Antibody binding to il-11, antigen-binding fragment thereof, and uses thereof

Abstract

The present invention relates to the field of biomedicine, and specifically provides an antibody binding to IL-11 or antigen-binding fragment thereof, comprising three heavy-chain complementarity-determining regions respectively represented by HCDR1, HCDR2, and HCDR3, and three light-chain complementarity-determining regions respectively represented by LCDR1, LCDR2, and LCDR3, the antibody or antigen-binding fragment thereof being selected from A-I, A-II, A-III, or A-IV. The provided antibody or antigen-binding fragment thereof has high binding capacity to the IL-11 antigen and can block the IL-11 antigen from binding to receptors thereof, thus effectively inhibiting the pro-fibrotic effect of IL-11 and inhibiting or preventing the generation or proliferation of fibroblasts, and can be effectively used for treating or preventing human fibrotic diseases, inflammation, cancers, or autoimmune diseases.

Description

Antibodies binding to IL-11, antigen-binding fragments thereof and uses thereof CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Chinese patent application 202310652547.9 filed on June 5, 2023, the contents of which are incorporated herein by reference. Technical Field The present invention relates to the field of biomedical technology, and in particular to an antibody binding to IL-11, an antigen binding fragment thereof and applications thereof. Background Art Fibrosis is a repair response of tissues after injury to protect the relative integrity of tissues and organs. A variety of harmful stimuli (including toxins, infectious pathogens, autoimmune responses, and mechanical stress) can induce cellular fibrotic responses. In response to tissue injury, fibroblasts from various sources (including resident fibroblasts, mesenchymal cells, circulating fibroblasts, and transdifferentiation of other cell types) can initiate wound healing responses by remodeling the extracellular environment to restore tissue integrity and promote the replacement of parenchymal cells. However, persistent injury and damage can lead to dysregulation of this process, resulting in pathological excessive deposition of extracellular matrix (ECM) proteins (including collagen, laminin, and fibronectin), accompanied by upregulation of fibroblast activity, resulting in a chronic inflammatory environment with infiltration of macrophages and immune cells. Cytokines and growth factors are released in large quantities, including members of the transforming growth factor-β (TGF-β) family and Wingless / Int-1 (Wnt1) proteins, which are the main effectors of the fibrotic process. TGF-β and Wnt1 bind to their stem cell surface receptors and initiate downstream signaling, leading to upregulation of target gene expression, which further functions to enhance fibroblast differentiation and the production and secretion of ECM proteins. Tissue fibrosis is the main cause of disability and death in many diseases worldwide. The main pathological changes are the increase of fibrous connective tissue in organ tissues and the decrease of parenchymal cells. Continuous progression can lead to organ structure destruction and functional impairment, and even failure, which seriously threatens human health and life. According to relevant statistics from the United States, nearly 45% of patients who died from various diseases in the country can be attributed to tissue fibrosis. Currently, about 25% of people in the world suffer from non-alcoholic fatty liver disease. Although non-alcoholic fatty liver disease can improve, untimely treatment will lead to its deterioration into non-alcoholic hepatitis. Non-alcoholic hepatitis is characterized by liver inflammation, liver cell death, and liver fibrosis, which eventually leads to cirrhosis and liver cancer. Pulmonary fibrosis is a terminal change of a large class of lung diseases characterized by fibroblast proliferation and a large amount of extracellular matrix aggregation accompanied by inflammatory damage and tissue structure destruction, that is, the normal alveolar tissue is damaged and repaired abnormally, resulting in structural abnormalities (scar formation). The incidence and mortality of pulmonary fibrosis are increasing year by year. Pulmonary fibrosis is mostly sporadic, with an incidence of about 3 to 5 / 100,000, accounting for about 65% of all interstitial lung diseases. The average survival period after diagnosis is only 2.8 years, and the mortality rate is higher than that of most tumors. It is called a "tumor-like disease". Therefore, the development of drugs to treat anti-fibrotic diseases is particularly urgent. Mature IL-11 (interleukin-11) is a polypeptide with 178 amino acids and a molecular weight of approximately 23KD. The three-dimensional structure of IL-11 has been shown to be a four-helix bundle structure consisting of four α-helices and loops connecting the α-helices. IL-11 is a pleiotropic cytokine and a member of the IL-6 cytokine family. They share the same signal transduction receptor subunit GP130. This family plays a vital role in the occurrence, development and metastasis of tumors. The production of IL-11 is caused by known major pro-fibrotic factors, including TGFβ, FGF, PDGF, CTGF or IL-13. Local overexpression of IL-11 can lead to local tissue fibrosis. The activation of the IL-11 signaling pathway depends on the binding of IL-11 to cell surface receptors. The IL-11 receptor is composed of two glycoprotein chains, IL-11Ra and GP130. IL-11Ra has the ability to bind to ligands. IL-11 first binds to IL-11Ra with low affinity to form IL-11 / IL-11Ra heterodimers, which bind to GP130 with high affinity to form heterotrimeric proteins. IL-11 / IL-llRa / GP130 heterotrimers homodimerize to form hexamers, which then phosphorylate and activate downstream STAT signaling pathways or MAPK cascades. Ultimately, IL-11 transmits signals to the cell through the GP130 signal transduction chain, allowing cells to obtain proliferation and activation signals. Studies have shown that blocking this signaling pathway can be an effective treatment for a variety of tumors, chronic fibrosis, and inflammatory diseases. Therefore, the development of antibodies that bind to IL-11 and its antigen-binding fragments has important clinical significance. Summary of the invention In order to meet the needs of patients with fibrotic diseases at home and abroad, the present invention screened and obtained antibodies and antigen-binding fragments thereof that can specifically bind to IL-11 and block the binding of IL-11 to its receptor. The specific technical solutions of the present invention are as follows: The present invention provides an antibody or an antigen-binding fragment thereof that binds to IL-11, comprising three heavy chain complementary determining regions represented by HCDR1, HCDR2 and HCDR3, respectively, and three light chain complementary determining regions represented by LCDR1, LCDR2 and LCDR3, respectively, wherein the antibody or the antigen-binding fragment thereof is selected from any one of the following: AI: the amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 1, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 2, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 3, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 4, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 5, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 6; A-II: the amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 1, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 2, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 3, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 4, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 5, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 7; A-III: the amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 8, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 9, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 10, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 11, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 12, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 13; A-IV: The amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 1, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 14, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 15, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 4, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 5, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 6. The above antibodies or antigen-binding fragments thereof provided by the present invention can specifically bind to IL-11, block the binding of IL-11 antigen to its receptor, and inhibit IL-11-mediated signal transduction. The above antibodies provided by the present invention have good biological activity. The present invention further comprises a heavy chain variable region and a light chain variable region, wherein the antibody or antigen-binding fragment thereof is selected from the following Either: MA-Ⅰ: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 16, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 17; MA-Ⅱ: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 16, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 18; MA-III: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 19, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 20; MA-IV: The amino acid sequence of the heavy chain variable region is shown in SEQ ID No:21, and the amino acid sequence of the light chain variable region is shown in SEQ ID No:17. The present invention further includes a heavy chain constant region and a light chain constant region, wherein the amino acid sequence of the heavy chain constant region is one of SEQ ID No: 23, SEQ ID No: 24, SEQ ID No: 25 or SEQ ID No: 26; and the amino acid sequence of the light chain constant region is as shown in SEQ ID No: 22. Furthermore, the antibody or antigen-binding fragment thereof is a chimeric antibody molecule, and the chimeric antibody molecule also includes a human antibody constant region. The present invention further comprises a heavy chain variable region and a light chain variable region, and the antibody or antigen-binding fragment thereof is selected from any one of the following: HA-IA: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 32; HA-IB: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 33, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 34; HA-IC: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 35; HA-ID: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 36, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 37; HA-II-A: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 38; HA-II-B: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 39; HA-II-C: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 33, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 39; HA-II-D: The amino acid sequence of the heavy chain variable region is shown in SEQ ID No:36, and the amino acid