WO2007134538A1 - Anticorps monoclonal murin contre les facteurs d'inhibition de la migration des macrophages humains et application de celui-ci - Google Patents

Anticorps monoclonal murin contre les facteurs d'inhibition de la migration des macrophages humains et application de celui-ci Download PDF

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WO2007134538A1
WO2007134538A1 PCT/CN2007/001651 CN2007001651W WO2007134538A1 WO 2007134538 A1 WO2007134538 A1 WO 2007134538A1 CN 2007001651 W CN2007001651 W CN 2007001651W WO 2007134538 A1 WO2007134538 A1 WO 2007134538A1
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monoclonal antibody
antibody
sequence
cgmcc
mif
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Jie Tang
Yanfang Wu
Yunbo Wang
Hongzhe Zhou
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Institute Of Biophysics Chinese Academy Of Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a mouse monoclonal antibody against human macrophage migration inhibitory factor and uses thereof. Background technique
  • Macrophage migration inhibitory factor is one of the early discovered cytokines.
  • the MIF cDNA encodes a protein of 115 amino acids that does not belong to any cytokine superfamily and does not have strong homology to any other protein in mammalian cells.
  • MIF proteins including humans, rats, mice, and cattle
  • MIF may have important biological functions.
  • Macrophages in the immune system are the main cells that produce MIF, and are widely distributed in other tissues. It is worth noting that cells or tissues that express MIF, such as the lungs, epithelial layer of the skin, gastrointestinal tract, genitourinary tract, etc., are directly related to the host's natural environment. Another distinctive feature of MIF is that some tissues of the endocrine system can express MIF at high levels, especially those associated with stress response, such as the hypothalamus, pituitary gland, and adrenal gland.
  • Glucocorticoid is a broad-spectrum anti-inflammatory drug, and MIF is the first antagonistic protein found in glucocorticoid function. MIF - released, can invalidate the immunosuppressive effects of steroids (glucocorticoids), thus showing a unique physiological role, as if it is a negative regulator induced by glucocorticoids (Bucala, R. (1996) MIF re-discovered : pituitary hormone and glucocorticoid-induced regulator of cytokine production. Cytokine Growth Factor Rev. 7, 19-24; Donnelly, SC and Bucala, R. (1997) . Macrophage migration inhibitory factor : a regulator of glucocorticoid Activity with a critical role in inflammatory disease. Mol. Med. Today 3, 502-507. ).
  • MIF plays an important role in the innate immune system as a cytokine.
  • LPS LPS
  • MIF TNF- ⁇ , IFN- ⁇ and other stimulating macrophages release MIF.
  • MIF When MIF is released into tissues or circulating throughout the body, it acts as a classical pro-inflammatory cytokine, promoting intrinsicity through macrophage and T cell activation. Adaptive immune response.
  • MIF production is detrimental in acute infections. In animal models, inhibition of MIF is evident in sepsis, acute lung injury, and systemic inflammatory response syndrome.
  • Therapeutic effect (Calandra, T. and BUcala, R. (1995). Macrophage migration inhibitory factor: a counter-regulator of glucocorticoid action and critical mediator of septic shock. J. Inflamm. 47, 39-51 ; Calandra, T., Echtenacher, B., Roy, DL, Pugin, J., Metz, CN, Hultner, L., Heumann, D., Mannel, D., Bucala, R., and Glauser, MP (2000) .
  • MIF is also associated with autoimmune diseases such as rheumatoid arthritis, asthma, multiple sclerosis, and diabetes.
  • anti-MIF antibodies can well slow the progression of the disease in rats and inhibit mortality by 100%. Due to the antagonism of MIF on glucocorticoids, anti-MIF antibodies combined with low-dose glucocorticoids may enhance the anti-inflammatory effects of hormones and reduce the side effects of hormones (Baugh, JA and Donnelly, SC (2003). Macrophage migration inhibitory Factor: a neuroendocrine modulator of chronic inflammation. J. Endocrinol. 179, 15-23; Morand, EF (2005) . New .
