Method for treating antibody-mediated rejection using taci-fc fusion protein

Abstract

The present invention relates to a drug, a dosage regimen, a dosing interval, and an administration mode for treating antibody-mediated rejection using an effective amount of drugs that target Blys and / or APRIL. The results show that the effective amount of provided drugs that target Blys and / or APRIL exhibit good safety and therapeutic effects in the prevention, treatment or mitigation of antibody-mediated rejection in patients who are to accept, are accepting or have accepted solid organ transplantation.

Description

Method for treating antibody-mediated rejection using TACI-Fc fusion protein Technical Field

[0001] The present invention relates to a TACI-Fc fusion protein drug for treating antibody-mediated rejection reaction, a dosage regimen, a dosing interval and an administration method. Background Art

[0002] Antibody-mediated rejection (ABMR), also known as humoral rejection, is the most common cause of late allograft loss after organ transplantation and a major obstacle to long-term graft survival [Reference 1: Sellarés J, de Freitas DG, Mengel M, et al.. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 2012;12:388–399]. According to the Banff (2019) classification criteria, antibody-mediated rejection is mainly divided into four categories: active antibody-mediated rejection (Active ABMR, also known as acute active antibody-mediated rejection, Acute active ABMR), chronic active antibody-mediated rejection (Chronic active ABMR), chronic inactive antibody-mediated rejection (Chronic inactive ABMR), and C4d staining without evidence of rejection (C4d staining without evidence of rejection) [Reference 2: Loupy A, et al.. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep; 20(9): 2318-2331.].

[0003] Currently, no drug for the treatment of antibody-mediated rejection has been approved for marketing worldwide. Only a few published randomized clinical trials have evaluated the treatment of antibody-mediated rejection in renal transplant recipients [see https: / / clinicaltrials.gov / search?cond=ABMR, https: / / clinicaltrials.gov / search?cond=AMR]. However, most studies have small sample sizes and are unable to detect differences between treatment regimens, resulting in significant heterogeneity in the treatment of antibody-mediated rejection. Currently, patients with active antibody-mediated rejection are generally treated clinically with a combination of antibody removal (i.e., removal of existing or newly generated antibodies in the patient's body), glucocorticoids, intravenous immunoglobulin, anti-CD20 antibodies, proteasome inhibitors, and / or complement blockade. However, since chronic active antibody-mediated rejection can cause irreversible damage to graft tissue, leading to a significant decrease in graft survival, no treatment has been proven to be effective for chronic active antibody-mediated rejection [Reference 3: Rodriguez-Ramirez S, Al Jurdi A, Konvalinka A, Riella LV. Antibody-mediated rejection: prevention, monitoring and treatment dilemmas. Curr Opin Organ Transplant. 2022 Oct 1; 27(5): 405-414.]. In addition, although two studies have shown that plasma exchange can improve allograft survival in the treatment of antibody-mediated rejection [Reference 4: Bonomini V, Vangelista A, Frascà GM, et al.. Effects of plasmapheresis in renal transplant rejection. A controlled study. Trans Am Soc Artif Intern Organs 1985; 31: 698–703.], other plasma exchange trials have not shown significant benefits [Reference 5: Allen NH, Dyer P, Geoghegan T. Plasma exchange in acute renal allograft rejection. A controlled trial. Transplantation 1983; 35: 425–428.].Regarding anti-CD20 therapy, randomized clinical trials have shown that adding a single dose of rituximab to glucocorticoids, plasma exchange, and immunoglobulin therapy did not improve allograft function or survival [Reference 6: Sautenet B, Blancho G, Büchler M, et al.. One-year results of the effects of rituximab on acute antibody-mediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation 2016; 100: 391–399.]. In addition, there are findings suggesting that the combined use of immunoglobulin and rituximab may shorten the half-life of anti-CD20 monoclonal antibodies, accelerate B cell recovery, and thus affect the efficacy of anti-CD20 [Reference 7: Laws LH, Parker CE, Cherala G, et al.. Inflammation causes resistance to anti-CD20-mediated B cell depletion. Am J Transplant 2016;16:3139–3149.] Therefore, developing and determining long-term prognostic treatment options for antibody-mediated rejection in patients after transplantation remains an urgent need.

[0004] Currently, organ transplantation remains the most effective treatment for patients with end-stage renal disease. However, approximately 30% of patients awaiting transplantation have a certain amount of donor-specific antibodies (DSA) pre-existing in their bodies due to a history of blood transfusion, pregnancy, or previous transplantation, resulting in sensitization. The main component of DSA is anti-human leucocyte antigen (HLA) antibodies. According to the results of preoperative panel reactive antibodies (PRA) test, PRA>10% is generally defined as sensitization, and PRA>50% is defined as high sensitization [Reference 8: Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial[J]. J Am Soc Nephrol 2004, 15(12): 3256-3262.; Reference 9: Vieira CA, Agarwal A, Book BK, et al Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacokinetics, and pharmacokinetics[J]. Transplantation 2004, 77(4): 542-548.]. Sensitized patients often have difficulty obtaining a matching donor kidney, and the risk of antibody-mediated rejection after transplantation is increased. Therefore, HLA antibody desensitization therapy is required before kidney transplantation. This is done by physically or pharmacologically removing DSA from the circulation of highly sensitized patients, and by targeted inhibition of T and B cell activation to block DSA synthesis, thereby preventing hyperacute rejection and antibody-mediated rejection, and enabling highly sensitized patients to successfully undergo transplantation [Reference 10: Wang Zhiyong, Zhang Geng, Yuan Jianlin. Research progress on desensitization therapy before transplantation for patients with presensitized renal disease [J]. Chinese Journal of Organ Transplantation, 2017, 38(12): 761-764.].

