has previously received treatment for an IgG4-related disease, administering an effective amount of a drug targeting Blys and/or APRIL, further a TACI-Fc fusion protein, to the patient having the IgG4-related disease.

Specifically, the present invention also provides a method for treating a patient with an IgG4-related disease who has received a treatment regimen for an IgG4-related disease, the method comprising (1) determining whether the patient has received a treatment regimen for an IgG4-related disease, and (2) if the patient has not previously received treatment for an IgG4-related disease, administering an effective amount of a drug targeting Blys and/or APRIL, further a TACI-Fc fusion protein, to the patient with the IgG4-related disease.

Specifically, the present invention also provides a use of a drug targeting Blys and/or APRIL in the preparation of a drug for treating patients with IgG4-related diseases.

Furthermore, the present invention also provides a use of a TACI-Fc fusion protein in preparing a drug for treating patients with IgG4-related diseases.

Furthermore, the TACI-Fc fusion protein described in any of the above items comprises: (i) the TACI extracellular region or a fragment thereof that binds to Blys and/or APRIL; and (ii) a human immunoglobulin constant region fragment.

Preferably, the TACI extracellular region or a fragment thereof comprises the amino acid sequence shown in SEQ ID NO:1.

Preferably, the human immunoglobulin is IgG1.

Furthermore, the human immunoglobulin constant region fragment comprises the amino acid sequence of 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 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

Furthermore, the human immunoglobulin constant region fragment comprises modifications of amino acids at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:2.

Furthermore, the modification is amino acid substitution, deletion or insertion.

Furthermore, the substitution is selected from the following group: P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

Preferably, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:3.

Preferably, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:4.

Preferably, the TACI-Fc fusion protein is Telitacicept.

Furthermore, the single dosage of the TACI-Fc fusion protein is about 0.1 to 10 mg/kg, further including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 ,5.0,5.1,5.2,5.3,5.4,5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2,6.3,6.4,6.6,6.6,6.7,6.8,6.9,7.0,7.1,7.2,7.3,7.4,7.7,7.6,7.7,7.8,7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.8, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.9, 9.6, 9.7, 9.8, 9.9, 10mg/kg.

Furthermore, the single dose of the TACI-Fc fusion protein is 80-240 mg, and more preferably 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg.

Furthermore, the TACI-Fc fusion protein is used 2-4 times at intervals of one month, that is, the administration frequency of the TACI-Fc fusion protein is 2 times per month, 3 times per month, or 4 times per month.

Furthermore, the TACI-Fc fusion protein is administered once a week.

Further preferably, the treatment lasts for about 2-50 weeks. Further preferably, the treatment lasts for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks.

More preferably, glucocorticoid drugs can be used in combination at the initial stage of treatment. The initial stage of treatment is day 1, day 1-2, day 1-3, day 1-4, day 1-5, day 1-6 or day 1-7.

Further preferably, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously, and the administration site is preferably the thigh, abdomen or upper arm. In some specific embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously.

Further preferably, the injection sites of the TACI-Fc fusion protein are the same or different each time. In some specific embodiments, the injection sites of the TACI-Fc fusion protein are the same each time; in other specific embodiments, the injection sites of the TACI-Fc fusion protein are different each time.

Furthermore, the patient is an adult patient or a pediatric patient.

Furthermore, the patient has previously received a treatment regimen for IgG4-related diseases.

Furthermore, the treatment regimen for IgG4-related diseases includes: glucocorticoid treatment for IgG4-related diseases, hormone combined with immunosuppressant treatment, and biologic drug treatment.

Furthermore, the patient has not previously received treatment for IgG4-related diseases.