sequence of the light chain variable region is shown in SEQ ID No:40. The antibody or antigen-binding fragment thereof in the present invention further comprises a human antibody constant region. Furthermore, the human antibody constant region includes a human antibody heavy chain constant region and a human antibody light chain constant region, and the amino acid sequence of the human antibody heavy chain constant region is one of SEQ ID No:27, SEQ ID No:28 or SEQ ID No:29; the amino acid sequence of the human antibody light chain constant region is as shown in SEQ ID No:30. Furthermore, the antibody or antigen-binding fragment thereof is one or a combination of Fab, F(ab)2, Fv or ScFv. The present invention also provides a nucleic acid molecule encoding the antibody or antigen binding to IL-11. Combine the fragments. The present invention also provides a recombinant DNA expression vector, which contains the nucleic acid molecule. The present invention also provides a host cell transfected with the recombinant DNA expression vector, wherein the host cell includes a prokaryotic cell, a yeast cell, an insect cell or a mammalian cell; Preferably, the host cell is a mammalian cell, and the mammalian cell is a HEK293 cell, a CHO cell or a NS0 cell. The present invention also provides a medicine, which comprises the antibody or antigen-binding fragment thereof that binds to IL-11. The present invention also provides a detection reagent, which is used to detect the antibody or antigen-binding fragment thereof that binds to IL-11. The present invention also provides a combination pharmaceutical composition, which includes the antibody or antigen-binding fragment thereof that binds to IL-11, and a second composition selected from an antibody or antigen-binding fragment thereof that binds to PD-1, PD-L1, VEGF, VEGFR, TNF-α or TSLP. The present invention further provides the use of the antibody or antigen-binding fragment thereof that binds to IL-11 in the preparation of a drug for treating or preventing human fibrotic diseases, inflammation, cancer or autoimmune diseases. Preferably, the fibrotic disease comprises fibrosis of the heart, liver, kidney, lung, gallbladder, bladder, stomach, bone marrow, penis, breast, blood vessels, eyes, pancreas, spleen, brain, intestine, muscle or skin. Preferably, the inflammation includes hepatitis, myocarditis, nephritis, pneumonia, cholecystitis, cystitis, gastritis, osteomyelitis, prostatitis, mastitis, pancreatitis, enteritis, arthritis, polymyositis, dermatomyositis or dermatitis. Preferably, the cancer comprises leukemia, lung cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, melanoma, kidney cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer or bladder cancer. Preferably, the autoimmune disease comprises psoriasis, Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus or multiple sclerosis. The beneficial effects of the present invention are as follows: the antibody or antigen-binding fragment thereof provided by the present invention has a high binding ability with the IL-11 antigen, can block the binding of the IL-11 antigen to its receptor, thereby effectively inhibiting the profibrotic effect of IL-11, inhibiting or preventing the production or proliferation of fibroblasts, and can be effectively used to treat or prevent human fibrotic diseases, inflammation, cancer or autoimmune diseases, wherein fibrotic diseases include but are not limited to the heart, liver, kidney, lung, gallbladder, bladder, stomach, bone marrow, penis, breast, blood vessels, eyes, pancreas, spleen, Fibrosis of the brain, intestines, muscles or skin; inflammation including but not limited to hepatitis, myocarditis, nephritis, pneumonia, cholecystitis, cystitis, gastritis, osteomyelitis, prostatitis, mastitis, pancreatitis, enteritis, arthritis, polymyositis, dermatomyositis or dermatitis; cancer including but not limited to leukemia, lung cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, melanoma, kidney cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer or bladder cancer; autoimmune diseases including but not limited to psoriasis, Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus or multiple sclerosis. BRIEF DESCRIPTION OF THE DRAWINGS FIG1 is a plasmid map of the pScFv-Disb-HS vector in Example 2 of the present invention; FIG2 is a comparison chart of the affinity of the gradient dilution ELISA anti-IL-11 phage monoclonal antibody in Example 3 of the present invention; FIG3 is a diagram of the vector pTSE in Example 5 of the present invention; FIG4 is a denaturing polyacrylamide gel electrophoresis diagram of the mouse antibody molecules in Example 5 of the present invention; FIG5 is a graph comparing the binding ability of mouse antibody molecules to IL-11 in Example 6 of the present invention; FIG6 is a comparison diagram of the competitive inhibition experiment between the mouse antibody and the IL-11 receptor protein IL-11RA in Example 7 of the present invention; FIG7 is a comparison diagram of the inhibition of IL-11 binding to the IL-11RA receptor on the surface of BaF / 3-IL-11RA cells by the mouse antibody in Example 8 of the present invention; FIG8 is a comparative diagram of the inhibition of TIMP-1 secretion by the mouse-derived antibody in Example 9 of the present invention by embryonic lung fibroblasts MRC-5; FIG9 is a denaturing polyacrylamide gel electrophoresis diagram of the humanized antibody molecule of Example 14 of the present invention; FIG10 is a graph comparing the binding ability of humanized antibody molecules to IL-11 in Example 18 of the present invention; FIG11 is a comparison diagram of the inhibition of IL-11 binding to the IL-11RA receptor on the surface of BaF / 3-IL-11RA cells by the humanized antibody molecules in Example 19 of the present invention; FIG12 is a comparison diagram of the inhibition of IL-11 binding to the GP130 receptor on the surface of BaF / 3-GP130 cells by the humanized antibody molecule in Example 20 of the present invention; FIG13 is a comparison diagram of biological activity detection (reporter gene) of humanized antibody molecules in Example 21 of the present invention; FIG14 is a comparative diagram of the inhibition of TIMP-1 secretion by embryonic lung fibroblasts MRC-5 by the humanized antibody molecules in Example 22 of the present invention; FIG15 is a comparison diagram of cross-binding experiments between humanized antibody molecules and IL-11 of different species in Example 23 of the present invention; FIG16 is a bar graph showing changes in the ratio of lung to body weight in the mouse pulmonary fibrosis model in Example 24 of the present invention; FIG17 is a diagram of hematoxylin and eosin (HE) staining and Masson's staining of lung tissue sections in the mouse pulmonary fibrosis model in Example 24 of the present invention; FIG18 is a bar graph showing changes in the ratio of heart to body weight in the mouse cardiac fibrosis model in Example 25 of the present invention; FIG19 is a diagram showing hematoxylin and eosin (HE) staining and Masson's staining of cardiac tissue sections in the mouse cardiac fibrosis model in Example 25 of the present invention; FIG20 is a bar graph of urine protein content in the kidney of a mouse renal fibrosis model in Example 26 of the present invention; FIG21 is a diagram showing hematoxylin and eosin (HE) staining and Masson's staining of kidney tissue sections in the mouse renal fibrosis model in Example 26 of the present invention; FIG22 is a bar graph showing changes in liver weight in the mouse liver fibrosis model in Example 27 of the present invention; FIG23 is a bar graph showing changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mouse serum in the mouse liver fibrosis model in Example 27 of the present invention; FIG24 is a diagram showing hematoxylin and eosin (HE) staining and Masson's staining of liver tissue sections in the mouse liver fibrosis model in Example 27 of the present invention; Figure 25 is a graph showing the thermal stability evaluation of the anti-IL-11 monoclonal antibody HA-IA in Example 28 of the present invention. DETAILED DESCRIPTION In order to make the present invention more easily understood, before describing the embodiments, some technical and scientific terms of the present invention are explained as follows: The term "antibody" as used herein includes whole antibodies and any antigen-binding fragments thereof. Antibodies include murine antibodies, humanized antibodies, bispecific antibodies or chimeric antibodies. Antibodies may also be fragments such as Fab, F(ab)2, Fv or ScFv (single-chain antibody). Antibodies may be naturally occurring antibodies or antibodies that have been altered (e.g., mutated, deleted, replaced, etc.), as long as they show binding to the relevant target molecule. The "antibody" herein includes fragments and derivatives thereof, including synthetic antibodies and fragments. As used herein, an antibody is an antibody that is capable of specifically binding to a relevant target molecule (i.e., the antibody has specificity for the target molecule). Antigen) polypeptide. The terms "variable region" and "constant region" used in this article refer to the sequence region near the N segment of the antibody heavy chain and light chain as the variable region (V region), and the remaining amino acid sequence near the C segment is relatively stable, which is the constant region (C region). The variable region includes three complementarity determining regions (CDRs) and four framework regions (FRs). Each light chain variable region and heavy chain variable region consists of three CDR regions and four FR regions. The three CDR regions of the heavy chain are represented by HCDR1, HCDR2 and HCDR3, respectively, and the three CDR regions of the light chain are represented by LCDR1, LCDR2 and LCDR3, respectively. The term "murine antibody molecule" as used herein refers to antibodies obtained by immunizing mice with human IL-11 antigen. The term "chimeric antibody molecule" used herein refers to an antibody formed by fusing the variable region of a mouse antibody with the constant region of a human antibody, which can reduce the immune response induced by the mouse antibody in the human body. Chimeric antibodies are produced by inserting the light and heavy chain variable region genes of mouse monoclonal antibodies into an expression vector containing the constant region of a human antibody using DNA recombination technology. In this way, the variable regions of the light and heavy chains in the expressed antibody molecules are mouse-derived, while the constant regions are human-derived. Nearly 2 / 3 of the entire antibody molecule is human-derived. The antibodies produced in this way reduce the immunogenicity of the mouse antibody while retaining the ability of the parent antibody to specifically bind to the antigen. The term "humanized antibody molecule" used in this article refers to the transplantation of the CDR of the mouse monoclonal antibody into the