  • MIF macrophage migration inhibitory factor
  • MIF is a very important cytokine, and inhibition of MIF activity is expected to provide new treatment options for patients with severe sepsis and inflammation, autoimmune diseases and cancer.
  • One technical problem to be solved by the present invention is to provide a secretory specific binding human macrophage A hybridoma cell line of a monoclonal antibody to a cell migration inhibitory factor.
  • the hybridoma cell line is a hybridoma cell line 10C3 CGMCC No. 1717.
  • Hybridoma cell line 10C3 CGMCC No. 1717 was deposited with the General Microbiology Center (CGMCC) of the China Microbial Culture Collection Management Committee on May 22, 2006. The address of the deposit center is No. 13, North Section of Zhongguancun, Haidian District, Beijing, China. The number is CGMCC No. 1717.
  • CGMCC General Microbiology Center
  • Another technical problem to be solved by the present invention is to provide a monoclonal antibody that specifically binds to a human MIF protein, or a single-chain antibody, Fab fragment, or human-mouse chimeric antibody derived from such a monoclonal antibody.
  • the monoclonal antibody provided by the present invention is a monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717; the derivative of the monoclonal antibody is a single chain antibody, a Fab fragment or a human-mouse chimeric antibody.
  • the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717, the Fab fragment derived from the monoclonal antibody or the heavy chain variable region of the human-mouse chimeric antibody has SEQ ID NO: 1 in the sequence listing.
  • the amino acid residue sequence, the light chain variable region has the amino acid residue sequence of SEQ ID NO: 2 in the Sequence Listing.
  • the light chain of the human-mouse chimeric antibody derived from the monoclonal antibody has the amino acid residue sequence of SEQ ID NO: 8 in the Sequence Listing, and the heavy chain has the amino acid residue sequence of SEQ ID NO: 9 in the Sequence Listing. Its name is ch-10C3.
  • the single-chain antibody derived from the monoclonal antibody has the amino acid residue sequence of SEQ ID NO: 3 in the sequence listing, and its name is 10C3 scFV.
  • the light chain encoding gene of the human-mouse chimeric antibody derived from the monoclonal antibody may have the nucleotide sequence of SEQ ID NO: 6 in the Sequence Listing, and the heavy chain encoding gene may have the nucleotide sequence of SEQ ID NO: 7 in the Sequence Listing.
  • the gene encoding the single-chain antibody 10C3scFV may have the nucleotide sequence of SEQ ID NO: 10 in the Sequence Listing.
  • Figure 1 shows the dissociation curve of monoclonal antibody secreted by hybridoma cell line 10C3 CGMCC No: 1717 and human MIF by ELISA.
  • FIG. 2 shows the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717. MIF stimulates Raw264. 7 cells to produce NO curve
  • Figure 3 is a hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody inhibits human MIF stimulation Raw264. 7 cells produce TNF- alpha results
  • Figure 4 shows the survival of mice injected with LPS and injected with monoclonal antibodies raised by LPS and hybridoma cell line 10C3 CGMCC No. 1717.
  • the fusion protein contained 6 Xhis Tag and was purified by Ni-NTA affinity chromatography.
  • Immunized NZB/W F1 mice (Nanjing University Model Animal Institute), 80 micrograms of human MIF plus MPL + TDM emulsion adjuvant (sigma) foot immunization, once a week, a total of three times. After 3 days of the third immunization, NZB/W F1 mice were immunized with lymphocytes and mixed with murine myeloma SP2/0 cells in a ratio of 5:1, and fused with polyethylene glycol. After HAT screening, hybridomas were obtained.
  • Hybridoma secretion secreting specific binding to MIF antibody GST-MIF recombinant protein expressed in E. coli (10 ⁇ g/ml) (The coding region of huMIF was cloned into PET-41a vector (Novagen, USA), and the cloned plasmid was in DH5. Amplification in ⁇ , and expression in BL21. Fusion protein with GST Tag, purified by glutathione affinity chromatography.) Plate, hybridoma supernatant (gradient dilution) is primary antibody, HRP coupling The goat anti-mouse IgG polyclonal antibody (R&D Systems) was subjected to ELISA for the secondary antibody to obtain a dissociation curve. The 50% of the maximum ELISA reading corresponds to the antibody concentration as the dissociation constant of the antibody.
