CN115645537A - Application of FcRn inhibitor in preparation of medicine for inhibiting recurrence of autoimmune disease - Google Patents
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Abstract
The invention provides application of an FcRn inhibitor in preparation of a medicine for inhibiting recurrence of autoimmune diseases, and belongs to the field of pharmacy. The invention discovers for the first time that the FcRn target is closely related to the recurrence of ulcerative colitis, and the anti-FcRn antibody is given to antagonize the FcRn function, so that the clearance of serum ANCA of a rat can be accelerated, the formation of colon NET can be reduced, the ulcerative colitis can be effectively treated, and the recurrence of the ulcerative colitis can be effectively inhibited; however, SASP, which is a clinical drug for treating ulcerative colitis, does not antagonize FcRn function and does not inhibit the recurrence of ulcerative colitis. Therefore, the FcRn inhibitor including the anti-FcRn antibody has wide application prospect in preparing the medicine for inhibiting the recurrence of autoimmune diseases such as ulcerative colitis.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to an application of an FcRn inhibitor in preparation of a medicine for inhibiting recurrence of autoimmune diseases.
Background
Autoimmune diseases refer to diseases caused by the body's immune response to autoantigens resulting in damage to its tissues or organs. Autoimmune diseases are classified into: (1) Organ-specific autoimmune diseases, characterized in that pathological lesions and dysfunctions of tissues and organs are limited to only one organ to which antibodies or sensitized lymphocytes are directed, such as Ulcerative Colitis (UC), crohn's Disease (CD), and the like; (2) Systemic autoimmune diseases, which are systemic multiple organ damages caused by the reason that antigen-antibody complexes are widely deposited on blood vessel walls, such as systemic lupus erythematosus, rheumatoid arthritis and the like.
UC is a chronic nonspecific inflammatory bowel disease, and pathological changes are mostly seen in large intestine mucous membrane and submucosa and are distributed in a continuous and diffuse manner. The clinical manifestations are abdominal pain, persistent or recurrent diarrhea, mucopurulent bloody stool, malabsorption, etc. The clinical treatment process of UC has a long course, patients may relapse due to the stimulation of various physiological and pathological factors or environmental factors, and the problem that UC is easy to relapse also becomes a key factor that UC is difficult to control or cure. At present, the understanding about the pathogenesis of UC mainly considers that UC is induced by inflammatory reaction of intestinal mucosa due to the influence of intestinal flora disorder, autoimmune regulation imbalance, genetic factors and the like. The autoimmune disorder is one of the key factors for the generation and development of UC, and a large amount of neutrophil infiltration appears in the colon part with pathological inflammation in the early stage of the UC generation, and a phenomenon of Neutrophil Extracellular Trap (NET) is generated. NET formation is considered to be a key factor in the persistence of UC inflammation. NET is generated to break neutrophils, release various inflammatory factors and neutrophilic particles, such as Myeloperoxidase (MPO) and protease 3 (PR3) and the like, which are respectively combined with DNA in chromatin to form a complex with antigenicity, the complex is then recognized by abnormally activated T cells, a cellular immune pathway is activated to generate autoantibodies, namely anti-neutrophil cytoplasmic antibodies (ANCA), and the ANCA can be combined with the MPO or PR3 on the surface of the neutrophil membrane to activate and chemotaxis, so that NET-ANCA circulation is repeatedly formed. ANCA, as an intermediate link in maintaining this cycle, is clinically thought to be highly correlated with UC disease progression and risk of recurrence.
ANCAs belong to the IgG class of autoantibodies, the transport of which in vivo is mediated primarily by the neonatal Fc receptor (FcRn). The physiological function of FcRn is exerted by binding to its ligand, which is mainly known as IgG and serum albumin, and after binding to the Fc fragment of IgG or the DIII domain of albumin, fcRn can be protected from lysosomal degradation, thereby significantly prolonging its half-life. Therefore, fcRn plays a crucial role in the in vivo clearance of autoimmune or pathogenic IgG. At present, the research on FcRn as a target for treating autoimmune diseases is concerned by applying the effect of FcRn on the half-life of IgG, and part of protein polypeptide FcRn inhibitors enter the clinical experiment stage.