variable region of the human antibody to replace the human antibody CDR, so that the human antibody acquires the antigen binding specificity of the mouse monoclonal antibody while reducing its heterology. The term "CHO ​​cell" refers to Chinese hamster ovary cell; the term "HEK293E cell" refers to human embryonic kidney 293E cell; and the term "NS0 cell" refers to mouse NS0 thymoma cell. In this specification, "IL-11" refers to IL-11 from any species, and includes isoforms, fragments, variants or homologues of IL-11 from any species. As used herein, a "fragment", "variant" or "homologue" of a protein may optionally be characterized as having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of the reference protein. In some embodiments, the fragments, variants, isoforms and homologues of the reference protein may be characterized as being able to have the function possessed by the reference protein. The present invention is further described in detail below with reference to the following examples. Example 1 Example 1 of the present invention provides an antibody or an antigen-binding fragment thereof that binds to IL-11, comprising three heavy chain complementary determining regions represented by HCDR1, HCDR2 and HCDR3, respectively, and three light chain complementary determining regions represented by LCDR1, LCDR2 and LCDR3, respectively, the antibody or the antigen-binding fragment thereof being selected from any one of the following, and the following CDRs are determined based on the Kabat numbering system. Example 2 Screening of mouse antibody molecules The present invention uses IL-11 antigen (subsequent experiments IL-11 protein, IL-11-Fc antigen, IL-11-mFc ligand protein All mice were immunized with human IL-11), the immunization method was optimized, and a phage display library was created. The specific construction, screening and identification of the phage display library are as follows: Step 1: Immunization of mice with IL-11 antigen 1. Experimental animals: Species and strain: BALB / c, female, mice; Body weight: 18-20 g; Experimental animal provider: Beijing Huafukang Biotechnology Co., Ltd. 2. Immunization: Mice were immunized with human IL-11 as the immunizing antigen (synthesized gene by Nanjing GenScript Biotechnology Co., Ltd., and the vector was constructed and expressed and purified by our company). Step 2: Construction of phage antibody library: Take mouse spleen cells with high titer, use Trizol reagent (purchased from Ambion, catalog number: 15596026) to extract total RNA from mouse spleen cells, obtain cDNA by RT-PCR, use cDNA as template, use degenerate primers (reference for degenerate primers used: Journal of Immunological Methods 233 (2000) 167-177) for PCR amplification, thereby obtaining immune mouse antibody heavy chain variable region gene library (VH) and light chain variable region gene library (VL). pScFv-Disb-HS vector is a vector pComb3 vector (purchased from China Plasmid Vector Strains and Cell Lines Gene Collection Center) modified by a series of gene cloning methods, so that it can be used for the construction and expression of phage single-chain antibody library, the modified vector is named pScFv-Disb-HS vector, and its plasmid map is shown in Figure 1, and based on this vector, a mouse immune phage antibody library is constructed. The light chain and heavy chain variable region gene libraries were double-digested and ligated to the vector pScFv-Disb-HS that had been similarly digested in steps to construct the pScFv-Disb-HS-VH-VL gene library. Step 3: Use IL-11 as antigen to coat the immunotubes, with an antigen coating volume of 5 μg / 500 μL / tube, coat overnight at 4°C, and then use 4% skim milk powder / PBST to block the immunotubes and immune phage antibody library respectively, and block at room temperature for 1 hour. The blocked immune phage antibody library is added to the immunotube for antigen-antibody binding, and the phage input volume is about 10 9 ~10 12 After reacting at room temperature for 1 h, unbound phages were washed away with PBST-PBS, eluted with 0.1 M Glycine-HCl at pH 2.2, and finally neutralized with 1.5 M Tris-HCl at pH 8.8 to a pH of about 7.0. Step 4: Infect 10 ml of TG1 bacterial solution grown to the logarithmic phase with the neutralized phages above, place in a 37°C incubator for 30 minutes, take out part of the bacterial solution for gradient dilution, and spread on 2YTAG plates for calculating the phage output. Centrifuge the remaining bacterial solution and discard the supernatant, resuspend the bacterial pellet in a small amount of culture medium, aspirate it and spread it on a 2YTAG large plate to prepare for the next round of screening. Step 5: Scrape the infected bacteria from the large plate, inoculate into 2YTAG liquid culture medium, shake to the logarithmic phase, add M13KO7 helper phage for superinfection, culture overnight at 28°C and 220rpm to prepare phage, PEG / NaCl precipitation to purify phage for the next round of screening, and conduct one round of phage library enrichment screening. Step 6: Screening of positive clones of IL-11 phage single-chain antibody: After one round of screening, well-separated monoclonal colonies were picked and inoculated into 96-well deep-well plates with 2YTAG liquid medium. They were cultured at 37°C and 220 rpm until the logarithmic growth phase. About 10 10 The helper phage M13KO7 was statically infected at 37°C for 30 minutes. Centrifuge at 4000rpm for 15 minutes, discard the supernatant, resuspend the precipitate with 2YTAK, and culture overnight at 28°C and 220rpm. After centrifugation at 4000rpm and 4°C for 15 minutes, the amplified phage supernatant was aspirated for ELISA identification, and finally four mouse antibody molecules with high affinity were screened, named MA-I, MA-II, MA-III and MA-IV, and the monoclonal antibodies obtained above were sequenced to determine the correct antibody sequence. After sequencing, the sequences of the four monoclonal antibodies screened above are as follows: Specifically, SEQ ID No: 16 (amino acid sequence of the heavy chain variable region of MA-Ⅰ and MA-Ⅱ): SEQ ID No: 17 (amino acid sequence of the light chain variable region of MA-Ⅰ and MA-Ⅳ): SEQ ID No: 18 (amino acid sequence of the light chain variable region of MA-Ⅱ): SEQ ID No: 19 (amino acid sequence of the heavy chain variable region of MA-III): SEQ ID No: 20 (amino acid sequence of the light chain variable region of MA-III): SEQ ID No: 21 (amino acid sequence of the heavy chain variable region of MA-IV): From another perspective, the present invention also relates to an antibody or antigen-binding fragment thereof that binds to IL-11, specifically comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises three heavy chain complementary determining regions represented by HCDR1, HCDR2 and HCDR3, respectively, and the light chain variable region comprises three heavy chain complementary determining regions represented by LCDR1, LCDR2 and LCDR3, respectively, wherein HCDR1, HCDR2 and HCDR3 are HCDR1, HCDR2 and HCDR3 of the heavy chain variable region shown in SEQ ID No: 16, 19 or 21, respectively; LCDR1, LCDR2 and LCDR3 are LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in SEQ ID No: 17, 18 or 20, respectively. Those skilled in the art can determine the CDR sequence of the heavy chain variable region or light chain variable region whose amino acid sequence is known based on common numbering systems (such as Kabat, AbM, Chothia, Contact or IMGT, etc.). When the Kabat numbering system is used to determine the CDR, the CDR sequences of the heavy chain variable region and the light chain variable region are as shown in Example 1. Example 3 Comparison of antibody affinity by gradient dilution ELISA The four mouse antibody molecules (MA-I, MA-II, MA-III and MA-IV) obtained in Example 2 were displayed and purified by monoclonal phage, and then the affinity was identified by phage gradient dilution ELISA experiment. The specific method is as follows: IL-11 antigen was coated with carbonate buffer at pH 9.6, 100 ng / well / 100 μL, and the coating was performed at 4°C. Overnight. Wash three times with PBST, dilute the four phage monoclonal antibodies screened in Example 2 five-fold with PBST, add 100 μl of the diluted sample to each well, and let stand at room temperature for 1 hour. Wash the ELISA plate with PBST, add the HRP-anti-M13 (purchased from Bio-viewshine, item number: GE27-9421-01) monoclonal antibody diluted with 1% BSA-PBST to the ELISA plate, and let it stand at room temperature for 1 hour. Use TMB color development kit (purchased from Kangwei Century, item number: CW0050S) for color development at room temperature for 10 minutes. After terminating with 2M H2SO4, read the results at 450nm / 630nm with the microplate reader, and calculate the corresponding EC50 value. The specific data are as follows: According to the above data and as shown in FIG. 2 , the four different mouse antibody molecules screened in Example 2 can all bind to IL-11, which indicates that the monoclonal antibodies provided by the present invention have a high affinity to IL-11. Example 4 Example 4 of the present invention is further defined on the basis of Example 2, that the antibody or antigen-binding fragment further includes a heavy chain constant region and a light chain constant region, and the amino acid sequence of the heavy chain constant region is one of SEQ ID No: 23, SEQ ID No: 24, SEQ ID No: 25 or SEQ ID No: 26; the amino acid sequence of the light chain constant region is as shown in SEQ ID No: 22, and the specific sequence is as follows: SEQ ID No:22 (mouse C k The amino acid sequence of the light chain constant region of the type: SEQ ID No: 23 (amino acid sequence of the heavy chain constant region of mouse IgG1 type): SEQ ID No: 24 (amino acid sequence of the heavy chain constant region of mouse IgG2a type): SEQ ID No: 25 (amino acid sequence of the heavy chain constant region of mouse IgG2b type): SEQ ID No: 26 (amino acid sequence of the heavy chain constant region of mouse IgG3 type): Example 5 Preparation of mouse antibody molecules Example 5 of the present invention is based on Example 4 and preferably defines that the mouse antibody molecule includes a mouse IgG1 type heavy chain constant region (whose amino acid sequence is shown in SEQ ID No: 23) and a mouse C k The antibody preparation method is as follows: 1. The coding genes of the heavy chain VH and light chain VL of the four antibody molecules screened in Example 2 were cloned into the vector pTSE (as shown in FIG. 3 ) containing the heavy chain and light chain constant region genes. The preferred heavy chain constant region is the mouse IgG1 type constant region (the amino acid sequence is shown in SEQ ID No: 23), and the light chain constant region is the mouse C k The amino acid sequence is shown in SEQ ID No: 22, and the pTSE vector structure is shown in FIG3 (the preparation process of the pTSE vector is shown in the specification of CN103525868A, page 3,

