A method for treating antibody-mediated rejection using TACI-Fc fusion proteins.

Abstract

The present invention relates to drugs, dosing regimens, dosing intervals, and modes of administration for treating antibody-mediated rejection using effective doses of Blys and / or APRIL-targeted drugs. The results show that effective doses of Blys and / or APRIL-targeted drugs provide good safety and therapeutic efficacy in preventing, treating, or mitigating antibody-mediated rejection in patients who are planning to undergo, are undergoing, or have previously undergone solid organ transplantation.

Description

[Technical Field]

[0001] The present invention relates to TACI-Fc fusion protein medicaments, dosing regimens, dosing intervals, and modes of administration for treating antibody-mediated rejection. [Background Art]

[0002] Antibody-mediated rejection (ABMR), also referred to as humoral rejection for short, is the most common cause of delayed allograft loss after organ transplantation, and is the main obstacle affecting long-term graft survival [Reference 1: Sellares 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 classification criteria of Banff (2019), antibody-mediated rejection is mainly classified into the following four categories: active ABMR (also referred to as acute active ABMR), chronic active ABMR, chronic inactive ABMR, and 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 therapeutic drugs for antibody-mediated rejection are approved for commercial marketing worldwide, and only a few published randomized clinical trials have evaluated treatment regimens for antibody-mediated rejection in kidney transplant recipients [see https: / / clinicaltrials.gov / search?cond=ABMR, https: / / clinicaltrials.gov / search?cond=AMR]. However, most trials 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 clinically treated with combined antibody removal (i.e., removal of antibodies already present or newly generated in the patient), glucocorticoids, intravenous immunoglobulins, anti-CD20 antibodies, proteasome inhibitors, and / or complement blockade. However, there are no treatments proven effective for chronic active antibody-mediated rejection, as it can cause irreversible damage to tissue for transplantation and significantly reduces graft survival [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, two studies have shown that plasmapheresis in the treatment of antibody-mediated rejection can improve allograft survival [Reference 4: Bonomini V, Vangelista A, Frasca GM, et al. Effects of plasmapheresis in renal transplant rejection. A controlled study. Trans Am Soc Artif Intern Organs 1985;31:698-703.], but several other plasmapheresis trials have not shown a significant benefit [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, plasmapheresis, and immunoglobulin therapy did not improve allograft function or engraftment [Reference 6: Sautenet B, Blancho G, Buchler 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 application of immunoglobulin and rituximab may shorten the half-life of anti-CD20 monoclonal antibodies, promote B cell recovery, and thus affect the effectiveness 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 establishing treatment regimens to improve the long-term prognosis of antibody-mediated rejection in post-transplant patients remains an urgent and unmet need.

[0004] Currently, organ transplantation remains the most effective form of treatment for patients with end-stage renal disease and other conditions. However, approximately 30% of patients awaiting transplantation become sensitized due to a history of blood transfusions, pregnancy, or previous transplants, resulting in the development of pre-existing donor-specific antibodies (DSAs), the main component of which is anti-human leukocyte antigen (HLA) antibodies. Based on the detection results of preoperative panel-reactive antibodies (PRA), 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, pharmacodynamics, and pharmacokinetics [J]. Transplantation 2004, 77(4):542-548.]. Patients who become sensitized typically have difficulty obtaining a crossmatched donor kidney and face an increased risk of antibody-mediated rejection after transplantation.Therefore, in order to prevent the occurrence of hyperacute rejection and antibody-mediated rejection, and thereby enable highly sensitized patients to successfully undergo transplantation, HLA antibody desensitization therapy is required before kidney transplantation to deplete circulating DSA in highly sensitized patients by physical or pharmacological means, specifically inhibit T cell and B cell activation, and block DSA synthesis [Reference 10: Wang Zhiyong, Zhang Geng, Yuan Jianlin. Research progress in preoperative desensitization treatment for pre-sensitized patients with kidney disease before transplantation [J]. Chinese Journal of Organ Transplantation 2017, 38(12):761-764.].

[0005] Pobetacicept (ALPN-303) is an Fc fusion protein with an engineered TACI domain and, as a dual BAFF / APRIL antagonist, 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 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] Currently, Alpine Immune Sciences has disclosed information on three pobetacicept clinical trials: RUBY1 (NCT05034484) is a Phase I safety trial in healthy volunteers demonstrating acceptable safety and tolerability, as well as expected pharmacodynamic (PD) effects on circulating immunoglobulin (Ig); and RUBY3 (NCT05732402) is an open-label Phase 1b / 2a trial of pobetacicept for the treatment of autoimmune kidney disease. Preliminary trial results show that pobetacicept 80 mg SC Q4W is well-tolerated after multiple doses in patients with IgA nephropathy and is expected to reduce the ratio of urinary protein to creatinine (UPCR) and Gd-IgA1. RUBY4 (NCT05757570) is an ongoing open-label Phase 1b trial of pobetasicept for the treatment of autoimmune cytopenia. In addition, pobetasicept is intended for the treatment of BAFF and / or APRIL-related inflammatory diseases such as systemic lupus erythematosus, and is currently undergoing clinical trials in China (registration number CTR20234038).