The Chinese patent application No. 2016800405166 discloses a humanized affinity matured anti-FcRn antibody with a specific sequence and the use of the anti-FcRn antibody with the specific sequence in the treatment of autoimmune diseases including ulcerative colitis, crohn's disease, systemic lupus erythematosus and rheumatoid arthritis. However, the treatment of autoimmune diseases and the suppression of recurrence of autoimmune diseases are two distinct effects. For the treatment of UC, the frequency of disease recurrence in patients is more important factor in selecting treatment regimens (see "(consensus opinion on diagnosis and treatment of inflammatory bowel disease (2018, beijing) section interpretation of ulcerative colitis, hui-bai, 11/5/2018, volume 33, phase 11.) at present, drugs that can effectively inhibit the recurrence of autoimmune diseases including ulcerative colitis are only rarely reported and cannot meet clinical needs.
Disclosure of Invention
The invention aims to provide application of an FcRn inhibitor in preparing a medicament for inhibiting the recurrence of autoimmune diseases.
The invention provides application of an FcRn inhibitor in preparing a medicament for inhibiting the recurrence of autoimmune diseases.
Further, the autoimmune diseases include ulcerative colitis, crohn's disease, systemic lupus erythematosus, rheumatoid arthritis.
Further, the autoimmune disease is ulcerative colitis.
Further, the medicament is a medicament for treating autoimmune diseases.
Further, the drug is a drug that reduces serum ANCA levels, a drug that reduces serum indices of inflammation, and/or a drug that reduces colonic NET formation.
Further, the inflammation index includes TNF-alpha, IL-1 beta and CRP.
Further, the FcRn inhibitor is a small molecule FcRn inhibitor or a protein polypeptide FcRn inhibitor.
Further, the protein polypeptide FcRn inhibitor is an anti-FcRn antibody.
Furthermore, the medicament is a preparation prepared by taking an FcRn inhibitor as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the preparation is an oral preparation, an injection preparation or a transdermal administration preparation.
In the present invention, fcRn is an abbreviation for neonatal Fc receptor (neonatal Fc receptor).
An FcRn inhibitor refers to a drug capable of targeted inhibition/antagonism of FcRn function or expression, and an anti-FcRn antibody is a known FcRn inhibitor.
According to the invention, the FcRn target point is closely related to the recurrence of ulcerative colitis for the first time, and the anti-FcRn function is antagonized by intravenous injection of anti-Fc-mAb, so that the clearance of rat serum ANCA can be accelerated, the formation of colon NET can be reduced, the ulcerative colitis can be effectively treated, and the recurrence of the ulcerative colitis can be effectively inhibited; however, SASP, which is a clinical drug for treating ulcerative colitis, does not antagonize FcRn function and does not inhibit the recurrence of ulcerative colitis.
The FcRn inhibitor including the anti-FcRn antibody has wide application prospect in preparing the medicine for inhibiting the recurrence of autoimmune diseases such as ulcerative colitis.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1: animal experimental roadmap.
FIG. 2: serum IgG concentration measurement results of NC group, UC group, SASP group, FC group, and DFC group. * /#/Δ and #/##represent p <0.05 and p <0.01, respectively; n.s means that the difference is not statistically significant (p > 0.05).
FIG. 3: the results of measurement of serum ANCA concentrations in the NC group, UC group, SASP group, FC group, and DFC group. * /#, # and # represent p <0.05, respectively, p-woven fabrics 0.01, p-woven fabrics 0.001; n.s means that the difference is not statistically significant (p > 0.05).
FIG. 4: NC group, UC group, SASP group, FC group, DFC group colon NET related protein (NAPs, including PAD4, MPO and NE). The expression level of NAPs and the expression level of the internal reference protein GAPDH are normalized to obtain the relative expression quantity. Data are presented as mean ± standard deviation (n = 6). #, and # are respectively represented by p <0.05, p- < -0.01, p < -0.001; n.s means that the difference is not statistically significant (p > 0.05).
FIG. 5: (a) Statistical analysis results of rat DAI and HS in NC group, UC group, SASP group, FC group, DFC group, data are expressed as mean ± standard deviation (n = 6). # and #/#indicatep <0.01 and p <0.001, respectively; n.s means that the difference is not statistically significant (p > 0.05). (b) And (c), (d), (e) and (f) are representative histopathology images of rats of NC, UC, SASP, FC and DFC groups in sequence.
FIG. 6: the serum TNF-alpha concentrations of rats in the NC group, the UC group, the SASP group, the FC group and the DFC group. Data are presented as mean ± standard deviation (n = 6). * /#, #/# Δ Δ and # Δ represent p <0.05, respectively, p-woven fabrics 0.01, p-woven fabrics 0.001; n.s means that the difference is not statistically significant (p > 0.05).