[0005] Povetacicept (ALPN-303) is an Fc fusion protein with an engineered TACI domain. As a BAFF / APRIL dual antagonist, it is being explored for the treatment of lupus nephritis (Phase I / II), membranous nephropathy (Phase I / II), IgA nephropathy (Phase I / II), immune thrombocytopenia (Phase I / II), cold agglutinin disease (Phase I / II), warm antibody-type autoimmune hemolytic anemia (Phase I / II), systemic lupus erythematosus (Phase I), autoimmune cytopenia (Phase I), myasthenia gravis (preclinical) and other indications, and is currently in different clinical stages.

[0006] Alpine Immune Sciences has announced information on three Povetacicept clinical trials. Among them, RUBY 1 (NCT05034484) is a Phase I safety study in healthy volunteers, which showed that Povetacicept has acceptable safety and tolerability, and exhibits the expected PD effect on circulating Ig. RUBY 3 (NCT05732402) is an open-label Phase 1b / 2a study of Povetacicept for the treatment of autoimmune kidney diseases. Its preliminary research results showed that Povetacicept 80mg SC Q4W showed good tolerability after multiple doses in patients with IgA nephropathy, and is expected to reduce urine protein-creatinine ratio (UPCR) and Gd-IgA1. RUBY 4 (NCT05757570) is an open-label Phase 1b study of Povetacicept for the treatment of autoimmune cytopenias, which is currently underway. In addition, Povetacicept is intended for the treatment of inflammatory diseases involving BAFF and / or APRIL, such as systemic lupus erythematosus, and clinical trials are underway in China (registration number CTR20234038).

[0007] Atacicept is a recombinant fusion protein consisting of the extracellular ligand-binding portion of the TACI receptor and the Fc portion of human IgG, capable of binding to BLyS and APRIL. The drug is currently in various clinical stages of development for the treatment of IgA nephropathy (Stage III), lupus nephritis (Stage III), systemic lupus erythematosus (Stage II / III), and autoimmune diseases.

[0008] The Phase 2b ORIGIN trial (NCT04716231) of Atacicept for the treatment of IgA nephropathy achieved positive results, with Atacicept treatment achieving the primary endpoint and key secondary endpoints. In addition, the safety of the Atacicept and placebo treatment groups was comparable. A Phase 3 clinical trial (NCT04716231) of Atacicept for the treatment of IgA nephropathy is currently recruiting, with the dose of Atacicept in the trial group being 150 mg subcutaneously, administered once a week. In addition, a Phase IIb / III clinical trial (registration number: CTR20242150) evaluating the efficacy and safety of Atacicept in subjects with IgA nephropathy (IgAN) is currently underway in China. Results from a Phase III clinical trial (NCT00624338) evaluating the efficacy and safety of Atacicept in preventing moderate to severe systemic lupus erythematosus (SLE) showed that only the 150mg Atacicept group showed efficacy compared to the placebo group (43% vs. 60%; OR 0.49 (0.26, 0.92), p=0.027). However, the Atacicept 150mg group was discontinued early due to the death of two subjects from pneumonia complicated by pulmonary hemorrhage. Three completed Phase II clinical trials of Atacicept for the treatment of rheumatoid arthritis, NCT00595413, NCT00430495, and NCT00664521, have been terminated because they did not reach their primary endpoints.

[0009] Tetasip is a first-in-class recombinant TACI-Fc fusion protein for B cell-related autoimmune diseases. It targets and neutralizes BLyS and APRIL, two key cell signaling molecules in the B cell pathway. It is an antibody-like fusion protein designed to treat human autoimmune diseases, consisting of a truncated TACI and an immunoglobulin Fc sequence optimized to reduce ADCC and CDC effects. It exhibits excellent biological activity and safety and has been approved for marketing in China for the treatment of systemic lupus erythematosus.

[0010] Summary of the Invention

[0011] During the treatment of real-world cases, the present invention surprisingly discovered that the TACI-Fc fusion protein has excellent biological activity and safety in preventing and treating patients with antibody-mediated rejection, and produces significant therapeutic effects.

[0012] To this end, the present invention provides a method for preventing, treating or alleviating antibody-mediated rejection in patients who will receive, are receiving or have received solid organ transplantation, the method comprising administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to patients with the antibody-mediated rejection.

[0013] The present invention also provides a use of a drug targeting Blys and / or APRIL in the preparation of a drug for preventing, treating or alleviating antibody-mediated rejection.

[0014] The present invention also provides a use of the TACI-Fc fusion protein in preparing a drug for preventing, treating or alleviating antibody-mediated rejection.

[0015] The present invention also provides the use of tetasip in preparing a drug for preventing, treating or alleviating antibody-mediated rejection.

[0016] Furthermore, the drug targeting Blys and / or APRIL is a TACI-Fc fusion protein.

[0017] Furthermore, the TACI-Fc fusion protein described in any one of the above items comprises:

[0018] (i) the extracellular domain of TACI or a fragment thereof that binds to Blys and / or APRIL; and

[0019] (ii) Human immunoglobulin constant region fragments.

[0020] Furthermore, the extracellular region of TACI or the fragment thereof that binds to Blys and / or APRIL comprises the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2 or SEQ ID NO: 3.

[0021] Furthermore, the amino acid sequence of the TACI extracellular region or the fragment thereof that binds to Blys and / or APRIL is shown in SEQ ID NO: 1.

[0022] Furthermore, the human immunoglobulin is IgG1.

[0023] Furthermore, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:4.

[0024] Furthermore, the human immunoglobulin constant region fragment 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:4.

[0025] Furthermore, the amino acid sequence of the human immunoglobulin constant region fragment is shown in SEQ ID NO: 4.

[0026] Furthermore, the human immunoglobulin constant region fragment comprises amino acid modifications at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:4.