[0007] Atacicept is a recombinant fusion protein containing the extracellular ligand-binding portion of the TACI receptor and the Fc portion of human IgG, capable of binding to BlyS and APRIL. This drug is being explored for the treatment of indications such as IgA nephropathy (Phase III), lupus nephritis (Phase III), systemic lupus erythematosus (Phase II / III), and autoimmune diseases, and is currently in different clinical stages.

[0008] The Phase 2b ORIGIN trial (NCT04716231) of atacicept for the treatment of IgA nephropathy yielded positive results, with atacicept treatment meeting the primary and major secondary endpoints. In addition, the safety profiles of the atacicept and placebo groups were comparable. The Phase 3 clinical trial of atacicept for the treatment of IgA nephropathy (NCT04716231) is currently recruiting participants, and the treatment group will receive atacicept subcutaneously once weekly at a dose of 150 mg per dose. In addition, a Phase IIb / III trial (Registration No.: CTR20242150) evaluating the efficacy and safety of atacicept in patients with IgA nephropathy (IgAN) is currently being conducted in China. Results from a Phase III clinical trial (NCT00624338) of atacicept for efficacy and safety in the prevention of moderate to severe systemic lupus erythematosus (SLE) showed that only the 150 mg dose of atacicept demonstrated efficacy compared to placebo (43% and 60%; OR 0.49 (0.26, 0.92), p=0.027). However, the trial was terminated early for the 150 mg dose of atacicept due to two deaths resulting from pneumonia with pulmonary hemorrhage. Three completed Phase II clinical trials of atacicept for the treatment of rheumatoid arthritis, NCT00595413, NCT00430495, and NCT00664521, were all terminated because the primary endpoint was not met.

[0009] Teritacicept is a first-in-class recombinant TACI-Fc fusion protein for B-cell-associated autoimmune diseases that can target and neutralize two major cellular signaling molecules in the B-cell pathway: B lymphocyte-stimulating factor (BLyS) and proliferation-inducing ligand (APRIL). It is an antibody-like fusion protein composed of cleaved TACI and an immunoglobulin Fc region, optimized to exhibit reduced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cell-mediated cytotoxicity (CDC) activity for the treatment of human autoimmune diseases, possesses excellent biological activity and safety, and is approved for market launch in China for the treatment of systemic lupus erythematosus. [Overview of the Initiative]

[0010] Remarkably, in the process of treating real-world cases, the present invention has been found to possess excellent biological activity and safety in the prevention and treatment of patients with antibody-mediated rejection, resulting in significant therapeutic effects.

[0011] For this purpose, the present invention provides a method for preventing, treating, or mitigating antibody-mediated rejection in patients who are about to undergo, are undergoing, or have previously undergone solid organ transplantation, the method comprising administering a therapeutically effective dose of a Blys and / or APRIL-targeted drug to a patient having antibody-mediated rejection.

[0012] The present invention further provides the use of Blys and / or APRIL-targeted drugs in the preparation of pharmaceuticals for preventing, treating, or mitigating antibody-mediated rejection in patients.

[0013] The present invention further provides the use of TACI-Fc fusion proteins in the preparation of drugs for preventing, treating, or mitigating antibody-mediated rejection in patients.

[0014] The present invention further provides the use of teritacicept in the preparation of drugs for preventing, treating, or mitigating antibody-mediated rejection in patients.

[0015] Furthermore, the aforementioned Blys and / or APRIL-targeting drugs are TACI-Fc fusion proteins.

[0016] Furthermore, a TACI-Fc fusion protein produced by any one of the above methods is (i) an extracellular domain or fragment of TACI that binds to Blys and / or APRIL, (ii) A fragment of a human immunoglobulin constant region, comprising

[0017] Furthermore, the TACI extracellular region or a fragment thereof that binds to Blys and / or APRIL comprises the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0018]

Chemical Formula

[0019] Furthermore, the amino acid sequence of the TACI extracellular region or a fragment thereof that binds to Blys and / or APRIL is as set forth in SEQ ID NO: 1.

[0020] Furthermore, the human immunoglobulin is IgG1.

[0021] Furthermore, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO: 4.

[0022] Furthermore, the human immunoglobulin constant region fragment comprises an amino acid sequence having 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% identity to SEQ ID NO: 4.

[0023]

Chemical Formula

[0024] Furthermore, the amino acid sequence of the human immunoglobulin constant region fragment is as set forth in SEQ ID NO: 4.

[0025] Furthermore, the human immunoglobulin constant region fragment comprises an amino acid modification at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 4.

[0026] Furthermore, the human immunoglobulin constant region fragment contains amino acid modifications at positions 1, 2, 3, 4, 5, 6, 7, 8, or more, compared to SEQ ID NO: 4.

[0027] Furthermore, modifications include amino acid substitutions, deletions, or insertions.

[0028] Furthermore, the substitution includes one or more of the following: P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T.

[0029] Furthermore, the insertion is the insertion of 1, 2, 3, 4, 5, 6, 7, 8, or more amino acids at the N-terminus of a human immunoglobulin constant region fragment.

[0030] Furthermore, the insertion involves the insertion of five amino acids at the N-terminus of a human immunoglobulin constant region fragment.