[0019] part). 2. HEK293 cells were transiently transfected (purchased from the Institute of Basic Medicine, Chinese Academy of Medical Sciences, catalog number GNHu43) for antibody expression, and four monoclonal antibodies were obtained by protein A affinity column purification using an AKTA instrument. The protein concentration was determined using a BCA kit (purchased from Beijing Huitian Oriental Technology Co., Ltd., catalog number: BCA0020), and the protein size was then identified by SDS-PAGE. The results are shown in Figure 4, from left to right, non-reduced MA-I, MA-II, MA-III and MA-IV, protein molecular weight Marker1, protein molecular weight Marker2, and reduced MA-I, MA-II, MA-III and MA-IV mouse anti-IL-11 monoclonal antibodies, and the molecular weight of each band was consistent with the theory. Example 6 Binding experiment of mouse antibody molecules and IL-11 IL-11 antigen was coated with carbonate buffer at pH 9.6, 100 ng / well / 100 μL, and coated overnight at 4°C. Washed five times with 300 μL / well PBST, then added 1% BSA-PBST, blocked at 280 μL / well at 37°C for 1 hour, and added MA-I, MA-II, MA-III and MA-IV mouse antibody molecules of different dilution concentrations. The starting maximum concentration of the four antibody molecules was 5 μg / mL, and each antibody was diluted 5 times, with a total of 8 gradients, and incubated at 37°C for 1 hour. Washed five times with 300 μL / well PBST, then added Goat Anti-Mouse IgG-HRP (purchased from solarbio, item number: SE131) diluted 1:2000 with 1% BSA-PBST, and incubated at 37°C for 1 hour. TMB colorimetric kit was used for color development, 100 μL / well, at room temperature for 8 min, and then 2M H2SO4 was used to terminate the color development. The microplate reader was read at 450nm / 630nm, and the corresponding EC50 value was calculated. The specific data are as follows: According to the above data and as shown in FIG5 , the four different mouse antibody molecules screened out can all bind to IL-11 with high affinity. Example 7 Competitive inhibition experiment between mouse antibody and IL-11 receptor protein IL-11RA IL-11-Fc was coated with carbonate buffer at pH 9.6, 200 ng / well / 100 μL, overnight at 4°C. Washed five times with 300 μL / well PBST, then blocked with 1% BSA-PBST, 280 μL / well at 37°C. 1h, first add IL-11RA-Fc (IgG4 type) diluted to 0.5μg / mL with 1% BSA-PBST, 50μL / well, then add different dilution concentrations of MA-Ⅰ, MA-Ⅱ, MA-Ⅲ and MA-Ⅳ mouse antibodies, 50μL / well, the starting maximum concentration of the five antibodies is 100μg / mL, respectively, after 2-fold gradient dilution, each antibody is diluted 13 gradients, incubate at 37℃ for 3h. Wash five times with 300μL / well PBST, then add Anti-Human IgG4-HRP Mouse monoclonal antibody (purchased from Sigma, catalog number: SAB4200770) diluted 1:5000 with 2% BSA-PBST, and incubate at 37℃ for 1h. TMB color development kit color, 100μl / well, color development at room temperature for 15min, and then stop color development with 2M H2SO4. The microplate reader reads at 450nm / 630nm and calculates the corresponding IC50 value. The specific data are as follows: According to the above data and as shown in FIG6 , the four different mouse antibodies screened out can compete with the receptor protein IL-11RA, indicating that they can effectively inhibit the binding of IL-11 to the receptor protein IL-11RA. Example 8 Mouse Antibodies Inhibit the Binding of IL-11 to the IL-11RA Receptor on the Surface of BaF / 3-IL-11RA Cells Count the BaF / 3-IL-11RA cell line, take a certain number of cells, centrifuge and resuspend in PBS buffer, adjust the cell density to 1E+6 cells / mL, 100μL / well, and add to the 96-well plate. Dilute the IL-11-mFc ligand protein with PBS, prepare the concentration to 18μg / mL, 50μL / well, and add it to the corresponding position of the 96-well plate containing BaF / 3-IL-11RA cells. After gently mixing, place the 96-well plate at 4℃ and incubate for 1h. PBS gradient dilution of 4 mouse antibody molecules MA-I, MA-II, MA-III and MA-IV, with an initial concentration of 800μg / mL, 3-fold gradient dilution, a total of 10 gradients, 50μL / well, add to the corresponding position of the 96-well plate containing BaF / 3-IL-11RA cells and IL-11-mFc ligand protein mixture. After mixing evenly, place it at 4℃ and incubate for 2h. After the incubation, centrifuge at 3000rpm, wash the cells once with PBS buffer, and collect the cell pellet. Add the pre-prepared goat anti-mouse IgG Human ads-FITC antibody (purchased from SouthernBiotech, catalog number 1030-02) to the cell pellet, incubate at 4°C for 30min, centrifuge at 3000rpm, wash once with PBS buffer, resuspend in 100μL PBS buffer, and detect on a flow cytometer to collect the fluorescence signal in the FL1-A channel. Draw a dose-effect curve and calculate the corresponding IC50 value. The specific data are as follows: It can be seen from the above data and Figure 7 that the four different mouse candidate molecules screened out can effectively inhibit the binding of IL-11 ligand protein to the cell surface IL-11RA receptor. Example 9 Mouse Antibodies Inhibit TIMP-1 Secretion by Embryonic Lung Fibroblasts MRC-5 Embryonic lung fibroblasts MRC-5 were digested with trypsin and counted. A certain number of cells were taken, centrifuged and resuspended in MEM complete medium (purchased from GIBCO, catalog number 10370-021), and the cell density was adjusted to 2E+5 cells / mL, 100 μL / well, and added to a 96-well plate. MEM complete medium was used to dilute the IL-11-mFc ligand protein to a concentration of 16 μg / mL, and 50 μL / well was added to the corresponding 96-well plate. MEM complete medium was used to gradient dilute the four mouse antibody molecules MA-I, MA-II, MA-III, and MA-IV to an initial concentration of 40 μg / mL, 2-fold gradient dilution, a total of 8 gradients, 50 μL / well, added to the 96-well plate containing the cell suspension and IL-11-mFc ligand protein suspension, gently mixed, and placed in a 37°C CO2 incubator for overnight incubation for about 20 hours. The cell culture supernatant was taken for detection using an ELISA kit for TIMP-1 (purchased from Ekosai Biotechnology Co., Ltd., catalog number EH021-96). Human TIMP-1 Detection Kit: Add cell supernatant and standard to sample wells, 100 μL / well. Immediately add Add 50 μL / well of phospholipid-binding antibody working solution (1:100 dilution), cover with sealing film, and incubate at room temperature for 2 hours. After incubation, wash the plate 4 times with washing solution, and add 100 μL / well of enzyme conjugate working solution (1:100 dilution) in TIMP-1 detection kit. Cover with sealing film and incubate at room temperature for 1 hour. After incubation, wash the plate 4 times with washing solution. Add TMB colorimetric solution, 100 μL / well, incubate at room temperature in the dark for about 15 minutes, and terminate the reaction with 100 μL / well Stop solution. Read the plate at 450nm with a microplate reader and calculate the corresponding IC50 value. The specific data are as follows: From the above data and FIG8 , it can be seen that the four different mouse candidate molecules screened out can effectively inhibit the release of TIMP-1 from human embryonic lung fibroblasts MRC-5 stimulated by IL-11 ligand protein. Example 10 Example 10 of the present invention further defines the antibody or its antigen-binding fragment as a chimeric antibody molecule, the chimeric antibody molecule also includes a human antibody constant region, the human antibody constant region includes a human antibody heavy chain constant region and a human antibody light chain constant region, the amino acid sequence of the human antibody heavy chain constant region is one of SEQ ID No: 27, SEQ ID No: 28 or SEQ ID No: 29; the amino acid sequence of the human antibody light chain constant region is shown in SEQ ID No: 30. SEQ ID No: 27 (human IgG1 heavy chain constant region amino acid sequence): SEQ ID No: 28 (human IgG2 heavy chain constant region amino acid sequence): SEQ ID No: 29 (human IgG4 type heavy chain constant region amino acid sequence): SEQ ID No:30 (human C k light chain constant region amino acid sequence): Example 11 Preparation of chimeric antibody molecules Example 11 of the present invention further defines, on the basis of Example 10, that the human antibody constant region includes a human IgG1 heavy chain constant region (whose amino acid sequence is shown in SEQ ID No: 27) and a human C k The light chain constant region of the type (the amino acid sequence of which is shown in SEQ ID No: 30). Specific preparation method: The heavy chain variable region VH (SEQ ID No: 16) of the mouse antibody molecules MA-I and MA-II obtained by screening the immune phage antibody library in Example 2, the light chain variable region VL gene (SEQ ID No: 17) of MA-I, and the light chain variable region VL gene (SEQ ID No: 18) of MA-II were