CN115192695A - Application of recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein in NMOSD - Google Patents

Abstract

The invention discloses an application of a recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein in neuromyelitis optica (NMOSD), relating to the technical field of medical treatment, and the technical key points are as follows: the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein is applied to the treatment of neuromyelitis optica lineage diseases. The invention applies the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein to the treatment of the neuromyelitis optica pedigree disease after plasma replacement filtration and pathogenic antibody removal, and has the functions of neutralizing and blocking BLyS and APRIL, thereby inhibiting autoimmune reaction, prolonging NMOSD recurrence interval, and overcoming the problems of lack of accurate intervention on effective treatment targets, high recurrence rate and obvious side effect in the existing treatment of the neuromyelitis optica pedigree disease.

Description

Application of recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein in NMOSD

Technical Field

The invention relates to the technical field of medical treatment, in particular to application of a recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein in NMOSD.

Background

Neuromyelitis optica (NMOSD) spectrum disease is an inflammatory disease of the central nervous system mainly mediated by B cells and AQP4 antibodies, characterized by severe immune-mediated demyelination and axonal injury, mainly involving the optic nerve and spinal cord. The prevalence rate of NMOSD in the population is as high as ten hundred thousand, which mainly affects young women, and the recurrence and disability are the troublesome problems of gradual deterioration of the disease of NMOSD patients. Over 60% of NMOSD patients relapse within the first year of first symptom onset, and over 90% recur within three years. In the course of recurrent attacks, some patients lose mobility or have severe consequences such as blindness. More than 1/3 of the patients are out of business for a long time, and most of the patients cannot take care of the daily life completely. Therefore, reducing NMOSD recurrence while reducing side effects associated with treatment regimens is a significant priority of current NMOSD treatment.

The current treatments for NMOSD vary depending on the stage of the disease. In the acute phase of relapse, initial treatment included high dose intravenous methylprednisolone and plasmapheresis. Remission therapy includes immunosuppressants such as azathioprine and mycophenolate mofetil to reduce relapse. However, the existing glucocorticoid and immunosuppressive agents have obvious side effects, such as femoral head necrosis, blood sugar increase, leucopenia and the like, which cause poor compliance of patients and poor disease prognosis. Plasmapheresis filters pathogenic antibodies but does not inhibit the production of new pathogenic antibodies.

In summary, the problems of the prior art are as follows:

1) The existing NMOSD patient treatment scheme fails to target targeted treatment, lacks accurate intervention on effective treatment targets and still has high recurrence rate.

2) The existing NMOSD patient treatment scheme has obvious side effects, so that the patient cannot use the NMOSD patient with poor compliance, and the treatment effect is influenced.

Therefore, the present invention is directed to solving the above problems by providing a recombinant human B lymphocyte stimulator factor receptor-antibody fusion protein for use in NMOSD.

Disclosure of Invention

The invention aims to solve the problems and provides an application of a recombinant human B lymphocyte stimulator receptor-antibody fusion protein in NMOSD, the recombinant human B lymphocyte stimulator receptor-antibody fusion protein is applied to the treatment of neuromyelitis optica pedigree diseases after plasma replacement filtration and removal of pathogenic antibodies, and the fusion protein has the effects of neutralizing and blocking BLyS and APRIL, so that autoimmune reaction is inhibited, NMOSD recurrence interval is prolonged, the problems of lack of effective target intervention, high recurrence rate and obvious side effect in the existing treatment of neuromyelitis optica pedigree diseases can be solved, and meanwhile, the disease indications of the recombinant human B lymphocyte stimulator receptor-antibody fusion protein are increased.

In order to achieve the purpose, the technical scheme of the invention is as follows: the application of the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein in NMOSD is used for treating the neuromyelitis optica lineage diseases.

Further, the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein is used for preparing a tay xipu medicament for injection.

Furthermore, the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein can inhibit autoimmune diseases by blocking B lymphocyte proliferation.