FIG. 7: the serum IL-1 beta concentration of rats in NC group, UC group, SASP group, FC group and DFC group. Data are presented as mean ± standard deviation (n = 6). * /#, # and # represent p <0.05, p-woven fabrics 0.01, respectively, p-woven fabrics 0.001; n.s means that the difference is not statistically significant (p > 0.05).
FIG. 8: serum CRP concentrations in rats of NC group, UC group, SASP group, FC group, and DFC group. Data are presented as mean ± standard deviation (n = 6). * /#, # and # represent p <0.05, respectively, p-woven fabrics 0.01, p-woven fabrics 0.001; n.s means that the difference is not statistically significant (p > 0.05).
FIG. 9: serum concentrations of ANCA (a), TNF-. Alpha. (b), IL-1. Beta. (c), CRP (d) at sampling points of N3 and N4 in UC group, SASP group, FC group, and DFC group. Data are presented as mean ± standard deviation (n = 6).
Diamond-solid and diamond-solid represent p <0.05 and p <0.01, respectively; n.s means that the difference is not statistically significant (p > 0.05).
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1: in vivo experiments for inhibition of ulcerative colitis recurrence by anti-rat FcRn antibodies
1. Experimental medicine
Anti-rat FcRn antibody (anti-Fc-mAb) was purchased from Bio X cell, usa under the following commercial information: 4.32mg/mL (1.2 mL), cat #: BE0222, lot #:680320D1.
Sulfasalazine (SASP), a clinical drug for the treatment of ulcerative colitis, was purchased from milnacle biotechnology limited with a purity of >97%, cas:599-79-1, lot.
2. Experimental methods
The experiment was carried out with reference to the scheme shown in FIG. 1. 30 SD rats of about 8-12 weeks of age were selected, weighed 250-300g, and randomly divided into 5 groups (n =6 per group) and designated as NC, UC, SASP, FC, DFC groups. NC group is normal control group; the other four groups were dosed as follows: the UC group rats were given purified water, the SASP group rats were given sulfasalazine (SASP, 400mg/kg, p.o/day), the FC group rats were given anti-rat FcRn antibody (anti-Fc-mAb, 80. Mu.g/kg, i.v/7 days), and the DFC group rats were given anti-rat FcRn antibody (anti-Fc-mAb, 160. Mu.g/kg, i.v/7 days). Rats in UC group, SASP group, FC group and DFC group are given 3% (w/v) dextran sodium sulfate (DDS) for 7 days, and pure water is used for replacing 7 days as a remission stage; 3% (w/v) DSS solution was given on day 15 for 3 days as the first recurrent inflammatory phase (IRP-1) and replaced with pure water for 7 days. Followed by feeding 3% DSS for 7 days as a second recurrent inflammatory phase (IRP-2); finally, pure water is replaced until the experiment is finished. Before the start of dosing, on day 7 after dosing, on day 14 after dosing, on day 21 after dosing, each group of rats had blood samples (200 μ L) taken from the orbit into microcentrifuge tubes (designated N1, N2, N3, N4 in order); on day 28 post-dose, rats were anesthetized by intraperitoneal injection of 50% urethane (3 mL/kg), blood samples were collected from the heart into microcentrifuge tubes (noted N5), and the colon was collected for biochemical and histopathological analysis.
Disease symptom changes are monitored in the experimental process, and the concentration of serum anti-neutrophil cytoplasmic antibodies (ANCA), immunoglobulin G (IgG), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) and the expression level of protein related to colon Neutrophil Extracellular Trap (NET) are determined.
3. Results of the experiment
Serum IgG levels are an indicator of antagonism of FcRn function. FIG. 2 shows the monitoring results of serum IgG level of rats in each group. It can be seen that, in the three sampling points of N3, N4 and N5, the water level of serum IgG of rats in the DFC group is significantly reduced compared to that in the UC group, and the serum IgG level of rats in the FC group at a smaller dosage is significantly reduced compared to that in the UC group only in the two sampling points of N4 and N5; the serum IgG level of the rats in the SASP group has no obvious change compared with that in the UC group in all sampling points; furthermore, in the N5 sampling point, the FC group was substantially comparable to the DFC group serum IgG levels. The experimental result shows that 28 days of continuous SASP administration can not affect the FcRn transport function in rats; however, the rat anti-Fc-mAb was administered intravenously at 160. Mu.g/kg for two doses to show significant FcRn functional antagonism; significant antagonism of FcRn function was also observed following intravenous administration of three doses of anti-Fc-mAb to rats at a dose of 80 μ g/kg.