Furthermore, the IgG4-related diseases include but are not limited to: IgG4-related sialadenitis, IgG4-related parotitis, IgG4-related dacryoadenitis, IgG4-related eye disease, IgG4-related thyroiditis, IgG4-related sinusitis, IgG4-related hypertrophic pachymeningitis, IgG4-related meningitis, IgG4-related neurological disease, IgG4-related hypophysitis, IgG4-related pneumonia, IgG4-related airway lesions, IgG4-related mediastinitis, IgG4-related pleurisy, IgG4-related pericardial lesions, type 1 autoimmune pancreatitis (autoimmune pancreatitis, AIP), IgG4-related sclerosing cholangitis (IgG4-related sclerosis osing cholangitis, IgG4-SC), IgG4-related autoimmune hepatitis (IgG4-related AIH), IgG4-related inflammatory pseudotumor (IPT), IgG4-related sclerosing mesenteritis, IgG4-related tubulointerstitial nephritis (IgG4-TIN), IgG4-related membranous nephropathy (IgG4-MN), IgG4-related retroperitoneal fibrosis (IgG4-RPF), IgG4-related prostatitis (IgG4-RP), IgG4-related testis, IgG4-related epididymitis, IgG4-related dermatitis, IgG4-related thoracic aortitis, and IgG4-related abdominal aortitis.

The TACI-Fc fusion protein provided by the present invention shows unexpected clinical efficacy and good safety in the process of treating patients with IgG4-related diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

The left area of Figure 1 shows the patients' treatment with oral prednisone, and the right area shows the patients' treatment with injectable tadalafil.

Figure 2 shows the maximum lesion area of the left submandibular gland and lymph nodes in the coronal plane and the maximum lesion area of the kidney in the cross-section before and after 60 weeks of treatment with tetasip.

DETAILED DESCRIPTION

Unless otherwise defined, all terms used herein have the same meanings as understood by those of ordinary skill in the art. Regarding definitions and terms in the art, professionals can specifically refer to Current Protocols in Molecular Biology (Ausubel).

The three-letter and one-letter codes for amino acids used in the present invention are as described in J. biol. chem, 243, p3558 (1968).

The term "TACI" in the present invention refers to transmembrane activator and CAML interactor, which is a member of the tumor necrosis factor receptor superfamily. The term "BLys" in the present invention refers to B lymphocyte stimulator, which is a member of the TNF ligand superfamily that exists in two forms: membrane-bound and soluble. 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) in the present invention is a tumor necrosis factor (TNF) analog, which can stimulate the proliferation of primitive B cells and T cells in the body, promote B cell accumulation and increase spleen content. APRIL can specifically bind to TACI and BCMA, and after binding, it can prevent APRIL from binding to B cells and inhibit the proliferation response of primitive B cells stimulated by APRIL. Moreover, APRIL can competitively bind to receptors (BCMA, TACI) with BLys.

The term "TACI-Fc fusion protein" involved in the present invention refers to a transmembrane activator, calcium regulator and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein). The TACI-immunoglobulin fusion protein provided by the present invention includes: (i) a TACI extracellular region or a fragment thereof that binds to Blys and/or APRIL; and (ii) a human immunoglobulin constant region fragment.

The term "TACI extracellular region or a fragment thereof that binds to Blys and/or APRIL" can be specifically referred to the extracellular domain of TACI 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), as well as specific fragments of the extracellular domain of TACI that can interact with the TACI ligand, or the amino acid fragment of position 13-118 of the TACI extracellular domain disclosed in Chinese Patent Publication No. CN101323643A.

In the term "human immunoglobulin constant region fragment", the immunoglobulin part is preferably IgG1, which may contain a heavy chain constant region, such as a human heavy chain constant region. The preferred "human immunoglobulin constant region fragment" of the present invention is an amino acid fragment containing part of the hinge region domain, the CH2 domain and the CH3 domain. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" of the present invention is as shown 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 94%, 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 "treatment" used in the present invention is related to a given disease or condition, including but not limited to The invention relates to: inhibiting 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 regress; or alleviating the symptoms caused by the disease or condition, such as alleviating, preventing or treating the symptoms of the disease or condition.

The term "amino acid" involved in the present invention is understood in the broadest sense, and is a general term for a class of organic compounds containing amino and carboxyl groups. Preferably, the amino acids involved in the present invention are the main units that constitute proteins in living organisms, including but not limited to: glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.

The three-letter code and the single-letter code of amino acids used in the present invention are as described in J. biol. chem, 243, p3558 (1968). There are many ways to number amino acid sites, such as the Kabat numbering system, the EU numbering system, the sequential numbering system, etc. In the present invention, the numbering method of amino acid sites is carried out in the form of "sequential numbering". For example, "position 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2" as described in the present invention refers to the 3rd amino acid, the 8th amino acid of SEQ ID NO: 2, and so on; for example, "P3T" as described in the present invention refers to the mutation of the 3rd amino acid sequence of SEQ ID NO: 2 from the previous "P" to "T", and for example, "L8P" refers to the mutation of the 8th amino acid sequence of SEQ ID NO: 2 from the previous "L" to "P", and so on.