[0031] Furthermore, the insertion is the insertion of five amino acid EPKSS at the N-terminus of a human immunoglobulin constant region fragment.

[0032] Furthermore, the human immunoglobulin constant region fragment contains the amino acid sequence of SEQ ID NO: 5.

[0033] [ka]

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

[0035] [ka]

[0036] 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.

[0037] [ka]

[0038] Furthermore, the amino acid sequence of the TACI-Fc fusion protein is as shown in Sequence ID No. 7.

[0039] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in Sequence ID No. 8.

[0040] [ka]

[0041] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in Sequence ID No. 9.

[0042] [ka]

[0043] Furthermore, drugs that target Blys and / or APRIL include teritacicept, atacicept, or pobetacicept.

[0044] Furthermore, the TACI-Fc fusion protein is teritacicept.

[0045] Furthermore, this method includes administering a therapeutically effective dose of TACI-Fc fusion protein prior to solid organ transplantation.

[0046] Furthermore, this method includes administering a therapeutically effective dose of TACI-Fc fusion protein after solid organ transplantation.

[0047] Furthermore, this method includes administering therapeutically effective doses of TACI-Fc fusion protein before and after solid organ transplantation.

[0048] Furthermore, the patient has donor-specific antibodies (DSAs) against human leukocyte antigens (HLA) prior to treatment.

[0049] Furthermore, this method further includes pre-transplant desensitization therapy to remove or reduce donor-specific antibodies (DSAs).

[0050] Furthermore, desensitization therapy may involve administering one or more of the following for treatment: plasma exchange, immunoadsorption, intravenous immunoglobulin (IVIG), anti-CD20 antibodies, anti-CD38 antibodies, combined antibody decontamination (i.e., removal of antibodies already present or newly generated in the patient), proteasome inhibitors, complement inhibitors, C1 esterase inhibitors (C1-INH), IL-6 / IL-6 receptor inhibitors, Streptococcus pyogenes IgG-degrading enzyme (IdeS), CTLA4-Fc fusion protein, neonatal Fc receptor-targeted inhibitors, and glucocorticoids.

[0051] Furthermore, anti-CD20 antibodies include rituximab and obinutuzumab, anti-CD38 antibodies include daratumumab and ferzaltamai, proteasome inhibitors include bortezomib, carfilzomib and ixazomib, complement inhibitors include eculizumab, C1 esterase inhibitors include Berinert and Cinryze, IL-6 / IL-6 receptor inhibitors include tocilizumab and crazakizumab, CTLA4-Fc fusion protein includes belatacept, and neonatal Fc receptor targeting inhibitors include rozanolixizumab.

[0052] Furthermore, solid organs include, but are not limited to, one or more of the kidneys, heart, liver, lungs, pancreas, skin, stomach, and intestines.

[0053] Furthermore, examples of antibody-mediated rejection reactions among the above include, but are not limited to, antibody-mediated kidney transplant rejection, antibody-mediated liver transplant rejection, antibody-mediated heart transplant rejection, and antibody-mediated lung transplant rejection.

[0054] Furthermore, any one of the above antibody-mediated rejection reactions may include, but is not limited to, one or more of the following: active antibody-mediated rejection (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.

[0055] In some preferred embodiments, antibody-mediated rejection is active antibody-mediated rejection (active ABMR); in other preferred embodiments, antibody-mediated rejection is chronic active antibody-mediated rejection (chronic active ABMR); in other preferred embodiments, antibody-mediated rejection is chronic inactive antibody-mediated rejection (chronic inactive ABMR); and in other preferred embodiments, antibody-mediated rejection is C4d staining without evidence of rejection. Clinically, antibody-mediated rejection may be classified into specific subtypes (i.e., 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, or further determination as any combination of two, three, or four of them) or may remain unclassified (uniformly referred to as antibody-mediated rejection), and it is understood that no specific disease subtype should be interpreted as a limitation of the present invention.

[0056] Furthermore, this method includes administering a therapeutically effective dose of a Blys and / or APRIL-targeting drug to patients with antibody-mediated rejection at stages such as post-transplant, relapse, and after the failure of other treatment methods (the Blys and / or APRIL-targeting drug is more preferably a TACI-Fc fusion protein, and more preferably teritacicept).

[0057] Furthermore, the patient may be an adult or a pediatric patient. In some preferred embodiments, the patient is an adult. In some other preferred embodiments, the patient is a pediatric patient.

[0058] Furthermore, the patient has never previously received treatment for antibody-mediated rejection.

[0059] Furthermore, the patient had previously received treatment regimens for antibody-mediated rejection.

[0060] Furthermore, treatment regimens previously received by the patient for antibody-mediated rejection include, but are not limited to, treatment with one or more of the following: combined antibody removal (i.e., removal of antibodies already present or newly generated in the patient), glucocorticoids, intravenous immunoglobulins, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, and plasmapheresis.

[0061] Furthermore, the method includes administering a therapeutically effective dose of a Blys and / or APRIL-targeted drug to a patient with antibody-mediated rejection in combination with treatment by one or more of the following methods: combined antibody removal (i.e., removal of antibodies already present or newly generated in the patient), glucocorticoids, intravenous immunoglobulins, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, and plasmapheresis.