[0027] Furthermore, the human immunoglobulin constant region fragment contains 1, 2, 3, 4, 5, 6, 7, 8 or more amino acid modifications compared to SEQ ID NO:4.

[0028] Furthermore, the modification is amino acid substitution, deletion or insertion.

[0029] Furthermore, the substitution comprises one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

[0030] Furthermore, the insertion is to insert 1, 2, 3, 4, 5, 6, 7, 8 or more amino acids into the N-terminus of the human immunoglobulin constant region fragment.

[0031] Furthermore, the insertion is to insert 5 amino acids into the N-terminus of the human immunoglobulin constant region fragment.

[0032] Furthermore, the insertion is to insert the five amino acids EPKSS into the N-terminus of the human immunoglobulin constant region fragment.

[0033] Furthermore, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO: 5.

[0034] Furthermore, the TACI-Fc fusion protein comprises the amino acid sequence shown in SEQ ID NO:6.

[0035] Furthermore, the TACI-Fc fusion protein has an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO:7.

[0036] Furthermore, the amino acid sequence of the TACI-Fc fusion protein is shown in SEQ ID NO:7.

[0037] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:8.

[0038] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:9.

[0039] Furthermore, the drug targeting Blys and / or APRIL is Telitacicept, Atacicept, or Povetacicept.

[0040] Furthermore, the TACI-Fc fusion protein is Telitacicept.

[0041] Furthermore, the method is to administer a therapeutically effective amount of TACI-Fc fusion protein before solid organ transplantation.

[0042] Furthermore, the method comprises administering a therapeutically effective amount of TACI-Fc fusion protein after solid organ transplantation.

[0043] Furthermore, the method comprises administering a therapeutically effective amount of TACI-Fc fusion protein before and after solid organ transplantation.

[0044] Furthermore, the patient contains donor specific antibodies (DSA) against human leukocyte antigen (HLA) before treatment.

[0045] Furthermore, the method further comprises desensitization treatment before transplantation to remove or reduce donor-specific antibodies (DSA).

[0046] Furthermore, the desensitization therapy includes administering one or more of the following methods: plasma exchange, immunoadsorption, intravenous immunoglobulin (IVIG), anti-CD20 antibodies, anti-CD38 antibodies, combined antibody removal (i.e., removal of existing or newly formed antibodies in the patient's body), proteasome inhibitors, complement inhibitors, C1 esterase inhibitors (C1 esterase inhibitor, C1-INH), IL-6 / IL-6 receptor inhibitors, IgG endopeptidase (IgG-degrading enzyme of streptococcus pyogenes, IdeS), CTLA4-Fc fusion protein, targeted neonatal Fc receptor inhibitors, glucocorticoids, etc.

[0047] Furthermore, the anti-CD20 antibodies include rituximab, obinutuzumab, etc.; the anti-CD38 antibodies include daratumumab, fezartamab, etc.; the proteasome inhibitors include bortezomib, carfilzomib, ixazomib, etc.; the complement inhibitors include eculizumab, etc.; the C1 esterase inhibitors include Berinert and Cinryze; the IL-6 / IL-6 receptor inhibitors include tocilizumab, clazakizumab, etc.; the CTLA4-Fc fusion proteins include belatacept, etc.; the neonatal Fc receptor targeted inhibitors include rozanolixizumab, etc.

[0048] Furthermore, the solid organs include but are not limited to one or more of the kidney, heart, liver, lung, pancreas, skin, stomach and intestine.

[0049] Furthermore, the antibody-mediated rejection reaction described in any of the above items includes but is not limited to antibody-mediated kidney transplant rejection reaction, antibody-mediated liver transplant rejection reaction, antibody-mediated heart transplant rejection reaction, and antibody-mediated lung transplant rejection reaction.

[0050] Furthermore, the antibody-mediated rejection reaction described in any of the above items includes but is not limited to: one or more of active antibody-mediated rejection reaction (Active ABMR), chronic active antibody-mediated rejection reaction (Chronic active ABMR), chronic inactive antibody-mediated rejection reaction (Chronic inactive ABMR), and C4d staining without evidence of rejection.

[0051] In some preferred embodiments, the antibody-mediated rejection reaction is active antibody-mediated rejection reaction (Active ABMR); in other preferred embodiments, the antibody-mediated rejection reaction is chronic active antibody-mediated rejection reaction (Chronic active ABMR); in other preferred embodiments, the antibody-mediated rejection reaction is chronic inactive antibody-mediated rejection reaction (Chronic inactive ABMR); in other preferred embodiments, the antibody-mediated rejection reaction is C4d staining without evidence of rejection. It is understandable that in clinical practice, there are cases where the disease types of antibody-mediated rejection reactions are classified (i.e., further determined as active antibody-mediated rejection reaction (Active ABMR), chronic active antibody-mediated rejection reaction (Chronic active ABMR), chronic inactive antibody-mediated rejection reaction (Chronic inactive ABMR), C4d staining without evidence of rejection (C4d staining without evidence of rejection) or any two, three or four of them combined), and there are also cases where the disease types of antibody-mediated rejection reactions are not classified (i.e., they are uniformly referred to as antibody-mediated rejection reactions). Therefore, the type of disease should not be regarded as a limitation on the disease.

[0052] Furthermore, the method includes administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the antibody-mediated rejection reaction at the post-transplantation stage, the relapse stage, or after failure of other treatment methods (the drug targeting Blys and / or APRIL is further preferably a TACI-Fc fusion protein, and further preferably tetasip).

[0053] Furthermore, the patient is an adult patient or a pediatric patient. In some preferred embodiments, the patient is an adult patient. In other preferred embodiments, the patient is a pediatric patient.

[0054] Furthermore, the patient has not received any treatment for antibody-mediated rejection in the past.

[0055] Furthermore, the patient has previously received treatment for antibody-mediated rejection.