  • Hybridoma cells secreting specific antibodies were cloned multiple times by restriction dilution method, and finally hybridoma cell line 10C3 CGMCC No. 1717 was obtained.
  • the dissociation curve of monoclonal antibody secreted by hybridoma cell line 10C3 CGMCC No. 1717 and MIF by ELISA is shown in Figure 1, indicating the dissociation constant of monoclonal antibody secreted by hybridoma cell line 10C3 CGMCC No. 1717 and human MIF. It is 3nM (SP 480ng/ml).
  • the abscissa of Fig. 1 is the concentration of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No.
  • Antibody subtype identification assay GST-MIF recombinant protein (10 ⁇ g/ml) coated with E. coli, hybridoma supernatant as primary antibody, HRP-conjugated rat anti-mouse IgG1, IgG2a, or IgG2b monoclonal
  • the antibody (BD Pharmingen) was tested for ELISA by secondary antibody.
  • the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 was confirmed to be an IgG2b subtype.
  • Preparation method of ascites Balb/C mice were intraperitoneally injected with 0.5% of the hypoxanthine. After 10 days, the hybridoma cell suspension was inoculated into the abdominal cavity of the mouse. After the abdominal cavity of the mouse was swollen, the ascites was collected and centrifuged to obtain the supernatant. . The antibody was purified by protein A/G affinity chromatography column (Pierce), eluted with 0.1 M Glycine/HCl (pH 2.5).
  • Hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody can block human MIF stimulation Raw264. 7 cells produce NO
  • the recombinant human MIF (prepared as above) and the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 purified in step 1 were stimulated to stimulate Raw264. 7 cells for 16 hours. A total of six treatments were carried out: a final concentration of 3 ug/ml recombinant human MIF and a final concentration of 100 ug/ml.
  • Step 1 Purified hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody mixed treatment, final concentration 3ug/ml Recombinant human MIF and a final concentration of 33. 3 ug/ml of the purified hybridoma cell line 10C3 CGMCC No.
  • 1717 secreted monoclonal antibody mixed treatment a final concentration of 3 ug / ml recombinant human MIF and a final concentration of 11. lug /ml of step 1 purified hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody mixed treatment, final concentration of 3ug / ml recombinant human MIF and final concentration of 3. 7ug / ml of step 1 purified hybridoma cells 10C3 CGMCC No. 1717 secreted monoclonal antibody mixed treatment, final concentration of 3ug/ml recombinant human MIF and final concentration of 1.23ug/ml step 1 purified hybridoma cell line 10C3 CGMCC No.
  • 1717 secreted monoclonal The antibody was mixed, and the final concentration of 3 ug/ml recombinant human MIF and the final concentration of 0. 41 ug/ml of the purified hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody were mixed. The amount of newly produced nitric oxide in the cell culture solution was measured by Griess reagent colorimetry. The results are shown in Fig. 2. It is shown that the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 purified in step 1 (the initial concentration of the antibody is 100 ug/ml, 3-fold dilution) can significantly reduce the MIF stimulation of Raw264 by mixing with MIF. .
  • Hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody can block MIF stimulation.
  • Raw264. 7 cells produce tumor necrosis factor (TNF-a)
  • the recombinant human MIF (prepared as above) and the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 purified in step 1 were stimulated to stimulate Raw264. 7 cells, and the supernatant was collected after 3 hours, diluted to 1/100 to stimulate L929.
  • the cells were added with 5 mg/ml MTT 20 ul/well after 16 h. After the culture was continued for 3 h, the supernatant was discarded, 150 ul of DMSO was added, and A 59 was measured after shaking. Absorbance value. The relative absorbance was obtained by subtracting the absorbance of the stimulated Raw264. 7 cell supernatant sample from the absorbance of the unstimulated Raw264.
  • recombinant human MIF and the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 purified in step 1 have six mixed treatments: a final concentration of 0 ug/ml recombinant human MIF and a final concentration of 0 ug/ml.