The action mechanism is as follows:

b lymphocyte stimulator (BLyS), also called B cell activating factor (BAFF), is an important regulatory factor in promoting the maturation and differentiation of B cells, and the transformation of immune types. The B cells start from primitive bone marrow hematopoietic stem cells, and the developmental differentiation process comprises progenitor B cells, precursor B cells, transitional stage B cells, mature B cells and the like, and the B cells are activated into effector B cells after meeting external antigens in the body, secrete antibodies and participate in humoral immunity of the body. In this process, the regulation of B cell differentiation is directly linked to the balance of the body's autoimmunity. BLyS is a member of the TNF superfamily, consisting of 285 amino acids, and is a type II transmembrane protein, and receptors include BCMA (B cell signalling), BAFF-R (BR 3), and TACI (transmembrane activator and calcium-modulator and cyclophilin ligand inter). BLyS has strong homology with another TNF family protein proliferation-inducing ligand (APRIL), in which BCMA and TACI of three receptors of BLyS can bind to both proteins. The BLyS receptor is mainly expressed on the surface of most lymphocytes, and after the BLyS is combined with the receptor, on one hand, the BLyS receptor promotes the maturation and the differentiation of B cells, also can regulate the types of B cells for transforming and secreting antibodies, and on the other hand, can also regulate T cell immune response through the presentation of self antigens. Elevated levels of BLyS can be measured in many autoimmune patients, such as SLE and NMOSD. Because the role of B cells in the pathogenesis of NMOSD is gradually valued, the promotion of clinical application is only a matter of time when there is a clear target. Therapeutic approaches aimed at the abnormal proliferation of B cells as therapeutic targets have gradually gained attention in NMOSD treatment. However, the treatment scheme using BLyS and APRIL as targets is not applied to NMOSD, and the inventor of the application detects the change of BLyS and ARPIL expression level in peripheral serum level of a plurality of NMOSD patients and finds that the expression level of the BLyS and the ARPIL is obviously increased in the acute stage of the disease of the patients. Whereas APRIL was at a higher level throughout the disease course than BLyS, APRIL decreased gradually after the disease entered remission, suggesting that while APRIL co-receptors with BLyS, BLyS was present in vivo at a greater time and extent, and was more strongly associated with the onset of the disease (fig. 1). The data detected by the inventors of the present application are also consistent with those reported in the literature.

The recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein (Tatasypu) is a soluble protein which is obtained by artificially fusing an extracellular segment of a TACI receptor and a human IgG FC fragment through biological engineering, can specifically bind to a BLyS and APRIL common receptor TACI, and is also an artificially synthesized protein immunosuppressant newly developed in recent years. Is a novel targeted therapeutic drug aiming at B cells and T cells. The action mechanism is that the TACI extracellular soluble part of the test drug can neutralize two key regulators BLyS (B lymphocyte stimulating factor) and APRIL (proliferation inducing ligand) of lymphocyte development and maturation, and efficiently block the interaction between BLyS and APRIL and the receptors thereof, and the TACI receptors are positioned on CD27+ memory B cells and plasma cells, so the TACI extracellular soluble part can effectively block the proliferation of B lymphocytes and has the function of inhibiting autoimmune diseases. The inventor of the application proves that the taixipu can obviously reduce clinical scores of Experimental Autoimmune Encephalomyelitis (EAE) mice, relieve inflammatory infiltration and demyelination of the central nervous system, and inhibit proliferation of activated B cells in the EAE mice through in vivo experiments (figures 2-4). Because it can inhibit the induced proliferation of BLyS and APRIL at the same time, it has been proved that it has curative effect in other autoimmune diseases such as systemic lupus erythematosus. However, no relevant research report is found in the autoimmune diseases such as NMOSD, which is definitely related to the abnormal proliferation of B cells. Plasmapheresis has been shown to be effective in the treatment of acute phase nmods, which filters out major pathogenic factors, such as AQP4 antibodies. Can eliminate the existing autoimmune antibody in blood circulation, and can inhibit the generation of the antibody by combining the Taixipu targeted drug, thereby prolonging the plasma replacement treatment effect, and treating and effectively preventing the recurrence of NMOSD.