FIG. 3 shows the monitoring results of serum ANCA levels of rats in each group. It can be seen that, starting from the N3 sampling point, serum ANCA levels of rats in the SASP group, FC group and DFC group are significantly reduced compared with those in the UC group. Since serum ANCA levels correlate with the degree of UC inflammation and serum ANCA levels decrease in the presence of inflammatory remission, the serum ANCA levels decreased in the SASP group rats due to the anti-inflammatory effects of the SASP itself, although FcRn transport function was not altered. It is noted that serum ANCA levels of rats in DFC group were further significantly reduced at three sampling points N3, N4 and N5 compared to SASP group, and serum ANCA levels of rats in FC group were further significantly reduced at two sampling points N4 and N5 compared to SASP group. This is because the action of antagonizing FcRn accelerates clearance of serum ANCA, and the antagonism of FcRn function exerted by the DFC group and FC group further reduces serum ANCA levels in rats, further alleviating inflammation in rats.
The formation of NET is a key factor for the persistence of the ulcerative colitis inflammation, and is closely related to the recurrence of the ulcerative colitis. FIG. 4 shows the expression of colon NET associated proteins (PAD 4, MPO, NE) in rats in each group, and it can be seen that after the four doses of anti-Fc-mAb are given (28 days of SASP), the levels of colon NET associated proteins (PAD 4, MPO and NE) in the FC group and the DFC group are significantly reduced compared with the UC control group; compared with the SASP group, the levels of colonic NET associated proteins (PAD 4, MPO and NE) were further reduced in the FC group and DFC group, and the differences were statistically significant. The anti-Fc-mAb can obviously reduce the formation of NET at the colon part of a rat and is beneficial to inhibiting the recurrence of ulcerative colitis; and compared with SASP, the anti-Fc-mAb has obviously improved effect of reducing NET formation at the colon part of a rat, and is more favorable for inhibiting the recurrence of ulcerative colitis.
Disease Activity Index (DAI) and Histopathological Score (HS) are commonly used indicators for determining the status of ulcerative colitis. FIG. 5 shows the result of statistical analysis of DAI and HS in various groups of rats. The results show that after the four doses of anti-Fc-mAb are finished (28 days of SASP administration), the DAI and HS of FC group and DFC group are obviously reduced compared with UC control group; the DAI and HS of the FC and DFC groups were further reduced compared to the SASP group, and the difference was statistically significant. The anti-Fc-mAb can obviously reduce disease activity index and histopathological score of rats and can effectively treat ulcerative colitis; and, compared with SASP, the anti-Fc-mAb has significantly enhanced effects on reducing disease activity index and histopathological score in rats, and has significantly enhanced effects on treating ulcerative colitis.
FIGS. 6-8 show the results of monitoring inflammation-related indexes (IRIs) such as TNF- α, IL-1 β, and CRP in rat serum during the experiment. It can be seen that from the N3 sampling point, the serum TNF-alpha, IL-1 beta and CRP levels of the rats in the SASP group, FC group and DFC group are all significantly reduced compared with those in the UC group. It is noted that the serum TNF-alpha, IL-1 beta and CRP levels of rats in the DFC group were further significantly reduced at three sampling points N3, N4 and N5 compared with those in the SASP group, and the serum TNF-alpha, IL-1 beta and CRP levels of rats in the FC group were further significantly reduced at two sampling points N4 and N5 compared with those in the SASP group. This is because the antagonism of FcRn function exerted by the DFC and FC groups further reduced rat serum TNF- α, IL-1 β and CRP levels, further alleviating rat inflammation.
In this experiment, the first simulated recurrent inflammatory phase (IRP-1) preceded by the N3 sampling point, and the N4 sampling point was within the second simulated recurrent inflammatory phase (IRP-2). By combining the monitoring results of serum TNF-alpha, IL-1 beta and CRP of rats in each experimental group of three sampling points of N3, N4 and N5, the inventor finds that intravenous injection of anti-Fc-mAb has a UC treatment effect which is obviously improved compared with SASP administration in the inflammatory relapse period.
By further transversely comparing the detection results of ANCA, TNF-alpha, IL-1 beta and CRP of rat sera among the experimental groups of the N3 and N4 sampling points (fig. 9), it can be found that the indexes of the N4 sampling point rat sera of the UC group and the SASP group are obviously increased compared with the N3 sampling point, while the indexes of the N4 sampling point rat sera of the FC group and the DFC group are not obviously different from the N3 sampling point, along with repeated stimulation of an exogenous inflammatory factor (DSS solution in the experiment). The SASP can not resist the inflammatory relapse of the ulcerative colitis caused by the exogenous inflammatory factors, and the antagonism of the FcRn function by intravenous injection of anti-Fc-mAb can effectively resist the inflammatory relapse of the ulcerative colitis caused by the exogenous inflammatory factors.