  • Step 1 Purified hybridoma cell line 10C3 CGMCC No. 1717 secreted monoclonal antibody mixed treatment, final concentration of 3ug/ml recombinant human MIF and final concentration of 11 ug / ml of step 1 purified hybridoma cell line 10C3 CGMCC No. 1717 secreted single Mixed polyclonal antibody treatment.
  • the results are shown in Fig. 3. It is shown that the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No.
  • 1717 purified in step 1 can significantly reduce the secretion of TNF-a caused by MIF stimulation of Raw264. 7 cells by mixing with MIF.
  • 10C3 Ab indicates a monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717.
  • Example 2 Preparation of anti-MIF human-mouse chimeric antibody ch-10C3
  • the present invention is the murine antibody humanization, the preparation of human - mouse chimeric antibody ch-10C3 o of the antibody variable region sequences of an antibody derived from a murine hybridoma cell line 10C3 CGMCC No. 1717 Secretion Monoclonal antibody, the constant region sequence is derived from human IgGl.
  • This antibody maintains the antigen binding specificity of the murine monoclonal antibody while reducing the immune rejection induced in the human body.
  • the steps for preparing a chimeric antibody are as follows:
  • the mRNA was isolated and purified from the hybridoma cell line 10C3 CGMCC No. 1717, and the first strand cDNA was synthesized using oligo-dT.
  • the antibody light and heavy chain variable regions were amplified by PCR, and the light chain primers were 5, GAY ATT GTG MTS ACM CAR WCT MCA 3' and 5' CTC CAG ATG TTA ACT GCT CAC 3; the heavy chain primers were: 5, ATG SAR GTN MAG CTG SAG SAG TC 3, and 5, GGT CAA GGT CAC TGG CTC AGG3, .
  • the light chain and heavy chain variable region genes of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 were ligated to the human light chain and heavy chain constant region genes, respectively, to construct a coding chimeric antibody ch-10C3.
  • a fusion gene the coding gene of the chimeric antibody light chain having the nucleotide sequence of SEQ ID NO:6 in the sequence listing, encoding a ch-10C3 light chain having the amino acid residue sequence of SEQ ID NO:8 in the sequence listing;
  • the coding gene has a nucleotide sequence of SEQ ID NO: 7 in the Sequence Listing, encoding a ch-10C3 heavy chain having the amino acid residue sequence of SEQ ID NO: 9 in the Sequence Listing.
  • the coding gene of the chimeric antibody light chain was inserted into the expression vector pCI-gpt (promega vector pCI) with a selectable marker (guanine phosphoribosyltransferase, gpt) and a gene expression regulatory region (CMV promoter, terminator)
  • pCI-gpt promega vector pCI
  • CMV promoter, terminator a selectable marker
  • the gene encoding the guanine phosphoribosyltransferase was inserted into the multiple cloning site of pCI to obtain the expression vector pCI-gpt), and the chimeric antibody light chain expression vector pCI-gpt-10C3L was obtained.
  • the coding gene of the chimeric antibody heavy chain was inserted into the expression vector pCI-DHFR with the selectable marker (dihydrofolate reductase DHFR) and the gene expression regulatory region (CMV promoter, terminator) (promega vector pCI was used as a template) Construction, reduction of dihydrofolate
  • the coding gene of the enzyme was inserted into the multiple cloning site of pCI to obtain the expression vector pCI-DHFR), and the chimeric antibody heavy chain expression vector pCI-DHFR-10C3H was obtained.
  • the expression vectors pCI-gpt-10C3L and pCI-DHFR-10C3H containing the chimeric antibody gene were introduced into mammalian cells NS/0 (purchased from ECACC) by electroporation. Transformed cells were screened in a medium containing Xanthine with Mycophenolate to obtain stably transfected cell lines. The secretion of the antibody was identified by ELISA according to the method of Example 1, and the results showed that the obtained ch-10C3 antibody retained the specificity and affinity of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717, and the ch-10C3 antibody and MIF The dissociation constant is 3 nM.