Compared with the prior art, the beneficial effect of this scheme: the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein is applied to the treatment of the neuromyelitis optica lineage disease after plasma replacement filtration and pathogenic antibody removal, has the effect of neutralizing and blocking BLyS and APRIL, so that the autoimmune reaction is inhibited, the recurrence interval of NMOSD is prolonged, the problems of lack of effective target intervention, high recurrence rate and obvious side effect in the existing treatment of the neuromyelitis optica lineage disease can be solved, and meanwhile, the disease indications of the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein are increased.

Drawings

FIG. 1 is a graph of the expression levels of BLyS and APRIL in different groups in an example of the invention;

FIG. 2 is a graph of EAE clinical scores for different groups in an example of the invention ([ p ] 0.01, mann-Whitney U test);

FIG. 3 is a graph of significant reduction in inflammatory infiltration of the central nervous system and loss of myelination by etanercept in examples of the present invention;

FIG. 4 is a graph of significant inhibition of activated B cell proliferation in the peripheral immune system by tai xipu in an example of the invention;

FIG. 5 shows NMOSD patient enrollment and follow-up in an embodiment of the invention;

FIG. 6 shows the number of NMOSD patient episodes before and after enrollment in accordance with an embodiment of the invention;

FIG. 7 shows the likelihood of recurrence of NMOSD patients in a group according to an embodiment of the invention;

FIG. 8 is a diagram of an exemplary recombinant human B-lymphocyte stimulating factor receptor-antibody fusion protein.

Detailed Description

In order to make the technical solutions of the present invention better understood, the technical solutions of the present invention will be described in further detail below with reference to the embodiments of the present invention and the accompanying drawings. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict. The present invention will be described in detail with reference to examples.

Example (b):

the invention uses the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein for treating the neuromyelitis optica lineage diseases.

The recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein is used for preparing a tay xipu medicament for injection.

The recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein realizes the effect of inhibiting autoimmune diseases by blocking the proliferation of B lymphocytes.

The following are specific contents of the experiments of the examples of the present invention:

1. preclinical testing

1) Expression levels of BLyS and APRIL in the acute and chronic stages of NMOSD

NMOSD diagnosis meets 2015 international consensus diagnosis standard of neuromyelitis optica (NMOSD), and patients are 18-75 years old. In the acute stage of NMOSD disease, new symptoms of neurological deficit exist within 30 days before screening, or the original symptoms are aggravated, and the symptoms last for at least 24 hours without concomitant fever. In the chronic period of NMOSD disease, more than or equal to 2 relapses appear 12 months before screening, no new symptoms of neurological deficit, no aggravation of original symptoms and no fever phenomenon exist within 30 days before screening. The normal control group has no NMOSD and progressive nervous system lesion irrelevant to the NMOSD, no new symptoms of neurologic impairment, no aggravation of original symptoms and no fever phenomenon within 30 days before screening. Subject baseline information is shown in table 1 below.

TABLE 1 subject Baseline information

By extracting peripheral serum BLyS and APRIL of three groups of subjects, the BLyS is obviously increased in the acute stage patients and the remission stage patients compared with the normal group. The average concentration of BLyS in the acute stage group is 101.1 +/-12.67 pg/ml; the average concentration of BLyS in the remission stage group is 98.59 +/-9.66 pg/ml; the concentration of healthy control group was 86.31 ± 9.39pg/ml (fig. 1A). APRIL was found in the highest concentration in the serum of patients in the acute phase, whereas there was no significant difference between the remission phase and the healthy group. The concentration in the acute phase is 104.5 +/-12.16 ng/ml; the concentration in the remission period is 85.11 +/-24.12 ng/ml; healthy controls were 83.38. + -. 19.48ng/ml (FIG. 1B).