[0056] Furthermore, the patient's previous treatment regimen for antibody-mediated rejection includes but is not limited to combined antibody removal (i.e., removal of existing or newly generated antibodies in the patient's body), glucocorticoids, intravenous immunoglobulin, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, plasma exchange, and one or more of the following methods.

[0057] Furthermore, the method comprises administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the antibody-mediated rejection reaction, combined with one or more of the following methods: antibody removal (i.e., removal of existing or newly generated antibodies in the patient's body), glucocorticoids, intravenous immunoglobulin, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, plasma exchange, etc. for treatment.

[0058] Furthermore, the single dose of the drug targeting Blys and / or APRIL 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, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7. 3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10mg / kg.

[0059] Furthermore, the single dose of the drug targeting Blys and / or APRIL is 40-240 mg, and more preferably 40 mg, 50 mg, 60 mg, 70 mg, 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, and 240 mg.

[0060] Furthermore, the protein content of the above-mentioned drug is detected by UV-visible spectrophotometry. Based on the maximum UV absorption of protein at 280 nm, the absorbance value of the tetasip sample at this wavelength is measured. After correcting the absorbance at 320 nm, the absorbance value at 280 nm is proportional to the protein concentration. The protein concentration is calculated according to the Lambert-Beer law to determine the protein content. The protein content calculation formula is as follows:

[0061] Where: ε is the extinction coefficient of tadalafil, unit is (mg / ml) -1 cm -1 ;

[0062] A 280 is the average absorbance of the sample solution at 280 nm;

[0063] A 280 (Correction) is the average value of the corrected absorbance of the sample solution at 280 nm.

[0064] Furthermore, the drug targeting Blys and / or APRIL is used 1-8 times during each monthly interval, that is, the administration frequency of the TACI-Fc fusion protein is 1, 2, 3, 4, 5, 6, 7 or 8 times per month.

[0065] Furthermore, the drug targeting Blys and / or APRIL is used 1-8 times every two months, that is, the administration frequency of the TACI-Fc fusion protein is 1, 2, 3, 4, 5, 6, 7 or 8 times every two months.

[0066] Furthermore, the drug targeting Blys and / or APRIL is used 1-8 times during every three months, that is, the administration frequency of the TACI-Fc fusion protein is 1, 2, 3, 4, 5, 6, 7 or 8 times every three months.

[0067] Furthermore, the drug targeting Blys and / or APRIL is administered once a week, twice a week, or three times a week.

[0068] Furthermore, the drug targeting Blys and / or APRIL is administered once every two weeks, once every three weeks, or once a month.

[0069] Furthermore, the drug targeting Blys and / or APRIL is administered on demand.

[0070] Furthermore, the drug targeting Blys and / or APRIL is administered continuously and / or intermittently.

[0071] Furthermore, the drug targeting Blys and / or APRIL is administered at regular intervals.

[0072] Furthermore, the drug targeting Blys and / or APRIL is administered at irregular intervals.

[0073] Furthermore, the drug targeting Blys and / or APRIL is administered subcutaneously, intramuscularly, or intravenously, preferably into the thigh, abdomen, or upper arm. In some specific embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously.

[0074] Furthermore, the drug targeting Blys and / or APRIL is injected into the same or different sites each time. In some specific embodiments, the TACI-Fc fusion protein is injected into the same site each time; in other specific embodiments, the TACI-Fc fusion protein is injected into different sites each time.

[0075] The present invention also provides a method for treating a patient with antibody-mediated rejection who has received a treatment regimen for antibody-mediated rejection, the method comprising (1) determining whether the patient has received a treatment regimen for antibody-mediated rejection, and (2) if the patient has previously received treatment for antibody-mediated rejection, administering an effective amount of a drug targeting Blys and / or APRIL, further comprising a TACI-Fc fusion protein, to the patient with the antibody-mediated rejection.

[0076] The drug targeting Blys and / or APRIL provided by the present invention (such as tetasip) shows unexpected clinical efficacy and good safety in the treatment of antibody-mediated rejection.Specifically, for antibody-mediated rejection reactions (such as active antibody-mediated rejection reaction (Active ABMR), chronic active antibody-mediated rejection reaction (Chronic active ABMR), chronic inactive antibody-mediated rejection reaction (Chronic inactive ABMR), C4d staining without evidence of rejection), the drugs targeting Blys and / or APRIL provided by the present invention (such as tetasip) have shown good safety and better efficacy, and have excellent therapeutic potential; for patients with acute antibody-mediated rejection reactions, the drugs targeting Blys and / or APRIL provided by the present invention (such as tetasip) have shown good safety and better efficacy; for patients with chronic active antibody-mediated rejection reactions, the drugs targeting Blys and / or APRIL provided by the present invention (such as tetasip) have shown good safety and better efficacy. For chronic inactive antibody-mediated rejection and no rejection by C4d staining, the drugs targeting Blys and / or APRIL provided by the present invention (such as tetasip) also show good safety and better efficacy; for patients with antibody-mediated rejection who have failed treatment with traditional treatment options (such as plasma exchange, intravenous immunoglobulin, etc.) and antibodies (such as daratumumab), the drugs targeting Blys and / or APRIL provided by the present invention (such as tetasip) can still show good therapeutic effects; the drugs targeting Blys and / or APRIL provided by the present invention (such as tetasip) can still show good therapeutic effects. Compared with traditional treatment options (such as plasma exchange, intravenous immunoglobulin, etc.) and antibodies (such as Zolpidem, i.e., daratumumab), drugs targeting Blys and / or APRIL provided by the present invention (such as telocycli) can show better therapeutic effects in the treatment of patients with antibody-mediated rejection (especially chronic active antibody-mediated rejection); for patients with antibody-mediated rejection, the drugs targeting Blys and / or APRIL (such as telocycli) provided by the present invention combined with other treatment methods (such as traditional treatment options, hormones, plasma exchange, intravenous immunoglobulin, antibodies, etc.) can show significant therapeutic effects. The present invention has a good therapeutic effect; for patients with chronic active antibody-mediated rejection whose creatinine level remains high for a long time, especially those with chronic active antibody-mediated rejection whose creatinine level does not decrease significantly after treatment, the drugs targeting Blys and / or APRIL (such as tetasip) provided by the present invention show a good therapeutic effect; for patients with antibody-mediated rejection who have failed treatment with traditional treatment options (such as cellulose, tacrolimus capsules, prednisone tablets, and diltiazem tablets), the drugs targeting Blys and / or APRIL (such as tetasip) provided by the present invention can still show a good therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] FIG1 shows the PRA-MFI and site changes of patient Case 5 in Example 1 (Note: in FIG1 , combined treatment with tetasip was started after the first detection). DETAILED DESCRIPTION