As an alternative embodiment, the constant region of the immunoglobulin provided by the present invention may introduce one or more amino acid changes, such as substitution (ie, mutation), addition (ie, insertion) or deletion (ie, deletion).

The term "Telitacicept" (or "Telitacicept", which can be used interchangeably in the present invention) in the present invention is a TACI-Fc fusion protein, whose INN name is Telitacicept, and whose amino acid sequence is shown in SEQ ID NO: 4, or as shown in 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 by any of a variety of routes, including but not limited to: oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intracardiac, transdermal, percutaneous, topical, subcutaneous, intranasal, enteral, sublingual, vaginal or rectal routes.

The term "IgG4-related disease" in the present invention refers to Immunoglobulin-G4-related disease, or IgG4-RD, which is an immune-mediated chronic inflammatory disease with fibrosis. IgG4 ⁺ plasma cell infiltration, occlusive phlebitis and storiform fibrosis are the significant pathological features of the disease. The disease can affect almost all organs in the body, such as the pancreas, bile duct, lacrimal gland, parotid gland, periorbital, central nervous system, thyroid, lung, kidney, retroperitoneal and periarterial tissues, skin and lymph nodes, etc. It is understood that in the present invention, the organs affected by IgG4-related diseases should not be regarded as limitations of the present invention. Due to the different affected organs, the clinical symptoms of patients with IgG4-related diseases are usually different. The affected sites and related clinical symptoms of IgG4-related diseases involved in the present invention include but are not limited to the following:

Head and Neck

(1) IgG4-related sialadenitis/mumps/dacryoadenitis: The salivary glands (submandibular glands, parotid glands) and lacrimal glands are usually the most prominent organs affected in the manifestations of IgG4-RD, accompanied by mild symptoms of Sjögren's syndrome (such as dry eyes and dry mouth). Ultrasound examination of IgG4-related sialadenitis may show nodular hypoechoic areas with high blood flow signals and/or superficial reticular hypoechoic areas. IgG4-related dacryoadenitis often manifests as chronic sclerosing dacryoadenitis, with swelling of the lacrimal glands and eyelids and exophthalmos.

(2) IgG4-related ophthalmopathy (IgG4-ROD): It can affect any orbital tissue, including the lacrimal gland, extraocular muscles, optic nerve, lacrimal sac, lacrimal duct, trigeminal nerve, eyelids, etc. The main manifestations are eyelid swelling or palpable soft masses, proptosis, restrictive eye movement disorders, diplopia, and orbital pain. The typical imaging manifestations of the lesions are diffuse symmetrical enlargement of bilateral lacrimal glands, soft tissue masses with clear orbital boundaries and uniform density, and thickening of bilateral infraorbital nerves or extraocular muscles. It can occur as IgG4-related ocular inflammatory pseudotumor, which is characterized by mass formation, infiltration of lymphocytes and plasma cells, and varying degrees of fibrosis.

(3) IgG4-related thyroiditis: The main histological features are interfollicular fibrosis, smaller thyroid follicles, obvious follicular degeneration, giant cell/histiocyte infiltration, and Riedle's thyroiditis (also known as fibrosing thyroiditis). This rare autoimmune thyroid disease is characterized by a significant enlargement and firm texture of the thyroid gland. Its pathological features mainly manifest as: inflammatory fibrotic process involving all or part of the thyroid gland, destruction of the thyroid follicle structure, fibrosis extending beyond the thyroid capsule to adjacent anatomical structures, and inflammatory cell infiltration.

(4) IgG4-related sinusitis: It is often manifested as nasal congestion, polyps, and sinusitis. A large number of lymphocytes and plasma cells can be seen infiltrating the nasal mucosal tissue. Different degrees of fibrosis can be seen in the interstitium, presenting as storiform or collagenous fibrosis. In the early stage, local sclerosis is common around the intrinsic glands or ducts, presenting a "collagen fiber sheath"-like change.