Through the experiment, the invention discovers that the FcRn target point is closely related to the recurrence of the ulcerative colitis for the first time, and the anti-FcRn function is antagonized by intravenous injection of anti-Fc-mAb, so that the clearance of rat serum ANCA can be accelerated, the formation of colon NET can be reduced, the ulcerative colitis can be effectively treated, and the recurrence of the ulcerative colitis can be effectively inhibited; however, administration of SASP failed to antagonize FcRn function and also failed to inhibit recurrence of ulcerative colitis.
In conclusion, the invention provides the application of the FcRn inhibitor in preparing the medicine for inhibiting the recurrence of the autoimmune disease. The invention discovers that the FcRn target point is closely related to the recurrence of the ulcerative colitis for the first time, and the anti-FcRn antibody is given to antagonize the FcRn function, so that the recurrence of the ulcerative colitis can be effectively inhibited; however, SASP, which is a clinical drug for treating ulcerative colitis, does not antagonize FcRn function and does not inhibit the recurrence of ulcerative colitis. Therefore, the FcRn inhibitor including the anti-FcRn antibody has wide application prospect in preparing the medicine for inhibiting the recurrence of autoimmune diseases such as ulcerative colitis.
Claims (10)
- Use of an fcrn inhibitor for the manufacture of a medicament for inhibiting recurrence of an autoimmune disease.
- 2. Use according to claim 1, characterized in that: the autoimmune diseases include ulcerative colitis, crohn's disease, systemic lupus erythematosus, and rheumatoid arthritis.
- 3. Use according to claim 2, characterized in that: the autoimmune disease is ulcerative colitis.
- 4. Use according to any one of claims 1 to 3, characterized in that: the medicament is a medicament for treating autoimmune diseases.
- 5. Use according to any one of claims 1 to 3, characterized in that: the drug is a drug that reduces serum ANCA levels, a drug that reduces serum inflammatory indicators, and/or a drug that reduces colonic NET formation.
- 6. Use according to claim 5, characterized in that: the inflammatory markers include TNF-alpha, IL-1 beta, and CRP.
- 7. Use according to any one of claims 1 to 6, characterized in that: the FcRn inhibitor is a small molecule FcRn inhibitor or a protein polypeptide FcRn inhibitor.
- 8. Use according to claim 7, characterized in that: the protein polypeptide FcRn inhibitor is an anti-FcRn antibody.
- 9. Use according to any one of claims 1 to 8, characterized in that: the medicament is a preparation prepared by taking an FcRn inhibitor as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
- 10. Use according to claim 9, characterized in that: the preparation is an oral preparation, an injection preparation or a transdermal administration preparation.
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| US20100048488A1 (en) * | 2008-08-01 | 2010-02-25 | Syntonix Pharmaceuticals, Inc. | Immunomodulatory peptides |
| CN101815723A (en) * | 2007-08-09 | 2010-08-25 | 森托尼克斯制药有限公司 | immunomodulatory peptides |
| CN102149729A (en) * | 2008-04-25 | 2011-08-10 | 戴埃克斯有限公司 | Antibodies against FcRn and use thereof |
| CN106103476A (en) * | 2013-12-24 | 2016-11-09 | 阿尔金-X有限公司 | FcRn antagonist and using method |
| CN114716550A (en) * | 2015-05-12 | 2022-07-08 | Synt免疫公司 | Humanized affinity matured anti-FcRn antibodies |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101815723A (en) * | 2007-08-09 | 2010-08-25 | 森托尼克斯制药有限公司 | immunomodulatory peptides |
| CN102149729A (en) * | 2008-04-25 | 2011-08-10 | 戴埃克斯有限公司 | Antibodies against FcRn and use thereof |
| US20100048488A1 (en) * | 2008-08-01 | 2010-02-25 | Syntonix Pharmaceuticals, Inc. | Immunomodulatory peptides |
| CN106103476A (en) * | 2013-12-24 | 2016-11-09 | 阿尔金-X有限公司 | FcRn antagonist and using method |
| CN114716550A (en) * | 2015-05-12 | 2022-07-08 | Synt免疫公司 | Humanized affinity matured anti-FcRn antibodies |
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