Compared with the normal control group, BLyS and APRIL are obviously increased in the NMOSD acute stage. BLyS and APRIL are the target of taixipu, and therefore taixipu has a target-targeting therapeutic target in the acute phase of NMOSD.

2) Taitasiplet alleviates clinical symptoms in NMOSD model animals

By MOG _35-55 Mouse NMOSD model was induced. Through MOG _35-55 After MOG is immunized by MOG35_55, mice generally begin to develop diseases on 8 th to 10 th days, and enter a disease peak period on 14 th to 20 th days. After grouping, the mice are treated according to different doses on the 16 th day of the inflammation peak period, intraperitoneal injection is carried out every other day, a negative control group is injected with normal saline for control, a positive control group is injected with FTY-720 for control, EAE symptom scoring is carried out every day, and the treatment lasts until the 35 th day after immunization. Warp beamAfter treatment, the clinical score of the taituxipu group (fig. 2) was significantly reduced, and the effect of FTY-720 in the positive control group was similar, and the results are shown in fig. 2. It can be noted that clinical scores of each experimental group began to decline after administration, there was fluctuation in the subsequent clinical scores, and the clinical scores of the higher dose groups (10 mg/kg,3.33 mg/kg) declined slowly in the lower dose groups (0.35 mg/kg,1.105 mg/kg), but all reached about 0.5-1 point in the chronic phase. The results show that the Taitasipin can obviously improve the clinical score of EAE and relieve the symptoms of weakness of hind limbs of EAE in vivo level.

3) Taitasipin significantly reduces central nervous system inflammatory infiltration in NMOSD model animals

The EAE mice enter the inflammation elimination period at 35 days of immunization, the spinal cord and lumbar enlargement segments are fixedly embedded after the mice are sacrificed, HE staining is carried out after slicing, and 1mm of white matter area 10 is randomly taken under a light lens quadruple lens ² The area of (2) was subjected to inflammatory cell counting (unit: pieces/mm) ² ) The average number of inflammatory cells per square millimeter was calculated for statistical analysis. After treatment with tatarsopril, there was a significant decrease in central nervous system inflammatory infiltration (fig. 3a, b). It can also be seen from fig. 3 that there was more inflammatory cell infiltration in the peripheral white matter of spinal cord in the mice in the model group, compared to the significant decrease in inflammatory cell infiltration in spinal cord after the tai xipu treatment, the quantitative score of inflammatory infiltration in the experimental group was decreased.

On the 35 th day of immunization, EAE mice enter an inflammation regression period, spinal cord lumbar enlargement segments are taken to be fixedly embedded after the mice are sacrificed, LFB staining is carried out after slicing, and in a typical model animal group, large-area myelin sheath loss of white matter areas around the spinal cord of the mice is also a pathological basis directly related to symptoms such as hind limb weakness and the like observed in mouse behaviors. After treatment, the demyelination of the mouse is obviously better, only a few spot-shaped small demyelinations of the surrounding cortex remain, and after quantitative analysis (the quantitative analysis is a specific value and no unit), the demyelination of the mouse can be improved to different degrees by a drug treatment group, wherein the most obvious improvement effect is achieved by 3.33mg/kg (fig. 3C and D).

The results show that the tylosin is capable of remarkably reducing the central nervous system inflammation infiltration of the NMOSD model animal.