cloned into the vector pTSE (as shown in FIG. 3 ) containing the heavy chain constant region and the light chain constant region gene, respectively. The heavy chain constant region was of human IgG1 type (amino acid sequence as shown in SEQ ID NO: 27), and the light chain constant region was of human C k Type (amino acid sequence as shown in SEQ ID NO: 30). HEK293E cells (purchased from: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, catalog number: GNHu43) were transiently transfected to express antibodies and obtain chimeric antibodies CA-I and CA-II. Example 12 Humanization of murine antibody molecules First, the sequences of the mouse antibody molecules MA-I and MA-II in Example 2 were selected and compared with the human antibody germline database (v-base) to find the human antibody light and heavy chain germlines with higher homology as candidate sequences, and then the sequences of the CDRs of the mouse antibody molecules MA-I and MA-II were transplanted to the human candidate sequences for homology modeling. Then, the key framework amino acid residues that may play an important role in maintaining the CDR ring structure were calculated by three-dimensional structural simulation to design the back mutation of the humanized antibody. The light and heavy chain variable region sequences of the designed humanized antibodies containing back mutations were optimized and synthesized by Nanjing GenScript Biotechnology Co., Ltd., respectively, and then connected to the transient expression vector, and the light and heavy chain combinations obtained by humanization were analyzed, where MA-I obtained the following humanized antibody molecules: HA-IA, HA-IB, HA-IC, HA-ID; MA-II obtained the following humanized antibody molecules: HA-II-A, HA-II-B, HA-II-C, HA-II-D; The above-screened 8 monoclonal antibody sequences are as follows: Specifically, SEQ ID No: 31 (amino acid sequence of the heavy chain variable region of HA-IA, HA-IC, HA-II-A and HA-II-B): SEQ ID No: 32 (amino acid sequence of the light chain variable region of HA-IA): SEQ ID No: 33 (amino acid sequence of the heavy chain variable region of HA-IB and HA-II-C): SEQ ID No: 34 (amino acid sequence of the light chain variable region of HA-IB): SEQ ID No: 35 (amino acid sequence of the light chain variable region of HA-IC): SEQ ID No: 36 (amino acid sequence of the heavy chain variable region of HA-ID and HA-II-D): SEQ ID No: 37 (amino acid sequence of the light chain variable region of HA-ID): SEQ ID No: 38 (amino acid sequence of the light chain variable region of HA-II-A): SEQ ID No: 39 (amino acid sequence of the light chain variable region of HA-II-B and HA-II-C): SEQ ID No:40 (amino acid sequence of the light chain variable region of HA-II-D): Example 13 Example 13 of the present invention further defines, on the basis of Example 12, that the human antibody constant region includes a human antibody heavy chain constant region and a human antibody light chain constant region, and the amino acid sequence of the human antibody heavy chain constant region is one of SEQ ID No: 27, SEQ ID No: 28 or SEQ ID No: 29; the amino acid sequence of the human antibody light chain constant region is as shown in SEQ ID No: 30. The specific sequence of the above human antibody constant region is the same as that in Example 10. Example 14 Preparation of humanized antibody molecules Example 14 of the present invention further defines, on the basis of Example 13, that the human antibody constant region includes a human IgG1 heavy chain constant region (whose amino acid sequence is shown in SEQ ID No: 27) and a human C k The light chain constant region of the type (the amino acid sequence of which is shown in SEQ ID No: 30). The coding genes of the heavy chain VH and light chain VL of the eight humanized antibody molecules HA-IA, HA-IB, HA-IC, HA-ID, HA-II-A, HA-II-B, HA-II-C, and HA-II-D obtained by humanization in Example 12 were cloned into the vector pTSE (as shown in FIG. 3 ) containing the heavy chain constant region and the light chain constant region genes. The heavy chain constant region was of human IgG1 type (the amino acid sequence is shown in SEQ ID NO: 27), and the light chain constant region was C k chain (the amino acid sequence is shown in SEQ ID NO: 30). The two chimeric antibodies CA-I and CA-II obtained in Example 11 and the eight humanized antibody molecules HA-IA, HA-IB, HA-IC, HA-ID, HA-II-A, HA-II-B, HA-II-C, and HA-II-D obtained in Example 12 were transiently transfected into HEK293 cells (purchased from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, with the catalog number GNHu43) for antibody expression. The protein expression was performed using an AKTA instrument. The monoclonal antibody was purified by affinity column A, and the protein concentration was determined using a BCA kit (purchased from Beijing Huitian Oriental Technology Co., Ltd., catalog number: BCA0020). The protein size was then identified by SDS-PAGE. The results are shown in Figure 9. From left to right are the non-reduced protein molecular weights HA-IA, HA-IB, HA-IC, HA-ID, the chimeric antibody CA-I prepared in Example 11, the reduced protein molecular weight Marker, HA-II-A, HA-II-B, HA-II-C, HA-II-D, and the chimeric antibody CA-II. The molecular weight of each band is consistent with the theory. Embodiment 15 Example 15 defines the antibodies or antigen-binding fragments thereof disclosed in the present invention as one or a combination of Fab, F(ab)2, Fv or ScFv, and is not limited to the monoclonal antibodies disclosed in the present invention. Example 16 Embodiment 16 of the present invention further provides a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof that binds to IL-11. The present invention also provides a recombinant DNA expression vector, which contains the nucleic acid molecule described above. The present invention also provides a host cell transfected with the above-mentioned recombinant DNA expression vector, the host cell includes a prokaryotic cell, a yeast cell, an insect cell or a mammalian cell; Further preferably, the host cell is a mammalian cell, and the mammalian cell is a HEK293 cell, a CHO cell or a NS0 cell. The present invention also provides a medicine, which comprises the antibody or antigen-binding fragment thereof that binds to IL-11. The present invention also provides a detection reagent, which is used to detect the antibody or antigen-binding fragment thereof that binds to IL-11. The present invention also provides a combination pharmaceutical composition, which includes an antibody or an antigen-binding fragment thereof that binds to IL-11, and also includes a second composition, which is selected from an antibody or an antigen-binding fragment thereof that binds to PD-1, PD-L1, VEGF, VEGFR, TNF-α or TSLP. Preferably, the antibody or antigen-binding fragment thereof that binds to PD-1 is selected from DFPD1-9, DFPD1-10, DFPD1-11, DFPD1-12, DFPD1-13, Nivolumab, Pembrolizumab, Teplizumab, Sintilimab, Tislelizumab, Carrelizumab, Penpulimab or Sepalimab, wherein the heavy chain constant region and light chain constant region sequences of DFPD1-9, DFPD1-10, DFPD1-11, DFPD1-12, and DFPD1-13 are the same as the heavy chain constant region and light chain constant region of the anti-PD-1 monoclonal antibody provided in patent application No. CN201510312910.8. Preferably, the antibody or antigen-binding fragment thereof that binds to VEGF is selected from aflibercept, bevacizumab, or lenalizumab. Embodiment 17 Example 17 of the present invention provides the use of an antibody or an antigen-binding fragment thereof that binds to IL-11 in the preparation of a drug for treating or preventing human fibrotic diseases, inflammation, cancer or autoimmune diseases. Preferably, the fibrotic disease includes, but is not limited to, fibrosis of the heart, liver, kidney, lung, gallbladder, bladder, stomach, bone marrow, penis, breast, blood vessels, eyes, pancreas, spleen, brain, intestine, muscle or skin. Preferably, inflammation includes, but is not limited to, hepatitis, myocarditis, nephritis, pneumonia, cholecystitis, cystitis, gastritis, osteomyelitis, prostatitis, mastitis, pancreatitis, enteritis, arthritis, polymyositis, dermatomyositis or dermatitis. Preferably, the cancer includes, but is not limited to, leukemia, lung cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, melanoma, kidney cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer or bladder cancer. Preferably, the autoimmune disease includes, but is not limited to, psoriasis, Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus or multiple sclerosis. The present invention also provides a method for treating or preventing a subject suffering from human fibrotic disease, inflammation, cancer or autoimmune disease, comprising administering to the subject a therapeutically or prophylactically effective amount of an antibody or antigen-binding fragment thereof that binds to IL-11. Example 