[0062] Furthermore, the single dose of drugs targeting Blys and / or APRIL is approximately 0.1 to 10 mg / kg, and also 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 Contains 0.5, 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, and 10 mg / kg.

[0063] Furthermore, the single dose of a drug targeting Blys and / or APRIL is 40 to 240 mg, 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.

[0064] Furthermore, the method for detecting the protein content of the above drug is ultraviolet-visible spectrophotometry. The absorbance value of the teritacicept sample at this wavelength is measured based on the fact that the protein has the greatest ultraviolet absorbance at 280 nm. After correcting for the absorbance at 320 nm, the absorbance value at 280 nm is proportional to the protein concentration, and the protein concentration is calculated according to the Lambert-Beer law to calculate the protein content. The formula for calculating the protein content is as follows:

[0065]

number

[0066] In the formula, ε is (mg / ml) -1 ·cm -1 This is the extinction coefficient of teritasicept, A 280 This is the average absorbance of the sample solution at 280 nm. A 280 (Corrected) represents the average absorbance of the sample solution at 280 nm after correction.

[0067] Furthermore, drugs targeting Blys and / or APRIL are administered 1 to 8 times at one-month intervals. That is, the frequency of TACI-Fc fusion protein administration is 1, 2, 3, 4, 5, 6, 7, or 8 times per month.

[0068] Furthermore, drugs targeting Blys and / or APRIL are administered 1 to 8 times at 2-month intervals. That is, the frequency of TACI-Fc fusion protein administration is 1, 2, 3, 4, 5, 6, 7, or 8 times every 2 months.

[0069] Furthermore, drugs targeting Blys and / or APRIL are administered 1 to 8 times at 3-month intervals. That is, the frequency of TACI-Fc fusion protein administration is 1, 2, 3, 4, 5, 6, 7, or 8 times every 3 months.

[0070] Furthermore, the frequency of administration of drugs targeting Blys and / or APRIL is once, twice, or three times per week.

[0071] Furthermore, the frequency of administration of drugs targeting Blys and / or APRIL is once every two weeks, once every three weeks, or once a month.

[0072] Furthermore, the frequency of administration of drugs targeting Blys and / or APRIL is on an as-needed basis.

[0073] Furthermore, drugs targeting Blys and / or APRIL are administered continuously and / or intermittently.

[0074] Furthermore, drugs targeting Blys and / or APRIL are administered at regular intervals.

[0075] Furthermore, drugs targeting Blys and / or APRIL are administered at irregular intervals.

[0076] Furthermore, the administration method of drugs targeting Blys and / or APRIL may be subcutaneous, intramuscular, or intravenous, with the administration site preferably being the thigh, abdomen, or upper arm. In some specific embodiments, the administration method of TACI-Fc fusion protein may be subcutaneous, intramuscular, or intravenous injection.

[0077] Furthermore, the injection sites for drugs targeting Blys and / or APRIL are either the same or different for each injection. In some specific embodiments, the injection site for the TACI-Fc fusion protein is the same for each injection, while in other specific embodiments, the injection site for the TACI-Fc fusion protein is different for each injection.

[0078] The present invention also provides a method for treating a patient with antibody-mediated rejection who has previously received a therapeutic regimen for antibody-mediated rejection, the method comprising: (1) determining whether the patient has previously received a therapeutic regimen for antibody-mediated rejection; and (2) if the patient has previously received treatment for antibody-mediated rejection, administering to the patient with antibody-mediated rejection an effective amount of a Blys and / or APRIL-targeting drug, and further a TACI-Fc fusion protein.

[0079] The Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) exhibit unexpected clinical efficacy and good safety in the treatment of antibody-mediated rejection. Specifically, for antibody-mediated rejection (e.g., active antibody-mediated rejection (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), the Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) exhibit good safety and better efficacy, and have excellent therapeutic potential. In patients with acute antibody-mediated rejection, all Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) exhibited good safety and better efficacy. For patients with chronic active antibody-mediated rejection, all Blys and / or APRIL-targeted drugs (e.g., teritacicept) provided by the present invention demonstrated good safety and better efficacy. For chronic inactive antibody-mediated rejection and C4d staining without evidence of rejection, the Blys and / or APRIL-targeted drugs (e.g., teritacicept) provided by the present invention also demonstrated good safety and better efficacy. For patients with antibody-mediated rejection who have failed to treat with conventional treatment regimens (e.g., plasma exchange, intravenous immunoglobulin, etc.) and antibodies (e.g., Darzalex, i.e., daratumumab), the use of Blys and / or APRIL-targeted drugs (e.g., teritacicept) provided by the present invention can still demonstrate good therapeutic efficacy. The Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) can demonstrate better therapeutic efficacy in treating patients with antibody-mediated rejection (particularly chronic active antibody-mediated rejection) compared to conventional treatment regimens (e.g., plasma exchange, intravenous immunoglobulin, etc.) and antibodies (e.g., Darzalex, i.e., daratumumab).For patients with antibody-mediated rejection, the Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) can demonstrate significant therapeutic effects when combined with other therapeutic means (e.g., conventional treatment regimens, glucocorticoids, plasmapheresis, intravenous immunoglobulins, antibodies, etc.). For patients with chronic active antibody-mediated rejection in which creatinine levels remain high for extended periods, particularly those with chronic active antibody-mediated rejection in which creatinine does not show a clear downward trend after treatment, the Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) show good therapeutic effects. For patients with antibody-mediated rejection who have not responded to conventional treatment regimens (e.g., CellCept, tacrolimus capsules, prednisone tablets, and diltiazem tablets), the Blys and / or APRIL-targeting drugs provided by the present invention (e.g., teritacicept) can still show good therapeutic effects. [Brief explanation of the drawing]

