EP2152311A1 - Ensemble de moyens pour le traitement d'une pathologie maligne, d'une maladie auto- immune ou d'une maladie infectieuse - Google Patents

Ensemble de moyens pour le traitement d'une pathologie maligne, d'une maladie auto- immune ou d'une maladie infectieuse

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Publication number
EP2152311A1
EP2152311A1 EP08805512A EP08805512A EP2152311A1 EP 2152311 A1 EP2152311 A1 EP 2152311A1 EP 08805512 A EP08805512 A EP 08805512A EP 08805512 A EP08805512 A EP 08805512A EP 2152311 A1 EP2152311 A1 EP 2152311A1
Authority
EP
European Patent Office
Prior art keywords
antibody
cell
autoimmune
disease
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08805512A
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German (de)
English (en)
French (fr)
Inventor
Christophe De Romeuf
Nathalie Fournier
Nadine Fernandez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LFB Biotechnologies SAS
Original Assignee
LFB Biotechnologies SAS
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Filing date
Publication date
Application filed by LFB Biotechnologies SAS filed Critical LFB Biotechnologies SAS
Publication of EP2152311A1 publication Critical patent/EP2152311A1/fr
Withdrawn legal-status Critical Current

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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
    • C07K16/34—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood group antigens
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/563—Immunoassay; Biospecific binding assay; Materials therefor involving antibody fragments
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    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
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    • A61K35/14—Blood; Artificial blood
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P37/02—Immunomodulators
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    • A—HUMAN NECESSITIES
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    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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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
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to a treatment of a malignant pathology, an autoimmune disease, or an infectious disease, in particular via an effector cell that expresses a Fc ⁇ R receptor on its surface.
  • the tissues or organs most commonly affected by autoimmune disease are hematopoietic cells, blood vessels, connective tissues, endocrine glands, muscles, joints, and skin.
  • Autoimmune diseases are often associated with chronic inflammatory conditions. The most common case is rheumatoid arthritis and juvenile rheumatoid arthritis, which are two types of inflammatory arthritis.
  • Arthritis is a general term for inflammation of the joints. Most treatments have many side effects or do not completely prevent the progression of the disease.
  • B cells are the cells producing the autoantibodies often responsible for the development of autoimmune diseases, their destruction by administration of a monoclonal antibody specific for this cell type can only be beneficial for patients, as has been demonstrated for rituximab which has just been approved for the treatment of rheumatoid arthritis.
  • infectious diseases are a persistent and significant problem in modern medicine.
  • the most common disease, the common cold is an infectious disease in the same way as AIDS (Acquired Immunodeficiency Syndrome), the most feared disease. It has been proven that some neurological disorders classified as degenerative diseases were actually related to an infection. Infectious diseases will remain a major medical problem in the future.
  • monoclonal antibodies can have two complementary roles: a role of neutralization of the pathogen or toxins secreted during the acute phase of infection and a role in the destruction of reservoir cells during the passage to chronicity.
  • the destruction of the host cells allowing the low-noise duplication of the pathogen could prevent the transition to a chronic phase, most often leading to the development of serious pathologies such as autoimmune disease or cancer.
  • Today despite the existence of a real need, there is virtually no effective anti-infective treatment in the treatment of chronic phases.
  • the beneficial effects of small molecules (antibiotics, antiparasitic, anti-viral) during the acute phases of infections are increasingly compromised by the development of cross-resistance.
  • the appearance of multidrug-resistant bacteria poses a public health problem with 6% to 7% of hospitalizations complicated by nosocomial infection more or less serious, approximately
  • the cells resistant to a particular agent administered in the current protocol are unfortunately also resistant to other drugs, including those acting by a mechanism different from that used by the agent administered in the treatment protocol.
  • This phenomenon known as multidrug resistance, is often at the root of the therapeutic failure of standard chemotherapy protocols.
  • Chronic lymphocytic leukemia B (CLB-B), a disease characterized by malignant proliferation of B-lymphocytes (BBCs), is the most common form of leukemia.
  • the current treatment is essentially based on therapeutic abstention for the early stages of the disease.
  • patients are classically treated with corticosteroids alone or association with anti-mitotic molecules.
  • resistance to treatment is established in the more or less long term. It usually results in the failure of the therapeutic effort with the appearance of chemo-resistant cells.
  • Chemotherapy is responsible for major side effects including myelotoxicity generating an immune deficiency responsible for the appearance of serious infections, sometimes fatal, in patients.
  • Several therapeutic approaches aimed at destroying tumor B cells as specifically as possible have been evaluated.
  • the specific expression of the CD20 molecule by tumor LB (and normal) allowed the development of therapies based on the use of human anti-CD20 monoclonal antibodies.
  • rituximab (Rituxan, Genentech and Mabthera, Roche)
  • rituximab is currently available on the market. It is indicated for the treatment of patients with stage III-IV follicular lymphoma and in combination with chemotherapy for the treatment of patients with diffuse aggressive large B-cell CD20-positive non-Hodgkin's lymphoma (NHL).