18 Humanized Antibody Binding Experiment with IL-11 IL-11 antigen was coated with carbonate buffer at pH 9.6, 100 ng / well / 100 μL, overnight at 4°C. Wash five times with 300 μL / well PBST, and then add 1% BSA-PBST 280 μL / well to block for 1 hour at 37°C. Humanized antibodies HA-IA, HA-IB, HA-IC, HA-ID, HA-II-A, HA-II-B, HA-II-C, HA-II-D and chimeric antibodies CA-I and CA-II prepared in Example 11 were diluted with 1% BSA-PBST. The initial concentration of humanized antibodies was 10 μg / mL, and 8 gradients were diluted 5 times. Incubate at 37°C for 1 hour. Wash five times with 300 μL / well PBST, then add goat anti Human IgG Fab HRP (purchased from Invitrogen, catalog number: 31482) diluted 1:5000 with 1% BSA-PBST, and incubate at 37°C for 1 hour. TMB colorimetric kit was used for color development, 100 μL / well, color development at room temperature for 5 minutes, and then 2M H2SO4 was used to stop the color development. The microplate reader was read at 450nm / 630nm, and the corresponding EC50 value was calculated. The specific data are as follows: The above data and experimental results are shown in Figure 10. All eight humanized antibody molecules can bind to IL-11, and the EC50 values ​​of HA-IA, HA-IB, HA-IC, and HA-ID humanized antibody molecules are close to those of the chimeric antibody CA-I. The EC50 values ​​of HA-II-A, HA-II-B, HA-II-C, and HA-II-D humanized antibody molecules are close to those of the chimeric antibody CA-I. The humanized antibody molecules retained the high binding ability of the mouse parent antibodies MA-I and MA-II to IL-11. Example 19 Humanized antibody molecules inhibit the binding of IL-11 to the IL-11RA receptor on the surface of BaF / 3-IL-11RA cells Four humanized antibody molecules HA-IA, HA-IB, HA-IC and HA-ID with better binding activity at the protein level were selected for cell activity evaluation experiments. BaF / 3-IL-11RA cell lines were counted, a certain number of cells were taken, centrifuged and resuspended with PBS buffer, the cell density was adjusted to 1E+6 cells / mL, 100μL / well, and added to a 96-well plate. PBS was used to dilute the IL-11-mFc ligand protein to a concentration of 18μg / mL, 50μL / well, and added to the corresponding position of the 96-well plate containing BaF / 3-IL-11RA cells. After gently mixing, the 96-well plate was placed at 4°C and incubated for 1h. PBS buffer gradient dilution of four humanized antibody molecules HA-IA, HA-IB, HA-IC and HA-ID, prepared an initial concentration of 800μg / mL, 3-fold gradient dilution, a total of 10 gradients, 50μL / well, added to the corresponding position of the 96-well plate containing BaF / 3-IL-11RA cells and IL-11-mFc ligand protein mixture. After mixing evenly, incubate at 4°C for 2h. After the incubation, centrifuge the PBS buffer at 3000rpm to wash the cells once, and collect the cell pellet. Add the pre-prepared goat anti-mouse IgG Human ads-FITC antibody (purchased from SouthernBiotech, catalog number 1030-02) to the cell pellet, incubate at 4°C for 30min, centrifuge at 3000rpm to wash once, resuspend in 100μL PBS, and detect on the flow cytometer to collect the fluorescence signal in the FL1-A channel. Draw a dose-effect curve and calculate the corresponding IC50 value. The specific data are as follows: It can be seen from the above data and Figure 11 that the four humanized candidate molecules screened out can all inhibit the binding of IL-11 ligand protein to the IL-11RA receptor on the surface of BaF / 3-IL-11RA cells. Example 20 Humanized antibody molecules inhibit the binding of IL-11 to the GP130 receptor on the surface of BaF / 3-GP130 cells BaF / 3-GP130 cell lines were counted, a certain number of cells were taken, centrifuged and resuspended in PBS buffer, the cell density was adjusted to 1E+6 cells / mL, 100 μL / well, and added to a 96-well plate. IL-11-mFc ligand protein was diluted with PBS to a concentration of 12 μg / mL, 50 μL / well, and added to the corresponding position of the 96-well plate containing BaF / 3-GP130 cells. After gently mixing, the 96-well plate was placed at 4°C and incubated for 1 hour. 4 human antibody molecules HA-IA, HA-IB, HA-IC and HA-ID were gradiently diluted with PBS buffer to prepare an initial concentration of 2000 μg / mL, 2-fold gradient dilution, a total of 10 gradients, 50 μL / well, and added to the corresponding position of the 96-well plate containing BaF / 3-GP130 cells and IL-11-mFc ligand protein. After mixing evenly, the 96-well plate was incubated at 4°C for 2 hours. After the incubation, wash the cells once with PBS buffer by centrifugation at 3000rpm, and collect the cell pellet. Add the pre-prepared goat anti-mouse IgG Human ads-FITC antibody (purchased from SouthernBiotech, catalog number 1030-02) to the cell pellet, 100μL / well, and incubate at 4℃ for 30min. Wash once with PBS buffer by centrifugation at 3000rpm, resuspend the cells in 100μL / well PBS buffer, detect on the flow cytometer, and collect the fluorescence signal in the FL1-A channel. Draw the dose-effect curve and calculate the corresponding IC50 value. The specific data are as follows: It can be seen from the above data and Figure 12 that the four humanized candidate molecules screened out can all block the binding of IL-11 ligand protein to the GP130 receptor on the surface of BaF / 3-GP130 cells. Example 21 Biological Activity Detection of Humanized Antibody Molecules (Reporter Gene) Construction of BaF / 3-GP130-STAT3-Luc engineered cell line Methods: Plasmid GP130 (purchased from Sino Biological Biotechnology Co., Ltd., catalog number: HG10974-UT) and plasmid STAT3-Luc-NeoR (purchased from Jiman Biotechnology (Shanghai) Co., Ltd., catalog number: GM-021003) were respectively transferred into BAF / 3 cells (purchased from National Laboratory Cell Resource Center) by two electroporations, and the BaF / 3-GP130-STAT3-Luc engineered cell line was obtained by screening. The cell density was adjusted to 2E+6 cells / mL using sample diluent (its ingredients include 90% IMDM, 10% FBS, 10 ng / mL mouse IL-3). After gently mixing, the cell solution was added to a 96-well plate at 50 μL / well. The four humanized antibody molecules HA-IA, HA-IB, HA-IC and HA-ID were diluted to an initial concentration of 200 μg / ml using sample diluent, 5-fold gradient dilution, a total of 10 gradients, 100 μL / well, and added to the corresponding position of the 96-well plate containing the engineered cell line, and two replicates were set for each sample concentration. The sample diluent was used to prepare IL-11 protein at a concentration of 10 μg / mL, 50 μL / well, and added to the 96-well plate containing the engineered cell line and humanized antibody molecules. Gently mix the cell culture plate and place it in a 37°C CO2 incubator for 6 hours. Centrifuge and discard the supernatant, add the lysis solution, 10 μL / well to a 384-well plate, add an equal amount of luciferase reaction substrate (purchased from Promega Biotechnology Co., Ltd., catalog number E2610), react at room temperature for 5 minutes, read the fluorescence value under the microplate reader, and calculate the corresponding IC50 value. The specific data are as follows: According to the above data and FIG13 , the four humanized antibody molecules screened out can block the binding of IL-11 to IL-11RA and GP130 receptors, and inhibit the conduction of the signal pathway. Example 22 Humanized antibody molecules inhibit the secretion of TIMP-1 by embryonic lung fibroblasts MRC-5 Embryonic lung fibroblasts MRC-5 were digested with trypsin and counted, a certain number of cells were taken, and the cells were resuspended in MEM complete medium after centrifugation, and the cell density was adjusted to 2E+5 cells / mL, 100 μL / well, and added to a 96-well plate. MEM complete medium was used to dilute the IL-11-mFc ligand protein to a concentration of 16 μg / mL, 50 μL / well, and added to the corresponding 96-well plate. MEM complete medium was used to gradiently dilute 4 humanized antibody molecules HA-IA, HA-IB, HA-IC and HA-ID, with an initial concentration of 40 μg / mL, 3-fold gradient dilution, a total of 8 gradients, 50 μL / well, and added to a 96-well plate containing a cell suspension and an IL-11-mFc ligand protein suspension, gently mixed, placed in a 37°C CO2 incubator and incubated overnight, about 20 hours, and the cell culture supernatant was taken and detected using an ELISA kit of TIMP-1 (the method is the same as in Example 9). The microplate reader reads at 450nm and calculates the corresponding IC50 value. The specific data are as follows: It can be seen from the above data and Figure 14 that the four humanized antibody molecules screened out can effectively inhibit the release of TIMP-1 by human embryonic lung fibroblasts MRC-5 stimulated by IL-11 ligand protein. Example 23 Cross-binding experiment between humanized antibody molecules and IL-11 of different species The humanized antibody molecule HA-IA with better protein level and functional detection activity was selected for cross-binding detection with IL-11 of different species. Human IL-11, mouse IL-11 (purchased from Beijing Sino Biological Technology Co., Ltd., catalog number: 50117-MNCE), rat IL-11 (purchased from Kanglang Bio, catalog number: KL40001Ra), and cynomolgus monkey IL-11 (purchased from Sino Biological, catalog number: 90925-CNCE) were coated with pH 9.6 carbonate buffer at 100 ng / well / 100 μL, and coated overnight at 4°C. Wash five times with 300 μL / well PBST, then add 1% BSA-PBST, 280 μL / well, and block at 37°C for 1h. 1% BSA-PBST was used to dilute the humanized antibody HA-IA. The initial concentration was 50 μg / mL. The dilution was performed in 5-fold gradients, with a total of 9 gradients. Each gradient had two replicate wells. 