[0078] Unless otherwise defined, all terms used herein have the same meanings as understood by those of ordinary skill in the art. For definitions and terms in this field, professionals can refer to Current Protocols in Molecular Biology (Ausubel).

[0079] 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).

[0080] The term "TACI" as used herein stands for transmembrane activator and CAML interactor, 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 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) as used herein refers to a tumor necrosis factor (TNF) analog that stimulates the proliferation of naive B cells and T cells in the body, promoting B cell accumulation. APRIL specifically binds to TACI and BCMA, preventing APRIL from binding to B cells and inhibiting APRIL-stimulated naive B cell proliferation. Furthermore, APRIL competes with BLys for binding to receptors (BCMA and TACI).

[0081] 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) the TACI extracellular region or a fragment thereof that binds to Blys and / or APRIL; and (ii) a human immunoglobulin constant region fragment.

[0082] The term "TACI extracellular region or a fragment thereof that binds to Blys and / or APRIL" in the present invention includes 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, and the amino acid fragment of position 13-118 of the TACI extracellular domain disclosed in Chinese Patent Publication No. CN101323643A.

[0083] Examples of the "TACI-Fc fusion protein" include Telitacicept (amino acid sequence: SEQ ID NO: 7), Atacicept (amino acid sequence: SEQ ID NO: 8), and Povetacicept (amino acid sequence: SEQ ID NO: 9).

[0084] In the term "human immunoglobulin constant region fragment" referred to in the present invention, the immunoglobulin portion is preferably IgG1, which may include 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: 4, 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: 4. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" is as shown in SEQ ID NO: 5.

[0085] The term "treatment" as used herein is related to a given disease or condition, including but not limited 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 relapse; or alleviating the symptoms caused by the disease or condition, such as alleviating, preventing or treating the symptoms of the disease or condition; or reducing the chance of recurrence of the disease or preventing recurrence of the disease.

[0086] The term "remission" used in the present invention refers to the absence of clinical symptoms or signs related to GPA, MPA or EGPA at the beginning or end of treatment.

[0087] The term "amino acid" used 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 used in the present invention are the main units that make up 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.

[0088] The amino acid three-letter codes and single-letter codes used in the present invention are as described in J. biol. chem, 243, p3558 (1968). There are various ways to number amino acid sites, such as the Kabat numbering system, the EU numbering system, and sequential numbering. In the present invention, the numbering of amino acid sites is carried out in a "sequential numbering" manner. For example, "position 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 4" as described in the present invention refers to the 3rd amino acid, the 8th amino acid of SEQ ID NO: 4, 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: 4 from the previous "P" to "T", and for example, "L8P" refers to the mutation of the 8th amino acid sequence of SEQ ID NO: 4 from the previous "L" to "P", and so on.

[0089] As an alternative embodiment, the constant region of the immunoglobulin provided by the present invention can introduce one or more amino acid changes, such as substitution (ie, mutation), addition (ie, insertion) or deletion (ie, deletion).

[0090] 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 its amino acid sequence is shown in SEQ ID NO: 7, or as shown in https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932.

[0091] 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, transdermal, topical, subcutaneous, intranasal, enteral, sublingual, vaginal or rectal routes.

[0092] The term "antibody-mediated rejection," also known as humoral rejection, is a type of immune response involving multiple humoral immune effectors, such as antibodies and complement. It plays a significant role in the pathogenesis of hyperacute, acute, and chronic rejection.

[0093] The term "biologic drug treatment regimen" in the present invention is often used to treat patients whose disease has failed traditional treatment, who have hormone resistance or intolerance, who have relapsed during hormone reduction, or who are refractory or severely ill. Exemplary biological targeted therapies with current application prospects include:

[0094] (1) B cell depletion therapy: non-limiting examples include anti-CD20 monoclonal antibody, anti-CD19 monoclonal antibody, B lymphocyte activating factor (BAFF) inhibitors, etc.

[0095] (2) Targeting T lymphocytes: non-limiting examples include abatacept, signaling lymphocyte activation molecule family member 7 (SLAMF 7) monoclonal antibody, and inducible co-stimulatory molecule ligand (ICOSL) inhibitor;

[0096] (3) Targeted cytokines (IL-4, IL-5\TNF-α) and intracellular signaling pathway JAK inhibitors, etc.

[0097] The term "inactive / active" as used herein refers to the presence of new, persistent, or worsening clinical symptoms and / or signs related to GPA, MPA, or EGPA.

[0098] The "severe illness" mentioned in the present invention refers to the presence of life-threatening symptoms or organ manifestations (such as alveolar hemorrhage, glomerulonephritis, central nervous system vasculitis, etc.).