  • Example 3 Preparation of anti-MIF single chain antibody 10C3 scFV
  • the light chain and heavy chain variable region genes of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 were amplified by PCR, and the heavy and light chain variable regions were further enriched in glycine and serine by PCR.
  • the 15 amino acid fragments were ligated to obtain the coding sequence of the anti-MIF single chain antibody 10C3 scFV (SEQ ID NO: 10).
  • the coding sequence of the 10C3 scFV gene was cloned into the expression vector pET-26b (Novagen, USA), and the cloned plasmid was amplified in DH5 ⁇ and expressed in BL21.
  • the fusion protein carries 6 X his Tag and is purified by Ni-NTA affinity chromatography.
  • the expressed 10C3 scFV has the amino acid residue sequence of SEQ ID NO:3 in the Sequence Listing.
  • the anti-MIF single chain antibody 10C3scFV was identified by ELISA according to the method of Example 1, and it was revealed that the anti-MIF single chain antibody 10C3scFV retains the specificity and affinity of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717, and the anti-MIF single chain
  • the dissociation constant of antibody 10C3scFV and MIF was 30 nM.
  • Example 4 Preparation of Fab fragment against MIF Preparation of 10C3Fab
  • the full-length antibody was degraded into a Fab and an Fc fragment by immobilized papain-digested monoclonal antibody secreted by hybridoma cell line 10C3 CGMCC No. 1717 in the ImmunoPure® Fab preparation kit (Pierce).
  • the digested product was purified using an immobilized Protein A column provided in the kit to obtain an antibody fragment of Fab.
  • the Fab fragment 10C3Fab of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 was identified by ELISA according to the method of Example 1, and the Fab fragment of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 was shown.
  • 10C3Fab retains the specificity and affinity of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717, and the dissociation constant of the Fab fragment against MIF 10C3Fab and MIF is 10 nM.
  • LPS group LPS
  • antibody group LPS + anti-MIF
  • the cage was kept in the SPF class for 48 hours, free to eat and water. Fasting 2 hours before the injection.
  • LPS group and antibody group Mice were given LPS (Sigma 0111: B4) 22. 5 mg/kg by weight.
  • the monoclonal antibody lOOug/only secreted by the hybridoma cell line 10C3 CGMCC No. 1717 was administered. Both drugs were diluted in sterile PBS to a final volume of 200 ul and injected intraperitoneally.
  • the two-component cage was fed and the condition after administration was observed. After 12 hr, similar tremors appeared, body hair was upright, and external stimuli were not sensitive. After 16 hours, mice died in the LPS group and the antibody group; 60 hours, the antibody group survival rate was 40%, and the LPS group survival rate was 20% (Fig. 4).
  • the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717 has a protective effect in the LPS-induced mouse sepsis model.
  • the dissociation constants of the monoclonal antibody secreted by the hybridoma cell line 10C3 CGMCC No. 1717, the single-chain antibody 10C3scFV derived from the monoclonal antibody, the human-mouse chimeric antibody ch-10C3 or Fab fragment and human MIF were respectively demonstrated. 3nM, 30nM, 3nM, 10nM.
  • Monoclonal antibody secreted by hybridoma cell line 10C3 CGMCC No. 1717, single-chain antibody 10C3scFV derived from the monoclonal antibody, human-mouse chimeric antibody ch-10C3 or Fab fragment can block human MIF stimulation of Raw264. 7 cell production
  • the inflammatory factors N0 and TNF_alpha have protective effects in the LPS-induced mouse sepsis model.
  • the above monoclonal antibodies and derivatives thereof can specifically recognize human macrophage migration inhibitory factor with high affinity and neutralize their biological activities, and can be used for treating inflammatory reactions such as sepsis, systemic inflammatory response syndrome or acute lung injury; It can be used to treat autoimmune diseases such as rheumatoid arthritis, asthma, multiple sclerosis, diabetes or lupus erythematosus; it can also inhibit tumor formation; the above monoclonal antibodies and their derivatives can be combined with glucocorticoids. Reduce the amount of glucocorticoids and side effects.