100 μL / well was added to a 96-well plate. Incubate at 37°C for 1 hour. Wash five times with 300μL / well PBST, dilute goat anti Human IgG Fab HRP (purchased from invitrogen, catalog number: 31482) with 1% BSA-PBST, the working solution concentration is 1:5000, 100μL / well is added to a 96-well plate, and incubate at 37°C for 1 hour. Wash five times with 300μL / well PBST, develop with TMB colorimetric kit, 100μL / well, develop at room temperature in the dark for 5 minutes, and then terminate with 2M H2SO4. The microplate reader reads at 450nm / 630nm and calculates the corresponding EC50 value. The specific data are as follows: According to the above data and as shown in FIG15 , the humanized antibody molecule HA-IA can bind to human IL-11, mouse IL-11, rat IL-11, and cynomolgus monkey IL-11 with high affinity. Example 24 Experimental study on the therapeutic efficacy of anti-IL-11 monoclonal antibody on pulmonary fibrosis The therapeutic effect of anti-IL-11 monoclonal antibody HA-IA on pulmonary fibrosis was studied using bleomycin (bLF) model. Animal species: C57BL / 6J mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) Number, gender and age of mice: 6 / group, male, 6-8 weeks; The control group was injected with saline only; The drug administration group was injected with HA-IA antibody molecules twice a week for 4 weeks. The animal body weight was measured once a week, and the animals were observed for any abnormalities. Organ weight detection: lung organs were collected, the weight of the lung organs was measured, and the ratio of lung to body weight was calculated. Lung pathology detection: lung sections were sliced ​​and stained with hematoxylin and eosin (HE) and Masson's staining to observe the degree of lung fibrosis. The results are shown in Figure 16. After the administration of HA-IA antibody molecules, the ratio of lung to body weight of mice in the drug administration group was significantly lower than that in the control group. The results are shown in Figure 17. Compared with the control group, the lung sections of the drug administration group showed a significant reduction in pulmonary fibrosis. This indicates that the anti-IL-11 monoclonal antibody HA-IA antibody molecule can effectively inhibit the occurrence of pulmonary fibrosis. Example 25 Experimental study on the therapeutic efficacy of anti-IL-11 monoclonal antibody on cardiac fibrosis The therapeutic effect of anti-IL-11 monoclonal antibody HA-IA on cardiac fibrosis was studied using isoproterenol modeling. Animal species: C57BL / 6J mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) Number, gender and age of mice: 6 / group, male, 6-8 weeks; The control group was injected with saline only; The drug-treated group was injected with HA-IA antibody molecules twice a week for 4 weeks. The animal body weight was measured once a week and the animals were observed for any abnormalities; organ weight detection: the heart was collected, the heart weight was measured, and the heart-body weight ratio was calculated; cardiac pathology detection: the heart was sectioned and the degree of cardiac fibrosis was observed using hematoxylin and eosin (HE) and Masson staining. The results are shown in Figure 18, and the ratio of heart to body weight of mice in the drug-treated group was significantly lower than that in the control group. The results are shown in Figure 19, and compared with the control group, the heart sections of the drug-treated group showed a significant reduction in cardiac fibrosis, thus indicating that the anti-IL-11 monoclonal antibody HA-IA antibody molecule can effectively inhibit the occurrence of cardiac fibrosis. Example 26 Experimental study on the therapeutic efficacy of anti-IL-11 monoclonal antibody on renal fibrosis The therapeutic effect of anti-IL-11 monoclonal antibody HA-IA on renal fibrosis was studied using doxorubicin (dKF) modeling. Animal species: BALB / c mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) Number, gender and age of mice: 6 / group, male, 6-8 weeks; The control group was injected with saline only; The drug-treated group was injected with HA-IA antibody molecules twice a week for 4 weeks. The animal body weight was measured once a week and the animals were observed for any abnormalities; organ weight detection: the heart was collected, the kidney weight was measured, and the urine protein content was detected; renal pathology detection: kidney sections were sliced ​​and the degree of renal fibrosis was observed using hematoxylin and eosin (HE) and Masson staining. The results are shown in Figure 20. Compared with the control group, the urine protein content in the kidneys of the mice in the drug-treated group was significantly lower than that in the control group. The results are shown in Figure 21. Compared with the control group, the kidney sections of the drug-treated group showed a significant decrease in renal fibrosis, which indicates that the anti-IL-11 monoclonal antibody HA-IA antibody molecule can effectively inhibit the occurrence of renal fibrosis. Example 27 Experimental study on the therapeutic efficacy of anti-IL-11 monoclonal antibody on liver fibrosis CCl4 modeling was used to study the therapeutic effect of anti-IL-11 monoclonal antibody HA-IA on liver fibrosis. Animal species: C57BL / 6J mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) Number, gender and age of mice: 6 / group, male, 6-8 weeks; The control group was injected with saline only; The drug-treated group was injected with HA-IA antibody molecules twice a week for 4 weeks. Body weight monitoring: The animal body weight was measured once a week, and the animals were observed for any abnormalities. Liver pathology detection: The liver was sectioned and the degree of liver fibrosis was observed using hematoxylin and eosin (HE) and Masson staining. Organ weight detection: The kidneys were collected, the liver weight was measured, and HE staining was performed. Serum detection: Serum was collected to detect the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mouse serum. The results are shown in Figure 22, compared with the control group, the liver weight of mice in the drug-treated group was significantly lower than that of the control group; the results are shown in Figure 23, the ALT and AST levels in the serum of mice in the drug-treated group were significantly lower than those in the control group; the results are shown in Figure 24, compared with the control group, the liver sections of the drug-treated group showed a significant decrease in liver fibrosis, which indicates that the anti-IL-11 monoclonal antibody HA-IA antibody molecule can effectively inhibit the occurrence of liver fibrosis. Example 28 Evaluation of thermal stability of anti-IL-11 monoclonal antibody HA-IA The thermal stability of the anti-IL-11 monoclonal antibody HA-IA was evaluated using a multifunctional protein thermal stability analysis system (purchased from Unchained Labs). The changes in protein conformation were detected by monitoring the change in endogenous protein fluorescence with temperature (starting from 25°C and heating to 95°C at a rate of 0.3°C / min), thereby determining the protein melting temperature Tm and evaluating the stability of the protein conformation. When the sample aggregates, it causes interference of scattered light waves and increases the scattered light signal. The colloidal stability of the protein (characterized by Tagg) is determined by static light scattering. The results are shown in the following table and Figure 25. The melting temperature Tm of anti-IL-11 monoclonal antibody HA-IA was 79.5℃, and the average Tagg was 75.9℃, showing good conformational stability and colloidal stability. The present invention is not limited to the above-mentioned optimal implementation mode. Anyone can derive other various forms of products under the inspiration of the present invention. However, no matter what changes are made in the shape or structure, all technical solutions that are the same or similar to those of the present application fall within the protection scope of the present invention.