  • NEL non-Hodgkin's lymphoma
  • Rituximab has also been evaluated in patients with B-CLL. Since this antibody was only weakly effective when used as monotherapy, it is currently being administered in combination with chemotherapy.
  • ⁇ .tuximab In order to increase the efficacy of ⁇ .tuximab, its association with macrophages activated ex vivo in the presence of ⁇ -interferon (IFN- ⁇ ) was evaluated in vitro in a test of CL-B primary cell lysis ( Lefebvre ML, Stefan W Krause, Salcedo M, Nardin Ex vivo activated hunnan macrophages kill chromium lymphocytic leukemia cells presence of Rituximab: Mechanism of antibody-dependent cellular cytotoxicity and impact of human serum. J.
  • CL-B primary cell lysis Lefebvre ML, Stefan W Krause, Salcedo M, Nardin Ex vivo activated hunnan macrophages kill chromium lymphocytic leukemia cells presence of Rituximab: Mechanism of antibody-dependent cellular cytotoxicity and impact of human serum.
  • This inhibition is related to the competition by the polyclonal immunoglobulins present in the serum with respect to the binding of the rituximab-LLC complex to the different RFCs expressed on the surface of the macrophages.
  • the intensity of this inhibition depends on the concentrations of rituximab and the ratio of effector cells: target cells
  • the cell expressing CD16 on its surface is chosen from monocytes expressing CD16, macrophages and dendritic cells.
  • the cell derived from monocyte or monocyte precursor, which expresses CD16 on its surface is a macrophage.
  • the monoclonal antibody is not displaced by the polyclonal immunoglobulins, particularly those present in the serum, this because of the high affinity of the Fc region of said monoclonal antibody for CD16.
  • the monoclonal antibody binds CD16 of said monocyte derived cell or a monocyte precursor with a higher affinity than 2.10 6 M "1.
  • the monoclonal antibody is directed against an antigen selected from the antigen 5C5 (tumor antigen expressed by renal cell carcinoma cells), the BCR (B CeIl Receptor), an idiotype such as that inhibitory anti-FVIIl antibodies, the antigen 5C5 (tumor antigen expressed by renal cell carcinoma cells), the BCR (B CeIl Receptor), an idiotype such as that inhibitory anti-FVIIl antibodies, the antigen 5C5 (tumor antigen expressed by renal cell carcinoma cells), the BCR (B CeIl Receptor), an idiotype such as that inhibitory anti-FVIIl antibodies, the antigen 5C5 (tumor antigen expressed by renal cell carcinoma cells), the BCR (B CeIl Receptor), an idiotype such as that inhibitory anti-FVIIl antibodies, the antigen 5C5 (tumor antigen expressed by renal cell carcinoma cells), the BCR (B CeIl Receptor), an idiotype such as that inhibitory anti-FVIIl antibodies,
  • TCR T CeII Receptor
  • the monoclonal antibody is directed against CD20.
  • the anti-CD20 antibody is produced by the cell line R509 deposited at the CNCM on November 8, 2004 under the accession number 1-3314, or by the cell line R603 deposited. at the CNCM on November 29, 2005 under the accession number I-3529 (CNCM: National Collection of Cultures of Microorganisms, Pasteur Institute, 25 rue du Dondel Roux, 75724 Paris Cedex 15 - France).
  • the set of means of the invention is intended for use in therapy simultaneously, sequentially or separately.
  • the monoclonal antibody induces cytotoxicity by ADCC activity or by phagocytosis of said target cell of the antibody in the presence of an effector cell expressing CD16.
  • Another object of the invention relates to the use of the set of means of the invention for the manufacture of a medicament.
  • the malignant pathology is selected from solid tumors and malignant hemopathies.
  • the solid tumors are selected from melanomas, carcinomas, sarcomas, gliomas and cutaneous cancers.
  • the carcinomas are selected from the group consisting of carcinomas of the kidney, breast, oral cavity, lungs, gastrointestinal tract, ovaries, prostate, uterus, bladder, carcinoma. pancreas, liver, gallbladder, skin and testes.
  • Another subject of the invention relates to the use of the set of means of the invention for the manufacture of a medicament for the treatment of a primary or secondary autoimmune and / or inflammatory disease, specific for organs or systemic and associated or not with pathogenic autoantibodies.
  • Another object of the invention relates to the use of the set of means of the invention for the manufacture of a medicament for the treatment of an infectious disease.
  • the combination of means of the invention is a drug combination containing, as active substance, an effector cell which expresses CD16 on its surface and a monoclonal antibody in which the affinity of the Fc region of this monoclonal antibody for CD16 is greater than the affinity of the Fc region of polyclonal immunoglobulins for CD16 for simultaneous, separate or sequential use in the treatment of malignancies, autoimmune diseases, or infectious diseases.