[0099] The term "about" is used herein to indicate that a numerical value includes the inherent error variation of the device or method used to determine the numerical value, or the variation between the samples tested. Unless otherwise stated or obvious from the context, the term "about" means within 10% of the reported numerical value (unless the number will exceed 100% or be less than 0% of the possible value). When used in conjunction with a numerical range or series, the term "about" applies to the endpoints of the range or each value listed in the series unless otherwise stated.

[0100] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0101] Example 1: Treatment effects of real-world cases

[0102] Case 1

[0103] The patient underwent a "DD (deceased donor) kidney transplant" and took a triple immunosuppressive regimen of tacrolimus, Mifu and Medrol to prevent rejection. Later, due to increased creatinine, he was given immunoadsorption and immunoglobulin treatment. A non-invasive rejection free DNA test was performed again, which showed a rejection risk coefficient of 0.46. Combined with other indicators, it was considered to be an acute antibody-mediated rejection reaction.

[0104] Subsequently, tetanusip was administered, and the treatment plan was as follows:

[0105] Tetasip 160 mg subcutaneously, once a week for three months;

[0106] The dose of tetanusap was subsequently adjusted to 80 mg subcutaneously once a week for two months.

[0107] During treatment with Tetasip, the patient experienced a mild rebound in antibodies in the second month, but antibodies continued to decline in the third month. During Tetasip, the patient's renal function fluctuated between 120 and 150 μmol / L, proteinuria remained negative, and there was no hepatotoxicity. The patient experienced no significant adverse reactions during the infusion period. These results demonstrate that Tetasip demonstrates a favorable safety profile and therapeutic efficacy for patients with acute antibody-mediated rejection.

[0108] Case 2

[0109] After renal transplantation, the patient took oral tacrolimus + mifuran to treat rejection. Later, due to creatinine fluctuations and proteinuria, the treatment with tripterygium wilfordii was ineffective. After comprehensive consideration of other indicators, it was determined to be a chronic active antibody-mediated rejection reaction.

[0110] Initially, the patient received PP (plasma exchange) + IVIG (intravenous immunoglobulin) combined with Zhaoke treatment: 6 PP + IVIG treatments were given, and after the last 5 treatments, 400 mg of Zhaoke was given intravenously each time. Later, due to the rebound of DR53 antibodies, the dosing regimen was adjusted to intravenous infusion of Actemra once a month, but the effect was not good.

[0111] The regimen was subsequently adjusted to a subcutaneous injection of 80 mg of tetacept once a week.

[0112] During the first and third month follow-up of using Tetasip, the patient's DR53 antibody and MFI values ​​continued to decrease, renal function remained stable, proteinuria remained negative, there was no hepatotoxicity, no obvious bone marrow suppression, no increased risk of infection, and no obvious adverse reactions during the injection period. The results showed:

[0113] ① For patients with chronic active antibody-mediated rejection, tetasip has shown good safety and therapeutic effects.

[0114] ② For patients with antibody-mediated rejection who have failed to respond to traditional treatment options (such as plasma exchange, intravenous immunoglobulin, etc.) and antibodies (such as daratumumab), the use of telocycli can still show good therapeutic effects.

[0115] ③ Compared with traditional treatment options (such as plasma exchange, intravenous immunoglobulin, etc.) and antibodies (such as daratumumab), tetanercept can show better therapeutic effects in the treatment of patients with antibody-mediated rejection reactions (especially chronic active antibody-mediated rejection reactions).

[0116] Case 3

[0117] The patient underwent a "DD donor kidney transplant" and took a triple immunosuppressive regimen of tacrolimus, Mifu and Medrol to prevent rejection after the operation. Later, due to increased creatinine and urine protein 3+, combined with other indicators, it was considered to be a chronic active antibody-mediated rejection reaction.

[0118] Immunoadsorption therapy was then performed with the following regimen:

[0119] ① Rituximab 100 mg intravenous drip;

[0120] ②Tetasip 160 mg subcutaneously, once a week for a total of three months.

[0121] During the treatment with Tetasip, the patient's urine protein remained at 2+, renal function remained relatively stable, there was no significant increase in the risk of infection, and the patient had no obvious adverse reactions during the injection. The results showed:

[0122] ① For patients with chronic active antibody-mediated rejection, tetasip showed good safety and therapeutic effect.

[0123] ②For patients with antibody-mediated rejection, especially those with chronic active antibody-mediated rejection, rituximab combined with tetanuscept can show significant therapeutic effects.

[0124] Case 4

[0125] After the patient underwent allogeneic renal transplantation, he was given triple rejection therapy. Later, due to no obvious cause, he developed fatigue, abnormal blood creatinine, and proteinuria. Combined with other indicators, it was considered to be a chronic active antibody-mediated rejection reaction.

[0126] Subsequently, the patient received conventional treatment with Cialis (4 tablets, twice a day), Tacrolimus capsules (1 mg, 5 tablets, twice a day), Prednisone tablets (5 mg, 5 tablets, once a day), and Diltiazem tablets (30 mg, 2 tablets, three times a day), but the creatinine level did not decrease significantly.

[0127] The treatment plan was adjusted to include tetacept on the basis of the above conventional treatment plan. The plan is as follows:

[0128] ①Tetasip 160 mg, administered subcutaneously once a week for a total of three months.

[0129] ②The dose of tetasip was then adjusted to 80 mg, administered subcutaneously once a week for a total of three months.

[0130] The patient's creatinine level had been maintained at a high level (190-200) for a long time, and there was no significant downward trend after conventional treatment. However, one month after using Tetasip, the level dropped significantly, and the creatinine level showed a good downward trend (down to 162) during the treatment period. During this period, renal function remained stable, proteinuria was also stable, and the patient had no obvious adverse reactions during the injection. The results showed:

[0131] ① For patients with chronic active antibody-mediated rejection, tetasip showed good safety and therapeutic effect.