[0080] [Figure 1] The PRA-MFI and locus changes in patient case 5 in Embodiment 1 are shown (Note: In Figure 1, combination therapy with teritacicept was started after the first measurement). [Modes for carrying out the invention]

[0081] Unless otherwise defined, all terms used herein have the same meaning as those generally understood by those skilled in the art. For definitions and terms in the art, experts may specifically refer to *Current Protocols in Molecular Biology* (Ausubel).

[0082] The three-letter and one-letter codes for the amino acids used in this invention are as described in J. Biol. Chem., 243, p3558 (1968).

[0083] In this invention, the term "TACI," i.e., transmembrane activators and CAML interactors, refers to members of the tumor necrosis factor receptor superfamily. In this invention, the term "BLys" refers to B lymphocyte stimulating factors, which exist in two forms, membrane-bound and soluble, specifically expressed on the surface of bone marrow cells, and are members of the TNF ligand superfamily that selectively stimulate B lymphocyte proliferation and immunoglobulin production. In this invention, the term "APRIL" (proliferation-inducing ligand) refers to tumor necrosis factor (TNF) analogs that can stimulate the proliferation of naive B cells and naive T cells in vivo and promote B cell accumulation. APRIL can specifically bind to TACI and BCMA, and after binding, it can prevent APRIL from binding to B cells, thereby inhibiting the APRIL-stimulated naive B cell proliferation response. Furthermore, APRIL can compete with Blys for binding to the receptors (BCMA, TACI).

[0084] The term "TACI-Fc fusion protein" in the present invention refers to a transmembrane activator, calcium regulator, and cyclophyllin ligand intercalator (TACI)-immunoglobulin fusion protein (i.e., a TACI-Fc fusion protein), the TACI-immunoglobulin fusion protein provided by the present invention comprises (i) an extracellular domain of TACI or a fragment thereof that binds to Blys and / or APRIL, and (ii) a fragment of a human immunoglobulin constant domain.

[0085] In the present invention, the term “TACI extracellular domain or fragment thereof that binds to Blys and / or APRIL” 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 Nos. 09 / 569,245 and 09 / 627,206 (the contents of which are incorporated herein by reference), specific fragments of the extracellular domain of TACI that can interact with TACI ligands, and amino acid fragments at positions 13-118 of the extracellular domain of TACI disclosed in Chinese Patent Publication No. CN101323643A.

[0086] Examples of "TACI-Fc fusion proteins" include teritacicept (amino acid sequence: SEQ ID NO: 7), atacicept (amino acid sequence: SEQ ID NO: 8), and pobetacicept (amino acid sequence: SEQ ID NO: 9).

[0087] In the term "human immunoglobulin constant region fragment" as used in the present invention, the immunoglobulin portion is preferably IgG1 and may include a heavy chain constant region such as the human heavy chain constant region. A preferred "human immunoglobulin constant region fragment" of the present invention is an amino acid fragment containing a partial hinge region domain, a CH2 domain, and a CH3 domain. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" according to the present invention is as shown in SEQ ID NO: 4, or includes an amino acid sequence having 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% identity 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.

[0088] The term “treatment” as used in this invention includes, but is not limited to, inhibiting a given disease or condition, for example, stopping the onset of the disease or condition; mitigating a disease or condition, for example, causing regression of the disease or condition; or alleviating symptoms caused by a disease or condition, for example, alleviating, preventing, or treating the symptoms of a disease or condition; or reducing the chance of a disease recurrence or preventing a disease recurrence.

[0089] As used in this invention, the term "remission" refers to the absence of clinical symptoms or signs associated with GPA, MPA, or EGPA at the start or end of treatment.

[0090] As used in this invention, the term "amino acid" is most broadly understood as a general term for a class of organic compounds containing an amino group and a carboxyl group. Preferably, the amino acids involved in this invention include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine, which are the main units that make up proteins in living organisms.

[0091] The three-letter and one-letter codes for amino acids used in this invention are as described in J. Biol. Chem., 243, p3558 (1968). There are multiple numbering schemes for amino acid positions, such as the Kabat numbering system, the EU numbering system, and sequential numbering. In this specification, amino acid positions are numbered using "sequential numbering," and "positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 4" as described in this invention refers to the amino acid at position 3 of SEQ ID NO: 4, the amino acid at position 8, etc., "P3T" as described in this invention refers to the original "P" to "T" mutation in the amino acid sequence at position 3 of SEQ ID NO: 4, "L8P" refers to the original "L" to "P" mutation in the amino acid sequence at position 8 of SEQ ID NO: 4, and so on.

[0092] As an alternative embodiment, the constant region of the immunoglobulin provided by the present invention may be subjected to changes in one or more amino acids, such as substitution (i.e., mutation), addition (i.e., insertion), or deletion.