(5) IgG4-related skin lesions: including cutaneous pseudolymphoma subtype. These lesions are usually seen on the scalp, face, neck, and auricle. Papules, plaques, and nodules are common skin manifestations and are extremely Spots and bullae are rare. Microscopically, nodular lymphocyte infiltration can be seen in the dermis and subcutaneous tissue, accompanied by lymphoid follicle formation and interstitial fibrosis. The infiltrating inflammatory cells are rich in IgG4-positive plasma cells and small lymphocytes, and sometimes plasmablasts and eosinophils.

Nervous system

(1) IgG4-related hypertrophic pachymeningitis/meningitis: IgG4-related pachymeningitis can cause headaches, hydrocephalus caused by cerebrospinal fluid obstruction, or cranial nerve palsies.

(2) IgG4-related neurological diseases: including mononeuritis multiplex, polyneuropathy, and perineural masses. The most common clinical manifestations of IgG4-related neurological diseases are endocrine symptoms, headaches, cognitive impairment, and focal neurological deficits.

(3) IgG4-related hypophysitis: manifested by glandular enlargement. Due to hormone deficiency in the anterior pituitary, posterior pituitary, or both, IgG4-related hypophysitis sometimes leads to hypopituitarism. The clinical manifestations of the nervous system are diverse, related to the affected area and the severity of the lesion, and often have no specific symptoms or signs.

Chest

(1) IgG4-related pneumonia: manifested as interstitial lung disease, pulmonary infiltration similar to bacterial pneumonia, and often causing nodules or masses related to malignant tumors. Patients with interstitial lung disease often have symptoms of shortness of breath and dyspnea.

(2) IgG4-related airway lesions: manifested as asthma-like syndrome, bronchial wall thickening, stenosis or tumors. Among them, patients with airway lesions often have cough and wheezing symptoms.

(3) IgG4-related mediastinitis: Mediastinal lesions manifest as lymphadenopathy or sclerosing mediastinitis. Patients with mediastinitis often present with chest pain, chest tightness, or hoarseness.

(4) IgG4-related pleurisy: manifested by thickening or effusion in the serous cavity, and may be accompanied by chest pain.

(5) IgG4-related pericardial disease: It can cause pericardial effusion, pericardial thickening and constrictive pericarditis, and can also lead to large coronary artery aneurysms or acute coronary syndrome.

(6) IgG4-related thoracic aortitis: IgG4-RD has been found to be one of the causes of non-infectious aortitis. A case series study involving 125 patients in a Japanese hospital reported that 2 patients (1.6%) were found to have IgG4-related aortitis among 120 patients who underwent thoracic aortic resection.

Abdomen and pelvis

(1) Type 1 autoimmune pancreatitis (AIP): Yes The most common manifestation of IgG4-RD is sausage-like swelling of the pancreas or space-occupying lesions, which often occur in the head of the pancreas, which can lead to bile duct compression and clinical manifestations related to obstructive jaundice, and can be easily misdiagnosed as pancreatic head cancer. The imaging features of the pancreas are pancreatic swelling and irregular stenosis of the main pancreatic duct. Histological manifestations include lymphoplasmacytic infiltration, fibrosis, and occlusive phlebitis. In long-term diseases, features of chronic pancreatitis may appear, including pancreatic atrophy and painless intraductal calcification, often accompanied by insufficiency, manifested as diabetes, steatorrhea, painless jaundice, or pancreatic masses similar to pancreatic cancer. The study by Hamano et al. believes that when AIP is differentiated from pancreatic cancer, the cutoff point of serum IgG4>135mg/dl can reach 97% accuracy, 95% sensitivity, and 97% specificity. In some cases, IgG4-related autoimmune pancreatitis is associated with severe abdominal pain, but it is usually far less obvious than the symptoms of alcohol-induced pancreatitis or biliary pancreatitis.