4) Taitascip can obviously inhibit B cell proliferation activated in peripheral immune system of NMOSD model animal

Taking the spleen of a mouse at the 25 th day after immunization, preparing a single cell suspension, incubating a corresponding flow antibody, and detecting by a flow cytometric fluorescence sorting technology. After detection and analysis, the animal model is found out

2. Clinical trial

1) Design of research

This is a single-center, single-arm, open label study to evaluate the safety and efficacy of plasmapheresis in combination with tataxicon in treating NMOSD patients

2) Study object

NMOSD diagnosis meets 2015 international consensus diagnosis standard for neuromyelitis optica (NMOSD). Patients are aged 18-75 years old; more than or equal to 2 times of relapse (including the relapse in the acute phase) appear 12 months before screening, the state of illness is in the acute phase, namely there is new symptom of neurologic impairment before screening 30 days, or the original symptom is aggravated, the symptom lasts for at least 24 hours, and there is no accompanying fever phenomenon. Subjects were not able to be included if they had the following: (1) Neurological lesions with progressive deterioration not associated with NMOSD; (2) Patients with active hepatitis or serious liver disease and history (liver function test > 2 times of the normal upper value); patients who are HBsAg-surface antigen positive are not allowed to be selected, but only anti-HBc single positive patients are subjected to HBV-DNA quantitative detection, and if the HBV-DNA quantitative detection is negative, the patients are not considered to be excluded; (3) Patients currently suffering from renal insufficiency (including acute kidney injury and chronic kidney disease, estimated creatinine clearance calculated according to the Cockcroft-Gault equation < 60 mL/min); (4) Pregnant women, lactating women, and patients with a birth schedule of approximately 48 weeks; (5) Patients who had been administered any clinical trial drug 28 days before enrollment or within a 5-fold half-life of the trial drug (whichever is shorter); (6) post splenectomy; (7) allergic reaction: patients with a history of allergy to parenterally administered contrast agents, human biologics; (8) Patients with severe psychotic symptoms who are not clinically compliant; (9) patients who cannot undergo magnetic resonance imaging examinations; (10) Patients who had used rituximab or mitoxantrone 3 months prior to enrollment.

3) Research method

All patients received 3 plasmapheresis treatments. The subcutaneous injection of tacrolimus drug was then given 14 days after the group, at a dose of 240mg, once a week (at least 48 hours apart), for a total of 46 times. Intravenous administration of glucocorticoids was not allowed during the study; other immunosuppressive agents such as tripterygium wilfordii, cyclosporine, methotrexate, mitoxantrone, cyclophosphamide, azathioprine, tacrolimus, leflunomide, mycophenolate mofetil, teriflunomide and the like are forbidden; other biological immunosuppressants such as rituximab are forbidden; hematopoietic stem cell transplantation, lymph irradiation, and immunoglobulin injection are prohibited.

During the study, subjects were interviewed at weeks 4, 12, 24, and 48 after enrollment, and were scored by 2 professional neurologists for EDSS, OSIS, hauser ambulation index, recording symptom changes, concomitant medication, and adverse events, and assessing whether there was a relapse. The post-exit trial was recorded if the subject had relapsed during the trial. The definition of recurrence must meet the following 4 conditions: (1) the abnormal symptoms of the new nervous system appear, or the original symptoms worsen; (2) symptoms last at least 24 hours; (3) more than 30 days from the last recurrence; (4) no concomitant fever, body temperature < 37.5 ℃, or no known infection. Blood-urine tests, including virological tests, blood routine, blood biochemistry, pregnancy tests and immunoglobulin, complement, lymphocyte subpopulation counts and urine routine in women, etc., will be performed at baseline, at weeks 4, 12, 24, 48, or at relapse after enrollment.

Visual Evoked Potentials (VEPs) record the latency and amplitude of evoked potentials P100. The blood AQP4 antibody and BLyS, april assays were performed at baseline, 24 and 48 weeks post-enrollment. The AQP4 antibody is detected by a cell-based transfection immunofluorescence (CBA) method to detect titer, and BLyS and April are detected by an enzyme-linked immunosorbent assay (ELISA) method to detect the titer. Magnetic resonance imaging of the head, eye, spinal cord is performed at baseline, at week 48 after enrollment, or at relapse, and 3T magnetic resonance is used to record the number of low-signal lesions on the T1-weighted image (T1 WI), the number of high-signal lesions on the T2-weighted image (T2 WI), the number of gadolinium-enhanced T1WI lesions, and the like. The magnetic resonance report was interpreted by a specialist in imaging department at the affiliated medical institution of Shanghai university of transportation, shanghai school of medicine.