[0093] In this invention, the term "teritacicept" (or "Tai'ai," as used interchangeably in this invention) refers to a TACI-Fc fusion protein whose INN is teritacicept, and whose amino acid sequence is shown in SEQ ID NO: 7 or at https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932.

[0094] The TACI-Fc fusion protein of the present invention can be administered via any of the following routes, but is not limited to oral, intravenous, intramuscular, intra-arterial, intra-bone marrow, intraperitoneal, intrathecal, intracardiac, transdermal, transdermal, topical, subcutaneous, intranasal, enteral, sublingual, vaginal, or rectal routes.

[0095] In this invention, the term "antibody-mediated rejection" is also referred to as humoral rejection and is an immunological injury resulting from a rejection reaction involving multiple humoral immune effector factors, such as antibodies and complement. It plays a significant pathogenic role in hyperacute rejection, acute rejection, and chronic rejection.

[0096] In this invention, the term "biological agent-based drug therapy regimen" is generally used to describe the treatment of patients who have failed conventional treatment, patients who are resistant to or intolerant to glucocorticoids, patients who have relapsed during glucocorticoid tapering, and patients with refractory or severe cases. Examples of currently promising biologically targeted therapies include: (1) B-cell depletion therapy: For example, non-limitingly, anti-CD20 monoclonal antibodies, anti-CD19 monoclonal antibodies, B lymphocyte activator (BAFF) inhibitors, (2) Targeted T lymphocytes: For example, non-limitingly, abatacept, signaling lymphocyte activator family member 7 (SLAMF7) monoclonal antibody, inducible costimulatory ligand (ICOSL) inhibitor, etc. (3) Examples include cytokine targeting agents (IL-4, IL-5, TNF-α) and intracellular signaling pathway-targeting JAK inhibitors.

[0097] As used in this invention, the terms “inactive / active” refer to the presence of novel, persistent, or worsening clinical symptoms and / or signs associated with GPA, MPA, or EGPA.

[0098] As used in this invention, the term "severe" refers to the presence of life-threatening symptoms or organ-related symptoms (e.g., alveolar hemorrhage, glomerulonephritis, central nervous system vasculitis, etc.).

[0099] In this invention, the term "approximately" is used to indicate that a numerical value includes error variability inherent in the device or method used to determine that value, or variability present between measured samples. Unless otherwise specified or evident from the context, the term "approximately" means within 10% of the reported value (except when the value is greater than 100% of its possible value or less than 0%). When used with a numerical range or sequence, the term "approximately" applies to both ends of the range or each number listed in the sequence, unless otherwise stated.

[0100] Embodiments of the present invention will be described in detail below in combination with the embodiments, but those skilled in the art will understand that the following embodiments are used only to illustrate the present invention and should not be interpreted as limiting the scope of the invention.

[0101] Embodiment 1: Therapeutic effect on real-world cases [Case 1] The patient underwent a deceased donor (DD) kidney transplant and received a triple immunosuppression regimen of oral tacrolimus + mycophenolate mofetil + methylprednisolone for postoperative rejection. Subsequently, due to elevated creatinine levels, the patient received immunoadsorption and immunoglobulin therapy. Non-invasive donor-derived cell-free DNA detection was performed again, showing a rejection risk coefficient of 0.46. In combination with other indicators, the case was considered as acute antibody-mediated rejection.

[0102] Subsequently, teritacicept treatment was administered, and the treatment regimen was as follows: Teritacicept 160 mg is administered subcutaneously once a week for a period of three months. Subsequently, the dose of teritacicept was adjusted to 80 mg of teritacicept administered subcutaneously once a week for a period of two months.

[0103] During teritacicept treatment, the patient's antibody levels showed a slight rebound at 2 months, but continued to decline at 3 months. During teritacicept use, the patient's renal function fluctuated between 120 and 150 umol / L, proteinuria remained consistently negative, there was no hepatotoxicity, and the patient experienced no apparent adverse reactions during injection. These results demonstrate that teritacicept offers good safety and therapeutic efficacy in patients with acute antibody-mediated rejection.

[0104] [Case 2] Following a kidney transplant, the patient received oral tacrolimus plus mycophenolate mofetil for anti-rejection treatment. Subsequently, due to fluctuations in creatinine levels and proteinuria, treatment with Tripterygium glycoside was initiated, but it showed poor efficacy. In combination with other indicators, the case was comprehensively considered as chronic active antibody-mediated rejection.

[0105] Initially, the patient received PP (plasma exchange) + IVIG (intravenous immunoglobulin) in combination with the following daratumumab treatment regimen. Six courses of PP + IVIG treatment were administered, with daratumumab 400 mg administered intravenously after each of the last five treatments. Subsequently, due to DR53 antibody rebound, the treatment regimen was adjusted to monthly intravenous tocilizumab infusions, but the efficacy was not satisfactory in any of these cases.

[0106] Next, the regimen was adjusted to administer teritacicept once a week via subcutaneous injection at a dose of 80 mg each time.