[0132] ② For patients with chronic active antibody-mediated rejection reactions in which creatinine levels remain high for a long time, especially those with chronic active antibody-mediated rejection reactions in which the creatinine level does not show an obvious downward trend after treatment, tetasip shows a good therapeutic effect.

[0133] ③For patients with antibody-mediated rejection, especially those with chronic active antibody-mediated rejection, tadalafil can show better therapeutic effects than conventional treatments (such as cyclisime, tacrolimus capsules, prednisone tablets, and diltiazem tablets).

[0134] ④ For patients with antibody-mediated rejection who have failed to respond to traditional treatment options (such as Cellcept, tacrolimus capsules, prednisone tablets, and diltiazem tablets), the use of tacrolimus can still show good therapeutic effects.

[0135] ⑤ The combination of tacrolimus and traditional treatment regimens (such as cytokine, tacrolimus capsules, prednisone tablets, and diltiazem tablets) can show good therapeutic effects in the treatment of patients with antibody-mediated rejection (especially patients with chronic active antibody-mediated rejection).

[0136]

Case 5

[0137] The patient had been proteinuria for 5 years and on hemodialysis for over 2 years. During preoperative evaluation for kidney transplantation, PRA was positive for category 1 and negative for category 2. HLA-specific antibody testing was multi-locus positive, which, combined with other indicators, indicated a highly sensitized kidney transplant recipient.

[0138] Conventional treatment combined with tetasip, 160 mg / week, subcutaneous injection.

[0139] After four months of treatment with the above regimen, the patient's urine microalbuminuria improved and HLA antibodies decreased. Compared with the first test, the fourth DSA MFI value after tetanusip treatment showed an overall downward trend, and the number of DSA-positive sites decreased. The changes in the patient's PRA MFI and sites are shown in Figure 1 (Note: Figure 1 shows that combination therapy with tetanusip was initiated after the first test).

[0140] The treatment results show that tetasip can reduce HLA antibodies, reduce the number of DSA sites and DSA intensity, and effectively improve urinary microalbumin. It has a good effect on delaying the progression of pathological damage of antibody-mediated rejection reaction of transplanted kidney and improving the long-term prognosis of transplanted kidney.

[0141] In summary, the application of tetasip in patients with antibody-mediated rejection has shown better safety and better therapeutic effect than existing treatment options / methods. Specifically, for antibody-mediated rejection (such as active antibody-mediated rejection (Active ABMR), chronic active antibody-mediated rejection (Chronic active ABMR), chronic inactive antibody-mediated rejection (Chronic inactive ABMR), C4d staining without evidence of rejection (C4d staining without evidence of rejection), tetasip is safer and more effective than existing treatment options / methods. rejection), Tetasipip has shown good safety and better efficacy, and has excellent therapeutic potential; for patients with acute antibody-mediated rejection, Tetasipip has shown good safety and better efficacy; for patients with chronic active antibody-mediated rejection, Tetasipip has shown good safety and better efficacy; for chronic inactive antibody-mediated rejection and no rejection reaction by C4d staining, Tetasipip also showed good safety and better efficacy; for patients with antibody-mediated rejection who have failed traditional treatment regimens (such as plasma exchange, intravenous immunoglobulin, etc.) and antibodies (such as Zoloft, i.e., daratumumab), Tetasipip can still show good therapeutic effects; for highly sensitized renal transplant recipients, Tetasipip treatment has shown good therapeutic effects; Tetasipip is superior to traditional treatment regimens (such as plasma exchange, intravenous immunoglobulin, etc.) etc.), and antibodies (such as daratumumab) can show better therapeutic effects in the treatment of patients with antibody-mediated rejection (especially chronic active antibody-mediated rejection); for patients with antibody-mediated rejection, the combined use of tetasip and other treatment methods (such as traditional treatment plans, hormones, plasma exchange, intravenous immunoglobulin, antibodies, etc.) can show significant therapeutic effects; for patients with chronic active antibody-mediated rejection with long-term high creatinine levels, especially patients with chronic active antibody-mediated rejection whose creatinine does not show an obvious downward trend after treatment, tetasip shows good therapeutic effects; for patients with antibody-mediated rejection who have failed to receive traditional treatment (such as cilcet, tacrolimus capsules, prednisone tablets, diltiazem tablets), the use of tetasip can still show good therapeutic effects; for the treatment of highly sensitized renal transplant recipients, conventional treatment combined with tetasip shows good therapeutic effects.

[0142] Example 2 Clinical trial study

[0143] Main Purpose

[0144] 1. To evaluate the effectiveness of tetasip in treating or alleviating antibody-mediated rejection (such as chronic active antibody-mediated rejection and / or acute antibody-mediated rejection).

[0145] 2. Secondary objective: To preliminarily evaluate the safety of tetasip in the treatment of refractory and / or alleviated antibody-mediated rejection (such as chronic active antibody-mediated rejection and / or acute antibody-mediated rejection).

[0146] The above description is merely a preferred embodiment, which is intended to be illustrative and non-limiting of the combinations 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 indicated, the absence of a numeral modifier includes the plural form, and "or" and "or" mean "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.

[0147] 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 will be 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 pattern that are apparent to those skilled in the relevant art are intended to be included in the scope of the appended claims.

Claims

1. A method for preventing, treating or alleviating antibody-mediated rejection, the method comprising administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient having the antibody-mediated rejection.

2. The method according to claim 1, characterized in that: The patient is a patient who will receive, is receiving or has received a solid organ transplant.

3. The method according to claim 1 or 2, characterized in that: The drug targeting Blys and / or APRIL is TACI-Fc fusion protein.

4. The method according to claim 3, characterized in that 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.

5. The method according to claim 4, characterized in that The TACI extracellular region or the fragment binding to Blys and / or APRIL comprises the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2 or SEQ ID NO:

3.