Safety assessments, including virological examinations, complete blood counts, serum biochemistry, urine routine and electrocardiogram were performed at baseline, weeks 4, 12, 24 and 48 or at relapse. Chest computed tomography (X-ray) scans were performed at weeks 24 and 48 after enrollment. Other safety assessments include physical examination, adverse Event (AE) records at each study visit, and the like.

The primary endpoint of this study was the time to first relapse after enrollment. The secondary endpoints included: the number of attacks in one year before and after the group is entered, EDSS score, OSIS score, hauser walking index score, the number of magnetic resonance imaging focuses, optical Coherence Tomography (OCT) examination of retinal nerve fiber layer thickness change, latency and amplitude of Visual Evoked Potential (VEP) P100, AQP4 antibody titer, igG, igM, igA, complement C3, C4, lymphocyte subpopulation absolute value, BLyS, april and other immune indexes. And simultaneously recording adverse events for safety evaluation. The evaluation was made according to the criteria of common terminology evaluation criteria for adverse events (CTCAE 4.03).

4) The first research result is as follows: basic characteristics of the subject

A total of 10 NMOSD subjects were screened and 8 subjects were enrolled in compliance with the inclusion criteria (as shown in FIG. 5). One patient was rejected by withdrawal of informed consent, and another patient was rejected by a history of severe liver disease (more than twice the normal value in liver function tests). Of the 8 patients, the female accounted for 87.5% (n = 7) and the male accounted for 12.5% (n = 1). The age of the subjects in the cohort varied from 24 to 66 years with a median age of 53 years. All patients were serum positive for AQP4 antibody. Patient characteristics are listed in table 1. Three patients had not received or could not tolerate relapse prevention therapy prior to enrollment. 5. The patients were treated with immunosuppressive agents prior to enrollment. All 8 patients had a high recurrence rate before treatment, with a 3 (2-7) recurrence frequency and a course of 1.20 (0.14, 18.43) years before group entry (as shown in table 2 below).

TABLE 2 previous treatment regimen and number of attacks before and after enrollment

AZA, azathioprine; MMF, mycophenolate mofetil; PDN, prednisone, difference in number of attacks before and after entering the group.

5) And a second research result: reduction in the number of relapses in a subject

Five subjects had no seizures during the 48 week treatment period. Subject No. 4 relapsed 234 days post-enrollment, and subject No. 9 relapsed 45 days post-enrollment. Compared with before-group, the time of first recurrence after group entry is longer than the previous recurrence interval, and the number of annual recurrences is reduced (p <0.001, power of test = 1). (see table 2, fig. 6, fig. 7). After 48 weeks of treatment, the EDSS score improved from 3.5 (2.5-4.5) to 3 (1-4). The motion and sensation scores of the OSIS scores are also improved. The median score of vision remained stable until 1 patient with normal vision exited after visit 4. The Hauser walk index score dropped from 1.0 (0.0-3.0) to 0.0 (0.0-1.0) points.

6) And (3) research results are as follows: neural image and function improvement of subject

8 subjects received an MRI examination during baseline. 5 patients without relapse completed MRI examination at week 48: 1) Brain: none of the 8 subjects had a high signal lesion in the skull. 2) Optic nerve: 6. there were no acute changes in NMOSD at the end of the clinical trial in 5 subjects with a focal of optic nerve enhancement high signal at baseline and no worsening of visual symptoms. 3) Spinal cord: spinal cord T1-enhanced lesions regressed at week 48, and the number of T2WI high signal intensities also declined from 1.5 at baseline (0,3) to 1 at week 48 (0,2). The number of T2WI high signal foci involvement spinal segment remained unchanged. In the aspect of optic nerve function, the thickness of a retinal nerve fiber layer and the latency and amplitude of VEP 100 waves in OCT tend to be stable.