(2) IgG4-related sclerosing cholangitis (IgG4-SC): The typical clinical manifestation of IgG4-SC is cholestasis. In the early stage of the disease, there are often non-specific symptoms such as abdominal discomfort, steatorrhea, weight loss, and new-onset diabetes. In the late stage, it may develop into inflammatory pseudotumor of the liver and biliary cirrhosis. Its imaging signs show symmetrical circumferential stenosis and/or intraluminal soft tissue masses in the affected bile duct wall. The thickened bile duct wall and intraluminal soft tissue masses can be enhanced on enhanced scanning. The bile duct wall thickening can be seen in both the stenotic and non-stenotic areas of the bile duct. The clinical characteristics are very similar to those of primary sclerosing cholangitis (PSC), but IgG4-SC is more likely to respond to immunosuppressive therapy than PSC. The study by Du et al. suggests that serum IgG4>157.5mg/dl in patients with IgG4-SC can be used as the differential value between IgG4-SC and cholangiocarcinoma.

(3) IgG4-related autoimmune hepatitis (IgG4-related AIH): IgG4-AIH has the basic characteristics of AIH and is more common in middle-aged and elderly women. Symptoms vary in severity, and mild cases may be asymptomatic. They are generally manifested as fatigue, lack of appetite, abdominal distension, nausea, vomiting, diarrhea, dark urine, fever, yellow skin with itching, weight loss, hepatosplenomegaly, etc. In the late stage, portal hypertension and liver failure may occur. The pathological characteristics are: elevated serum IgG4 levels, and immunohistochemical staining can reveal IgG4-positive plasma cell infiltration. This type responds well to hormone treatment and has a low recurrence rate.

(4) IgG4-related inflammatory pseudotumor (IPT): It is characterized by clear boundaries and is mainly located in the right lobe of the liver. Imaging manifestations include halo sign and ring sign, and persistent and delayed enhancement, which are characteristic and can be used to distinguish it from other tumor lesions.

(5) IgG4-related sclerosing mesenteritis: manifested by abdominal pain and abdominal mass.

(6) IgG4-related tubulointerstitial nephritis (IgG4-TIN): IgG4-TIN is the most common type of IgG4-related kidney disease (IgG4-RKD). It is more common in middle-aged and elderly male patients. The clinical manifestations are mild, often accompanied by mild to moderate proteinuria, and some may have microscopic hematuria. The degree of renal function damage varies, and most of them are chronically progressive. Some IgG4-TIN patients have normal renal function. Some IgG4-TIN patients already have renal insufficiency when they seek medical treatment, and their condition even rapidly progresses to the stage of renal failure.

(7) IgG4-related membranous nephropathy (IgG4-MN): IgG4-MN is the most common glomerular lesion in IgG4-RKD. The incidence is higher in the elderly male population. Most patients present with nephrotic syndrome and edema. The occurrence and severity of edema are positively correlated with hypoproteinemia. Some patients may have renal damage, suggesting that they may be accompanied by IgG4-TIN, and the diagnosis is often accompanied by clinical manifestations of IgG4-RD.

(8) IgG4-related retroperitoneal fibrosis (IgG4-RPF): The etiology of this disease is unknown. According to IgG4 immunohistochemistry, RPF can be divided into IgG4-related and non-IgG4-related. Patients mainly suffer from back and bilateral rib pain. Retroperitoneal soft tissue fibrosis surrounds the ureter and its surrounding soft tissue, causing ureteral obstruction and ultimately leading to renal damage. Studies have reported that compared with patients with idiopathic retroperitoneal fibrosis, patients with IgG4-RPF have a higher incidence of pain.

(9) IgG4-related prostatitis (IgG4-RP): The prostate is rarely affected, but patients with IgG4-RP may have elevated PSA levels similar to prostate cancer.

(10) IgG4-related orchitis/epididymitis: manifested by scrotal masses and scrotal pain.

(11) IgG4-related abdominal aortitis: A medical center in Japan confirmed 10 patients with inflammatory abdominal aortic aneurysm over a 15-year period, of which 4 had manifestations consistent with IgG4-RD, including IgG4+ plasma cell infiltration and elevated serum IgG4 levels. Inflammatory abdominal aortitis may be related to retroperitoneal fibrosis.

The term "glucocorticoid therapy for IgG4-related diseases" in the present invention is a recognized first-line treatment for IgG4-RD, and its dosage and administration cycle often vary due to different clinical practices. Non-restrictive: The treatment recommendations proposed by Japan are often used clinically: the initial dose is 0.6 mg·kg ^-1 ·d ^-1 , and the dose is reduced for 2 to 4 weeks, and the dose is reduced by 5 to 10 mg/d every 1 to 2 weeks, and the dose is reduced to 2.5 to 5.0 mg/d for no more than 3 years.