[0107] At the 1-month and 3-month follow-up visits following teritacicept use, the patient's DR53 antibody and MFI levels continued to decrease, renal function remained stable, proteinuria remained persistently negative, there was no hepatotoxicity, no apparent myelosuppression, no significant increase in infection risk, and the patient experienced no apparent adverse reactions during injection. The results indicated the following:

[0108]

number

[0109]

number

[0110]

number

[0111] [Case 3] The patient underwent a deceased donor (DD) kidney transplant, followed by oral administration of a triple immunosuppression regimen of tacrolimus + mycophenolate mofetil + methylprednisolone for anti-rejection therapy. Subsequently, based on elevated creatinine, proteinuria 3+, and in combination with other indicators, the patient was comprehensively considered to have chronic active antibody-mediated rejection.

[0112] Subsequently, immunoadsorption therapy was performed, and the regimen was as follows:

[0113]

number

[0114]

number

[0115] During treatment with teritacicept, the patient's urinary protein levels remained at 2+, renal function remained relatively stable, and the patient experienced no apparent adverse reactions during the injection period without a significant increase in the risk of infection. The results showed the following:

[0116]

number

[0117]

number

[0118] [Case 4] The patient underwent allogeneic kidney transplantation and triple anti-rejection therapy. Subsequently, based on fatigue without apparent trigger, abnormal serum creatinine, proteinuria, and in combination with other indicators, the patient was comprehensively considered to have chronic active antibody-mediated rejection.

[0119] Subsequently, conventional therapies were administered, including CellCept (4 tablets, twice daily), tacrolimus capsules (1 mg, 5 capsules, twice daily), prednisone tablets (5 mg, 5 tablets, once daily), and diltiazem tablets (30 mg, 2 tablets, three times daily), but no significant decrease in creatinine levels was observed.

[0120] The treatment regimen was adjusted to include teritacicept based on the above conventional treatment regimen, and the regimen was as follows:

[0121]

number

[0122]

number

[0123] The patient's creatinine levels remained high (190-200) for a long period, and no significant downward trend was observed after conventional treatment. However, a significant decrease was observed one month after the use of teritacicept, and throughout the administration period, creatinine showed an overall favorable downward trend (down to 162). During this period, renal function remained stable, proteinuria remained stable, and the patient experienced no significant adverse reactions during injection. The results showed the following:

[0124]

number

[0125]

number

[0126]

number

[0127]

number

[0128]

number

[0129] [Case 5] The patient had proteinuria for five years, underwent hemodialysis for more than two years, and preoperative evaluation for kidney transplantation showed PRA was class I positive and class II negative. HLA-specific antibody detection results showed positivity for multiple loci, and combined with other indicators, the patient was comprehensively considered a highly sensitized kidney transplant recipient.

[0130] Conventional treatment in combination with teritacicept, 160 mg / week, subcutaneous injection.

[0131] Following four months of treatment with the above regimen, patients' urinary microalbumin improved, HLA antibodies decreased, and, compared to the first measurement, the MFI values ​​of DSA in the fourth measurement showed an overall downward trend, and the number of DSA-positive loci decreased after treatment with teritacicept. Figure 1 shows the MFI and locus changes of PRA in patients. (Note: In Figure 1, teritacicept was used as adjunctive therapy after the first detection).

[0132] The treatment results showed that teritacicept can effectively reduce HLA antibodies, decrease the number of DSA loci and DSA intensities, improve urinary microalbumin, slow the progression of pathological damage due to antibody-mediated rejection of transplanted kidneys, and have a positive effect on improving the long-term prognosis of transplanted kidneys.

[0133] In summary, the application of teritacicept in patients with antibody-mediated rejection demonstrated better safety and superior therapeutic efficacy compared to existing treatment regimens / modalities. Specifically, for antibody-mediated rejection (e.g., active antibody-mediated rejection (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), teritacicept showed good safety and better efficacy, demonstrating superior therapeutic potential. In patients with acute antibody-mediated rejection, teritacicept showed good safety and better efficacy. In patients with chronic active antibody-mediated rejection, teritacicept showed good safety and better efficacy. For chronic inactive antibody-mediated rejection and C4d staining without evidence of rejection, teritacicept also showed good safety and better efficacy. In patients with antibody-mediated rejection who have failed to respond to conventional treatment regimens (e.g., plasma exchange, intravenous immunoglobulin, etc.) and antibodies (e.g., Darzalex, i.e., daratumumab), teritacicept can still demonstrate favorable therapeutic effects. In highly sensitized kidney transplant recipients, treatment with teritacicept shows favorable therapeutic effects. Compared to conventional treatment regimens (e.g., plasma exchange, intravenous immunoglobulin, etc.) and antibodies (e.g., Darzalex, i.e., daratumumab), teritacicept can demonstrate better therapeutic effects in patients with antibody-mediated rejection (particularly chronic active antibody-mediated rejection). In patients with antibody-mediated rejection, teritacicept in combination with other therapeutic means (e.g., conventional treatment regimens, glucocorticoids, plasma exchange, intravenous immunoglobulin, antibodies, etc.) can show significant therapeutic effects. Teritacicept shows good therapeutic efficacy in patients with chronic active antibody-mediated rejection in which creatinine levels remain high for a long period, particularly in patients with chronic active antibody-mediated rejection in which creatinine levels do not show a clear downward trend after treatment.In patients with antibody-mediated rejection who have failed conventional treatment regimens (e.g., CellCept, tacrolimus capsules, prednisone tablets, diltiazem tablets), teritacicept can still demonstrate good therapeutic efficacy. Conventional therapies combined with teritacicept also show good therapeutic efficacy in the treatment of highly sensitized kidney transplant recipients.