7) The research conclusion is that:

the study first applied plasmapheresis in combination with tataxicon to the acute relapsing phase of recurrent NMOSD. The plasma replacement filtration removes pathogenic factors, and the taitasipin is used after plasma replacement filtration removes pathogenic antibodies, and neutralizes and blocks the effects of BLyS and APRIL, thereby inhibiting autoimmune reaction and prolonging NMOSD recurrence interval. In our study, the time to first relapse of NMOSD patients was prolonged and the residual disease score was reduced, indicating that plasmapheresis in combination with etanercept may have a certain effect in preventing NMOSD relapse while avoiding the side effects of large dose of glucocorticoid use. Adverse events occurred during this study were mild, quickly alleviated, and no serious adverse events occurred, indicating that the safety of plasma replacement in combination with taixipu was adequate. This study suggests that plasmapheresis in combination with tatarstat may be an effective treatment option for patients with recurrent NMOSD.

In conclusion, the application study of the combination of the plasmapheresis and the taixipu in the recurrent NMOSD is the brand new treatment method, and the adaptation diseases of the taixipu are widened. This exploratory study showed that plasmapheresis in combination with tatarstat was well tolerated in NMOSD patients, showing a trend in extending the relapse interval and reducing the number of annual relapses in NMOSD patients.

In this example, figure 1 shows the expression levels of BLyS and APRIL in different groups. FIG. 1 (A) is the expression level of BLyS in the acute, remission, healthy control group; (B) The expression level of APRIL in the acute stage, the remission stage and the healthy control group is shown. Data are shown as mean ± SD, # p <0.05, # p <0.01, # p <0.001, mann-Whitney U-test.

Figure 3 is a graph showing that tatarsoprol significantly reduced central nervous system inflammatory infiltration and demyelination. After the NMOSD model mouse is sacrificed on day 35 after immunization, (a) taking the line HE staining of the spinal cord tissue at the site of lumbar enlargement, typical HE staining results (quadruplicate lens, twenty-fold lens), scale bar =100 μm; (B) HE staining quantitative analysis. (C) Taking a spinal cord tissue line LFB staining at the waist enlargement part, and obtaining a typical LFB staining result (a quadrupling mirror and a twenty-fold mirror) with a scale bar =100 μm; (D) quantitative analysis of LFB staining. Data are shown as mean ± SD, # p <0.01, # p <0.001, # p < o.0001; one-way ANOVA with Dunnett's post hoc test.

Figure 4 is a graph showing that tatarsoprol significantly inhibited activated B cell proliferation in the peripheral immune system. Wherein, (A, B) CD19+ CD23+ B cell typical flow chart and quantitative analysis; (C, D) CD19+ CD21/35+ B cells for typical flow mapping and quantitative analysis. Data are shown as mean ± SD, # p <0.01, # p <0.001, # p < o.0001; one-way ANOVA with Dunnett's post hoc test.

The above specific embodiments are merely illustrative of the present invention, and are not restrictive, and those skilled in the art can modify the embodiments without inventive contribution as required after reading the present specification, but only protected by the patent laws within the scope of the claims of the present invention.

Claims (3)

1. The application of the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein in NMOSD is characterized in that: the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein is used for treating the neuromyelitis optica lineage diseases.

2. The recombinant human B lymphocyte stimulator factor receptor-antibody fusion protein according to claim 1 for use in NMOSD, wherein: the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein is used for preparing a tay xipu medicament for injection.

3. The recombinant human B lymphocyte stimulator factor receptor-antibody fusion protein according to claim 1 for use in NMOSD, wherein: the recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein realizes the effect of inhibiting autoimmune diseases by blocking the proliferation of B lymphocytes and the maturation of T lymphocytes.

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