Claims

1. An antibody or antigen-binding fragment thereof that binds to IL-11, It is characterized in that The antibody or antigen-binding fragment thereof comprises three heavy chain complementary determining regions represented by HCDR1, HCDR2 and HCDR3, respectively, and three light chain complementary determining regions represented by LCDR1, LCDR2 and LCDR3, respectively, and the antibody or antigen-binding fragment thereof is selected from any one of the following: AI: the amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 1, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 2, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 3, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 4, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 5, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 6; A-II: the amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 1, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 2, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 3, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 4, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 5, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 7; A-III: the amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 8, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 9, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 10, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 11, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 12, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No: 13; A-IV: The amino acid sequence of the heavy chain complementary determining region HCDR1 is shown in SEQ ID No: 1, the amino acid sequence of the heavy chain complementary determining region HCDR2 is shown in SEQ ID No: 14, the amino acid sequence of the heavy chain complementary determining region HCDR3 is shown in SEQ ID No: 15, the amino acid sequence of the light chain complementary determining region LCDR1 is shown in SEQ ID No: 4, the amino acid sequence of the light chain complementary determining region LCDR2 is shown in SEQ ID No: 5, and the amino acid sequence of the light chain complementary determining region LCDR3 is shown in SEQ ID No:

6.

2. The IL-11-binding antibody or antigen-binding fragment thereof according to claim 1, It is characterized in that Comprising a heavy chain variable region and a light chain variable region, the antibody or antigen-binding fragment thereof is selected from any one of the following: MA-Ⅰ: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 16, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 17; MA-Ⅱ: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 16, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 18; MA-III: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 19, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 20; MA-IV: The amino acid sequence of the heavy chain variable region is shown in SEQ ID No:21, and the amino acid sequence of the light chain variable region is shown in SEQ ID No:

17.

3. The IL-11-binding antibody or antigen-binding fragment thereof according to claim 2, It is characterized in that It also includes a heavy chain constant region and a light chain constant region, wherein the amino acid sequence of the heavy chain constant region is one of SEQ ID No:23, SEQ ID No:24, SEQ ID No:25 or SEQ ID No:26; and the amino acid sequence of the light chain constant region is as shown in SEQ ID No:

22.

4. The antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 2, It is characterized in that The antibody or antigen-binding fragment thereof is a chimeric antibody molecule, and the chimeric antibody molecule also includes a human antibody constant region.

5. The antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 1, It is characterized in that Comprising a heavy chain variable region and a light chain variable region, the antibody or antigen-binding fragment thereof is selected from any one of the following: HA-IA: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 32; HA-IB: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 33, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 34; HA-IC: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 35; HA-ID: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 36, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 37; HA-II-A: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 38; HA-II-B: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 31, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 39; HA-II-C: the amino acid sequence of the heavy chain variable region is shown in SEQ ID No: 33, and the amino acid sequence of the light chain variable region is shown in SEQ ID No: 39; HA-II-D: The amino acid sequence of the heavy chain variable region is shown in SEQ ID No:36, and the amino acid sequence of the light chain variable region is shown in SEQ ID No:

40.

6. The antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 5, It is characterized in that The antibody or antigen-binding fragment thereof further comprises a humanized antibody constant region.

7. The IL-11-binding antibody or antigen-binding fragment thereof according to claim 4 or 6, It is characterized in that The human antibody constant region includes a human antibody heavy chain constant region and a human antibody light chain constant region, and the amino acid sequence of the human antibody heavy chain constant region is one of SEQ ID No:27, SEQ ID No:28 or SEQ ID No:29; the amino acid sequence of the human antibody light chain constant region is as shown in SEQ ID No:

30.

8. The antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 1, It is characterized in that The antibody or antigen-binding fragment thereof is one or a combination of Fab, F(ab)2, Fv or ScFv.

9. A nucleic acid molecule, It is characterized in that The nucleic acid molecule encodes the antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 1.

10. A recombinant DNA expression vector, It is characterized in that The recombinant DNA expression vector comprises the nucleic acid molecule of claim 9.

11. A host cell transfected with the recombinant DNA expression vector according to claim 10, It is characterized in that The host cell includes a prokaryotic cell, a yeast cell, an insect cell or a mammalian cell; Preferably, the host cell is a mammalian cell, and the mammalian cell is a HEK293 cell, a CHO cell or a NS0 cell.

12. A drug, It is characterized in that The drug comprises the antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 1.

13. A detection reagent, It is characterized in that The detection reagent is used to detect the antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 1.

14. A combination drug composition, It is characterized in that The combination composition includes the antibody or antigen-binding fragment thereof that binds to IL-11 as described in claim 1, and also includes a second composition, which is selected from an antibody or antigen-binding fragment thereof that binds to PD-1, PD-L1, VEGF, VEGFR, TNF-α or TSLP.

15. Use of the antibody or antigen-binding fragment thereof that binds to IL-11 according to claim 1 in the preparation of a drug for treating or preventing human fibrotic diseases, inflammation, cancer or autoimmune diseases.

16. The use according to claim 15, It is characterized in that The fibrotic disease includes fibrosis of the heart, liver, kidney, lung, gallbladder, bladder, stomach, bone marrow, penis, breast, blood vessels, eyes, pancreas, spleen, brain, intestine, muscle or skin.

17. The use according to claim 15, It is characterized in that The inflammation includes hepatitis, myocarditis, nephritis, pneumonia, cholecystitis, cystitis, gastritis, osteomyelitis, prostatitis, mastitis, pancreatitis, enteritis, arthritis, polymyositis, dermatomyositis or dermatitis.

18. The use according to claim 15, It is characterized in that The cancer includes leukemia, lung cancer, stomach cancer, esophageal cancer, ovarian cancer, head and neck cancer, melanoma, kidney cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer or bladder cancer.

19. The use according to claim 15, It is characterized in that The autoimmune disease includes psoriasis, Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus or multiple sclerosis.

Images