The term "immunosuppressant" in the present invention is also referred to as conventional synthetic disease-modifying anti-rheumatic drugs (cDMARDs). In the present invention, exemplary immunosuppressants include mycophenolate mofetil, azathioprine, methotrexate, leflunomide, cyclophosphamide, cyclosporine, tacrolimus, iramod, thalidomide and the like, which are drugs that have an inhibitory effect on the body's immune response, and can inhibit the proliferation and function of cells related to the immune response (macrophages such as T cells and B cells), and can reduce antibody immune response.

The term "biological drug treatment regimen" in the present invention is often used to treat patients who have failed traditional treatment, have hormone resistance or intolerance, relapse during hormone reduction, or are refractory or severely ill. Exemplary biological targeted therapies with application prospects currently include:

(1) B cell depletion therapy: non-restrictive anti-CD 20 monoclonal antibody, anti-CD 19 monoclonal antibody, B lymphocyte activating factor (BAFF) inhibitor, Janus tyrosine kinase (BTK) inhibitor, bortezomib, etc.

(2) Targeting T lymphocytes: non-restrictive ones include abatacept, signaling lymphocyte activation molecule family member 7 (SLAMF 7) monoclonal antibody, inducible co-stimulatory molecule ligand (ICOSL) inhibitor, etc.

(3) Targeted cytokines (IL-4, IL-5\TNF-α) and intracellular signaling pathways JAK inhibitors, etc.

In some preferred embodiments, the biologics are exemplified by Inebilizumab, Obexelimab, Elotuzumab, Zanubrutinib, Rilzabrutinib, Rituximab, Abatacept, Belimumab, and dupilumab.

The embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

Example 1 Prospective single-arm clinical trial of Tetasip

Inclusion and Exclusion Criteria

Inclusion criteria

1. Patients included in the study must meet the classification criteria for IgG4-related diseases (2019 ACR/EULAR);

2. Patients have not used the following drugs within six months before enrollment:

A) Tetasip or other biological agents with the same or similar targets;

B) Tumor necrosis factor inhibitor (TNFi) or tumor necrosis factor receptor antibody fusion protein;

C) Rituximab (or other B cell depleting agents);

3. Patients should be over 18 years old at the time of enrollment;

4. Patients must agree to take reliable contraceptive measures before registration;

5. The subjects or their guardians agree to participate in the study and sign the informed consent form.

Exclusion criteria

1. Currently pregnant or breastfeeding, or planning to become pregnant within six months;

2. Major health problems or diseases, including (but not limited to) the following: poorly controlled hypertension (>=160/95 mmHg), congestive heart failure (class III or IV according to the New York Heart Association), poorly controlled diabetes or poor function to the point of being unable to take care of oneself, and other autoimmune diseases;

3. The total white blood cell count before screening is <3000/μL, or the total platelet count is 100,000/μL

μL; total neutrophil count <1500/μL, or hemoglobin content <8.5g/dL (85g/L);

4. Active systemic infection within 2 weeks before screening (except common upper respiratory tract infection);

5. Currently have infection, chronic or recurrent infectious disease, or latent tuberculosis infection (PPD or T-SPOT test);

6. Known infection with HIV, hepatitis B or hepatitis C at the time of screening;

7. History of lymphoproliferative disease or any known malignant tumor or any organ system malignant tumor in the past 5 years;

8. Allergic to tadalafil;

9. Participate in other clinical trials;

10. Any medical or mental illness that the investigator believes will prevent the participant from following the protocol or completing the study according to the protocol;

11. The patient refuses to complete the study according to the requirements of this study;

12. Any other circumstances that the researcher deems unsuitable for participation in this study.

Case 1

The patient was a 54-year-old male who was diagnosed with IgG4-related disease in 2017. He had previously received oral prednisone (a glucocorticoid drug) 30 mg for 2 months, after which the oral dose was regularly reduced by 5 mg every 2 or 3 months, and the treatment was maintained for 20 months before being discontinued. 17 months after discontinuation of prednisone, the bilateral submandibular glands, parotid glands, and 12 lymph nodes enlarged again (accompanied by kidney damage). At admission, his ACR/EULAR (the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria) classification criteria score was 41, and his IgG4-related disease responder index (RI) was 12. After admission, he was treated with methylprednisolone (a glucocorticoid drug) for 7 days (0.6 mg/kg). However, since the patient was no longer willing to accept long-term use of systemic corticosteroids, he was treated with tetasip for 60 weeks at a dose of 160 mg per week by subcutaneous injection.