6. The method according to claim 4, characterized in that The human immunoglobulin is IgG1 or the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:4 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:

4.

7. The method according to claim 6, characterized in that The human immunoglobulin constant region fragment comprises amino acid modifications at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:

4.

8. The method according to claim 7, characterized in that The human immunoglobulin constant region fragment comprises 1, 2, 3, 4, 5, 6, 7, 8 or more amino acid modifications compared to SEQ ID NO:

4.

9. The method according to claim 7 or 8, characterized in that: The modification is amino acid substitution, deletion or insertion.

10. The method according to claim 9, characterized in that The substitutions include one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

11. The method according to claim 9, characterized in that The insertion is to insert 1, 2, 3, 4, 5, 6, 7, 8 or more amino acids into the N-terminus of the human immunoglobulin constant region fragment.

12. The method according to claim 7 or 8, characterized in that: The human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:

6.

13. The method according to claim 12, characterized in that The TACI-Fc fusion protein has an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO:

7.

14. The method according to claim 12 or 13, characterized in that The TACI-Fc fusion protein has an amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:8 or SEQ ID NO:

9.

15. The method according to claim 14, characterized in that The TACI-Fc fusion protein is Telitacicept, Atacicept or Povetacicept.

16. The method according to any one of claims 2-3, wherein a therapeutically effective amount of TACI-Fc fusion protein is administered prior to solid organ transplantation.

17. The method according to any one of claims 2-3, wherein the therapeutically effective amount of TACI-Fc fusion protein is administered after solid organ transplantation.

18. The method according to any one of claims 2-3, wherein a therapeutically effective amount of TACI-Fc fusion protein is administered before and after solid organ transplantation.

19. The method of any one of claims 1-3 or 16, wherein the patient comprises donor specific antibodies (DSA) against human leukocyte antigen (HLA) prior to treatment.

20. The method according to any one of claims 19, further comprising desensitization therapy before transplantation to remove or reduce donor specific antibodies (DSA).

21. The method according to claim 20, wherein the desensitization therapy comprises administering one or more of the following methods: plasma exchange, immunoadsorption, intravenous immunoglobulin (IVIG), anti-CD20 antibody, anti-CD38 antibody, combined antibody removal (i.e., removal of existing or newly generated antibodies in the patient's body), proteasome inhibitors, complement inhibitors, C1 esterase inhibitor (C1 esterase inhibitor, C1-INH)), IL-6 / IL-6 receptor inhibitors, IgG endopeptidase (IgG-degrading enzyme of streptococcus pyogenes, IdeS), CTLA4-Fc fusion protein, targeted neonatal Fc receptor inhibitors, glucocorticoids, etc. for treatment.

22. The method according to any one of claims 1 to 21, characterized in that: The solid organs include, but are not limited to, one or more of the kidney, heart, liver, lung, pancreas, skin, stomach and intestine.

23. The method according to any one of claims 1 to 22, characterized in that: The antibody-mediated rejection reaction includes, but is not limited to, one or more of antibody-mediated kidney transplant rejection reaction, antibody-mediated liver transplant rejection reaction, antibody-mediated heart transplant rejection reaction, and antibody-mediated lung transplant rejection reaction.

24. The method according to any one of claims 1 to 23, characterized in that The antibody-mediated rejection reaction includes, but is not limited to, one or more of active antibody-mediated rejection reaction (Active ABMR), chronic active antibody-mediated rejection reaction (Chronic active ABMR), chronic inactive antibody-mediated rejection reaction (Chronic inactive ABMR), and C4d staining without evidence of rejection.

25. The method according to any one of claims 1 to 24, characterized in that The method comprises administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the antibody-mediated rejection reaction at a stage such as after transplantation, at a relapse stage, or after failure of other treatment methods.

26. The method according to any one of claims 1 to 25, characterized in that The patient is an adult patient or a pediatric patient.

27. The method according to any one of claims 1 to 26, characterized in that The patient had not previously received treatment regimens for antibody-mediated rejection.

28. The method according to any one of claims 1 to 27, characterized in that: The patient had previously received treatment regimens for antibody-mediated rejection.

29. The method according to any one of claims 28, characterized in that The patient's previous treatment regimen for antibody-mediated rejection includes, but is not limited to, combined antibody removal (i.e., removal of existing or newly generated antibodies in the patient's body), glucocorticoids, intravenous immunoglobulin, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, plasma exchange, and one or more of the following methods.

30. The method according to any one of claims 1 to 29, characterized in that The method comprises administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the antibody-mediated rejection reaction, combined with conventional treatment, antibody removal (i.e., removal of existing or newly generated antibodies in the patient's body), glucocorticoids, intravenous immunoglobulin, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, plasma exchange, or one or more of the following methods for treatment; preferably, the anti-CD20 antibody is rituximab.

31. The method according to any one of claims 1 to 30, characterized in that The single administration dose of the drug targeting Blys and / or APRIL is about 0.1 to 10 mg / kg.

32. The method according to any one of claims 1 to 31, characterized in that in, The single dosage of the drug targeting Blys and / or APRIL is 40-240 mg; more preferably 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 240 mg; further preferably 80 mg or 160 mg.

33. The method according to any one of claims 1 to 32, characterized in that The drug targeting Blys and / or APRIL is administered on demand.

34. The method according to any one of claims 1 to 33, characterized in that The drug targeting Blys and / or APRIL is used 1-8 times at intervals of one month, and / or 1-8 times at intervals of two months, and / or 1-8 times at intervals of three months, or the administration frequency is once a week, or once every two weeks, or once every three weeks, or once a month.

35. The method according to any one of claims 1 to 34, characterized in that The drug targeting Blys and / or APRIL is administered subcutaneously, intramuscularly or intravenously, or the administration site is the thigh, abdomen or upper arm.

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