[0134] Embodiment 2 Clinical Trial Study Main purpose 1. To evaluate the efficacy of teritacicept in the treatment or mitigation of antibody-mediated rejection (e.g., chronic active antibody-mediated rejection and / or acute antibody-mediated rejection). 2. Secondary objective: To preliminarily evaluate the safety of teritacicept in the treatment and / or mitigation of refractory antibody-mediated rejection (e.g., chronic active antibody-mediated rejection and / or acute antibody-mediated rejection).

[0135] The foregoing description is merely of preferred embodiments and serves only as an example, and does not limit the combination of features necessary to carry out the invention. The headings provided are not intended to limit the various embodiments of the invention. Terms such as “comprising,” “containing,” and “including” are not intended to limit. Furthermore, unless otherwise stated, the singular form includes the plural form when not modified by a numerical modifier, and “or” means “and / or.” Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0136] All publications and patents referenced herein are incorporated by reference to the present invention. Various modifications and variations of the methods and compositions of the present invention described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the present invention has been described by certain preferred embodiments, it should be understood that the invention described in the claims should not be unduly limited to these particular embodiments. In fact, various variations of the described modes for carrying out the present invention that are apparent to those skilled in the art in the relevant field are intended to be included within the appended claims.

Claims

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

2. The method according to claim 1, wherein the patient is a patient who is scheduled to receive, is currently receiving, or has previously received a solid organ transplant.

3. The method according to claim 1 or 2, wherein the drug targeting Blys and / or APRIL is a TACI-Fc fusion protein.

4. The aforementioned TACI-Fc fusion protein, (i) an extracellular domain or fragment of TACI that binds to Blys and / or APRIL, (ii) The method according to claim 3, comprising a human immunoglobulin constant region fragment.

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

3.

6. The method according to claim 4, wherein the human immunoglobulin is IgG1, or the human immunoglobulin constant region fragment comprises the amino acid sequence shown in SEQ ID NO: 4, or comprises an amino acid sequence having 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% identity with SEQ ID NO:

4.

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

4.

9. The method according to claim 7 or 8, wherein the modification is an amino acid substitution, deletion, or insertion.

10. The method according to claim 9, wherein the substitution includes one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T.

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

12. The method according to claim 7 or 8, wherein 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, wherein 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, wherein the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO:

9.

15. The method according to claim 14, wherein the TACI-Fc fusion protein is teritacicept, atacicept, or pobetacicept.

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

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

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

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

20. The method according to claim 19, further comprising a pre-transplant desensitization treatment to remove or reduce donor-specific antibodies (DSAs).

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

22. The method according to any one of claims 1 to 21, wherein the solid organ includes, but is 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, wherein the antibody-mediated rejection reaction includes, but is not limited to, one or more of antibody-mediated kidney transplant rejection, antibody-mediated liver transplant rejection, antibody-mediated heart transplant rejection, and antibody-mediated lung transplant rejection.

24. The method according to any one of claims 1 to 23, wherein the antibody-mediated rejection reaction includes, but is not limited to, one or more of active antibody-mediated rejection (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.

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

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

27. The method according to any one of claims 1 to 26, wherein the patient has not previously received a treatment regimen for antibody-mediated rejection.

28. The method according to any one of claims 1 to 27, wherein the patient has previously received a treatment regimen for antibody-mediated rejection.

29. The method according to any one of claims 28, wherein the treatment regimen for antibody-mediated rejection previously received by the patient comprises, but is not limited to, treatment with one or more of the following: combined antibody removal (i.e., removal of antibodies already present in the patient or newly generated), glucocorticoids, intravenous immunoglobulins, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, and plasma exchange.

30. The method according to any one of claims 1 to 29, wherein the method comprises administering to a patient having the antibody-mediated rejection a therapeutically effective amount of a drug targeting Blys and / or April in combination with one or more of the following: conventional treatment, antibody removal (i.e., removal of antibodies already present in the patient or newly generated), glucocorticoids, intravenous immunoglobulins, anti-CD20 antibodies, proteasome inhibitors and / or complement blockade, and plasma exchange for treatment, wherein the anti-CD20 antibody is rituximab.

31. The method according to any one of claims 1 to 30, wherein the single 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, wherein the single dose of the drug targeting Blys and / or APRIL is 40 to 240 mg, more preferably 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, or 240 mg, and more preferably 80 mg or 160 mg.

33. The method according to any one of claims 1 to 32, wherein the frequency of administration of the drug targeting Blys and / or APRIL is administration as needed.

34. The method according to any one of claims 1 to 33, wherein the drug targeting Blys and / or APRIL is administered 1 to 8 times every month and / or 1 to 8 times every two months and / or 1 to 8 times every three months, or the frequency of administration 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, wherein the method of administration of the drug targeting Blys and / or APRIL is subcutaneous, intramuscular, or intravenous, or the administration site is the thigh, abdomen, or upper arm.

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