  • the above monoclonal antibodies and derivatives thereof can be used to clinically test the level of MIF.

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Abstract

Cette invention concerne un anticorps monoclonal murin contre les facteurs d'inhibition de la migration des macrophages humains ainsi que son application. L'anticorps monoclonal est sécrété par l'hybridome 10C3 CGMCC No.1717. L'anticorps monoclonal, l'anticorps simple chaîne, l'anticorps chimérique humain-murin ou le segment Fab provenant de l'anticorps monoclonal peuvent être utilisés pour traiter la septicémie, les syndromes de réaction inflammatoires systémiques ou une lésion pulmonaire sévère ainsi que d'autres réactions inflammatoires. Cet anticorps monoclonal peut également être utilisé pour traiter l'arthrite rhumatoïde, l'asthme, la sclérose en plaques, les diabètes ou le lupus érythémateux et d'autres maladies auto-immunes. Cet anticorps monoclonal peut également être utilisé pour freiner le développement tumoral. L'anticorps monoclonal et ses dérivés peuvent être combinés à un glucocorticoïde afin de réduire le dosage et les effets secondaires de ce dernier.
PCT/CN2007/001651 2006-05-24 2007-05-22 Anticorps monoclonal murin contre les facteurs d'inhibition de la migration des macrophages humains et application de celui-ci WO2007134538A1 (fr)

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WO2009086920A1 (fr) * 2008-01-04 2009-07-16 Baxter International Inc. Anticorps anti-mif
CN101602809B (zh) * 2008-12-29 2011-12-07 中国人民解放军疾病预防控制所 具有抗炎作用的抗体靶向补体抑制物
WO2018050833A1 (fr) * 2016-09-15 2018-03-22 Ablynx Nv Domaines variables uniques d'immunoglobuline dirigés contre le facteur inhibiteur de la migration des macrophages
US9958456B2 (en) 2011-10-07 2018-05-01 Baxalta Incorporated OxMIF as a diagnostic marker
CN114573693A (zh) * 2022-04-25 2022-06-03 中国人民解放军陆军军医大学 一种听觉发育中免疫调节分子mif抗体制备方法

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AU2013203957B9 (en) * 2012-04-16 2015-10-15 Baxalta GmbH Combination Therapy of Anti-MIF Antibodies and Glucocorticoids
AU2013202693B2 (en) * 2012-04-16 2015-01-22 Baxalta GmbH Combination Therapy of Anti-MIF Antibodies and Chemotherapeutics
EP3052943B1 (fr) * 2013-10-04 2019-11-20 Cell Ideas Pty Ltd. Biomarqueurs pour thérapie cellulaire
CN105087610A (zh) * 2015-09-11 2015-11-25 中国科学院海洋研究所 文蛤巨噬细胞迁移抑制因子基因及其编码蛋白和应用

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CN101983207A (zh) * 2008-01-04 2011-03-02 巴克斯特国际公司 抗mif抗体
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CN101983207B (zh) * 2008-01-04 2016-01-20 巴克斯特国际公司 抗mif抗体
CN103724430A (zh) * 2008-01-04 2014-04-16 巴克斯特国际公司 抗mif抗体
EP2548890A1 (fr) * 2008-01-04 2013-01-23 Baxter International Inc Anticorps contre mif
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KR101654678B1 (ko) 2008-01-04 2016-09-08 백스터 인터내셔널 인코포레이티드 항 ｍｉｆ 항체
WO2009086920A1 (fr) * 2008-01-04 2009-07-16 Baxter International Inc. Anticorps anti-mif
CN101602809B (zh) * 2008-12-29 2011-12-07 中国人民解放军疾病预防控制所 具有抗炎作用的抗体靶向补体抑制物
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US11098113B2 (en) 2016-09-15 2021-08-24 Vib Vzw Immunoglobulin single variable domains directed against macrophage migration inhibitory factor
CN114573693A (zh) * 2022-04-25 2022-06-03 中国人民解放军陆军军医大学 一种听觉发育中免疫调节分子mif抗体制备方法

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