After the start of treatment, the patient's symptoms gradually improved. During the treatment, IgG4, IgE, IgG and IgM levels decreased, serum complement C3, C4, creatinine and eGFR returned to normal, and after the 60th week of treatment, the patient's IgG4-related disease responder index decreased from 12 to 1 (see Figure 1). MRI examination showed that during the 60 weeks of treatment with tetasip, the size of the salivary glands and renal cortical lesions (almost reduced) gradually and continuously decreased, and after the 60th week of treatment, the salivary glands returned to normal size (see Figure 2).

Other cases

Nine patients with IgG4-related diseases were recruited (see Table 2 for treatment information) and treated with the same treatment strategy as case 1 (160 mg subcutaneous injection per week). No serious adverse events were observed except for mild and controllable injection site reactions (redness or mass formation). Treatment trend analysis showed that the IgG4-related disease responder index, serum IgM, IgE, and CD19 ⁺ CD24 ^- CD38 ^hi plasma blast levels were significantly reduced during the 24 weeks of follow-up.

Table 2 Patient information and treatment response to Tetasip

Note: There was no statistical difference between the "non-responder" group and the "responder" group in terms of affected organs and baseline RI indicators. Glucocorticoid treatment (0.6 mg/kg methylprednisolone per day) was given concurrently on days 1-7 of treatment and was discontinued after 7 days. Case 2 continued to receive glucocorticoid treatment in week 5 due to disease progression and withdrew from the trial. The endpoint IgG4-RDRI was recorded at the time of withdrawal.

During the 24-week follow-up period, among the above 10 patients, 6 patients (Case 1, Case 3, Case 5, Case 7, Case 8, Case 9) had a positive response to the treatment with tecept, and 4 patients (Case 2, Case 4, Case 6, Case 10) had an IgG4-RI improvement of less than 2 after the treatment with tecept (i.e., no response to the treatment with tecept), and the partial remission rate after the treatment with tecept was 60%.

Treatment options for patients with IgG4-related disease are limited, especially for those who are unable or unwilling to use long-term glucocorticoid therapy due to various diseases. This study is the first to investigate the therapeutic potential of a BLyS/APRIL-targeted biologic (tetrasip) in IgG4-related disease. Prospective studies have shown that the partial remission rate after 24 weeks of treatment with tetrasip was 60%, and it can be widely observed during continued treatment. Tetrasip has the potential to alleviate and improve lesion size, symptoms, and laboratory parameters in patients with IgG4-related disease, especially in patients with high ESR, IgG4, IgG, and plasmablast levels. The results of the study indicate that tetrasip has shown a very positive therapeutic effect in the treatment of IgG4-related disease, especially in the treatment of patients with IgG4-related disease who are not suitable for glucocorticoid therapy.

The above description is only a preferred embodiment, which is only used as an example and does not limit the combination of features necessary to implement the present invention. The titles provided are not intended to limit the various embodiments of the present invention. Terms such as "comprising", "including" and "including" are not intended to be limiting. In addition, unless otherwise specified, plural forms are included when there is no numeral modification, and "or" and "or" mean "and/or". Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as those 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 present invention, multiple modifications and variants of the described method and composition of the present invention are apparent to those skilled in the art. Although the present invention has been described by specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, those multiple variants of the described mode for implementing the present invention that are apparent to those skilled in the relevant art are intended to be included in the scope of the appended claims.

Claims (21)

1. A method for treating an IgG4-related disease, comprising administering a therapeutically effective amount of a drug targeting Blys and/or APRIL to a patient having the IgG4-related disease.
2. The method according to claim 1, wherein the drug targeting Blys and/or APRIL is a TACI-Fc fusion protein, wherein the TACI-Fc fusion protein comprises:

   (i) the extracellular domain of TACI or a fragment thereof that binds to Blys and/or APRIL; and

   (ii) Human immunoglobulin constant region fragments.
3. The method according to claim 2 is characterized in that the extracellular region of TACI or its fragment binding to Blys and/or APRIL contains the amino acid sequence shown in SEQ ID NO:1.
4. The method according to claim 3 is characterized in that 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 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.
5. The method according to claim 4 is characterized in that the human immunoglobulin constant region fragment contains modifications of amino acids at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:2.
6. The method according to claim 5, characterized in that the modification is amino acid substitution, deletion or insertion.
7. The method according to claim 6, characterized in that the substitution is selected from the following group: P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.
8. The method according to claim 7 is characterized in that the human immunoglobulin constant region fragment contains the amino acid sequence of SEQ ID NO: 3.
9. The method according to claim 1 is characterized in that the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:4.
10. The method according to claim 9, characterized in that the TACI-Fc fusion protein is Telitacicept.
11. The method according to claim 10, characterized in that the patient is an adult patient or a pediatric patient.
12. The method according to claim 11, characterized in that the patient has previously received a treatment regimen for IgG4-related diseases.
13. The method according to claim 11, characterized in that the patient has not previously received a treatment regimen for IgG4-related diseases.
14. The method according to any one of claims 11 to 13, characterized in that the single administration dose of the TACI-Fc fusion protein is about 0.1 to 10 mg/kg.
15. The method according to any one of claims 11 to 13, characterized in that the single administration dose of the TACI-Fc fusion protein is 80-240 mg, more preferably 80 mg, 160 mg or 240 mg.
16. The method according to claim 15 is characterized in that it can be further used in conjunction with a glucocorticoid drug in the initial stage of treatment.
17. The method according to claim 16, characterized in that the initial treatment period is day 1, days 1-2, days 1-3, days 1-4, days 1-5, days 1-6 or days 1-7.
18. The method according to any one of claims 11-13 or 17, characterized in that the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously, or the administration site is the thigh, abdomen or upper arm.
19. The method according to any one of claims 11-13 or 17, characterized in that the TACI-Fc fusion protein is used 2-4 times at intervals of one month and/or the treatment lasts for about 2-50 weeks.
20. The method according to claim 19, characterized in that the TACI-Fc fusion protein is administered once a week.
21. The method according to any one of claims 1 to 20, characterized in that the IgG4-related diseases include but are not limited to: IgG4-related sialadenitis, IgG4-related parotitis, IgG4-related dacryoadenitis, IgG4-related eye disease, IgG4-related thyroiditis, IgG4-related sinusitis, IgG4-related hypertrophic pachymeningitis, IgG4-related meningitis, IgG4-related neurological disease, IgG4-related hypophysitis, IgG4-related pneumonia, IgG4-related airway lesions, IgG4-related mediastinitis, IgG4-related pleurisy, IgG4-related pericardial lesions, type 1 autoimmune pancreatitis (autoimmune pancreatitis, AIP), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related autoimmune hepatitis (IgG4-related AIH), IgG4-related hepatitis pseudotumor (inflammatory hepatitis), IgG4-related hepatitis pseudotumor (inflammatory hepatitis pseudotumor), IgG4-related hepatitis pseudotumor (inflammatory hepatitis pseudotumor), IgG4-related hepatitis pseudotumor (inflammatory hepatitis pseudotumor), IgG4-related hepatitis pseudotumor (inflammatory hepatitis pseudotumor), IgG4-related hepatitis pseudotumor (inflammatory hepatitis pseudotumor), IgG4-related hepatitis pseudotumor (inflammatory hepatitis pseudotumor), IgG4-related hepatitis pseudotumor, ... pseudotumor, IPT), IgG4-related sclerosing mesenteritis, IgG4-related tubulointerstitial nephritis (IgG4-TIN), IgG4-related membranous nephropathy (IgG4-MN), IgG4-related retroperitoneal fibrosis (IgG4-RPF), IgG4-related prostatitis (IgG4-RP), IgG4-related testis, IgG4-related epididymitis, IgG4 Related dermatitis, IgG4-related thoracic aortitis, IgG4-related abdominal aortitis.