  • the set of means of the invention may also be in the form of a mixture.
  • Such cells are thus capable of inducing ADCC activity in the presence of the monoclonal antibodies of the invention, due to the binding between the Fc region of the monoclonal antibodies and the CD16 receptor expressed by the cell.
  • the effector cell is a macrophage.
  • this culture step may advantageously be preceded by a separation step, on the one hand, of the mononuclear cells, and, on the other hand, red blood cells, granulocytes and a part of the platelets contained in the composition derived from blood obtained by cytapheresis, and by a step of removing, by washing, a portion of blood platelets and anticoagulants remaining after the previous step.
  • any other method for obtaining macrophages, leading to the expression of CD16 on their surface is also applicable to the invention.
  • the terms “monoclonal antibody” or “monoclonal antibody composition” refer to a preparation of antibody molecules derived from a cell clone and having identical and unique specificity.
  • variable parts The region that determines the specificity of the antibody for the antigen is carried by the variable parts, while the constant parts can interact with the Fc receptors of effector cells or molecules such as complement proteins to induce different functional properties.
  • the antibody according to the invention is a chimeric, humanized or human antibody.
  • the antibody according to the invention is chimeric.
  • the chimeric antibodies according to the invention can be produced by co-transfection or simple transfection into a host cell of the light chain expression vector and the heavy chain or single vector expression vector using a well known method. of the skilled person (by for example, calcium phosphate co-precipitation, electroporation, microinjection, etc.).
  • variable domain sequence of a murine antibody is compared to a library of known human variable region sequences and the human variable sequence closest to the raurin sequence is retained as a FR region.
  • Framework of the humanized antibody [Riechmann et al., Nature 332: 323-7 (1988); Queen C. et al., Proc. Natl. Acad. Sci. USA 86 (24): 10029-33 (1989); Sims et al., J. Immunol., 151: 2296 (1993)].
  • humanized antibodies according to the invention are preferred for use in in vitro diagnostic methods, or in vivo prophylactic and / or therapeutic treatment.
  • the monoclonal antibodies of the invention may be produced by an isolated cell, for example selected from SP2 / 0, YB2 / 0, IR983F, Namalwa human myeloma, PERC6, CHO lines, especially CHO-KI, CHO-LeclO, CHO-Lecl, CHO-Lecl3, CHO Pro-5, CHO dhfr-, Wil -2, Jurkat, Vero, Molt-4, COS-7, 293-HEK, BHK, K6H6, NSO, SP2 / O-Ag 14 and P3X63Ag8.653, this list not being limiting.
  • an isolated cell for example selected from SP2 / 0, YB2 / 0, IR983F, Namalwa human myeloma, PERC6, CHO lines, especially CHO-KI, CHO-LeclO, CHO-Lecl, CHO-Lecl3, CHO Pro-5, CHO dhfr-, Wil -2
  • the monoclonal antibody of the invention is produced by the transgenic animal in its milk.
  • the gene coding for the protein of interest is associated with regulatory elements of genes specifically expressed in milk (for example the WAP gene promoter, whey acidic protein).
  • the expression vector thus obtained is microinjected under a microscope into mammalian embryos at the unicellular stage. Embryos are then transferred to recipient females. For example, after one month of gestation, the first mammals that have integrated the transgene (FO) into their genome are born and are identified by PCR analysis of ear biopsy. They will serve as founders to give birth to the second generation of transgenic mammals. The founders are selected for their efficiency in producing the protein of interest in their milk and for generating the second generation of transgenic rabbits (F1).
  • the CD16 receptor is traditionally referred to as a "low affinity receptor", and is expressed constitutionally on PMNs (polymorphonuclear neutrophils), a subpopulation of monocytes, macrophages, dendritic cells and Natural Killer cells (NK cells).
  • PMNs polymorphonuclear neutrophils
  • NK cells Natural Killer cells
  • CD16 participates in multiple effector functions, such as phagocytosis, opsonization of immune particles or complexes, and ADCC activity.
  • the monoclonal antibody of the set of means of the invention has a Fc region having a high affinity for Fc receptors present on the effector cells of the invention, and in particular for CD16.
  • the invention describes the synergism between the Fc region of the monoclonal antibodies of the invention and the CD16 of the effector cells of the set of means. This affinity is such that the addition of human polyvalent plasma IgG (important constituent of peripheral blood) in the medium containing antibodies and effector cells has little or no influence on the ADCC activity generated by the association. between the monoclonal antibody and the effector cells. This is because the affinity of the Fc region of the monoclonal antibody for CD16 is greater than that of human IgG present under physiological conditions.
  • polyvalent immunoglobulins also called polyvalent plasma IgG or polyclonal IgG or serum IgG.
  • the monoclonal antibody of the set of means induces activation of the effector cells via the Fc receptors including CD16 and CD64 leading to cell lysis by ADCC or phagocytosis. It is now generally accepted that polyvalent plasma IgGs inhibit the mechanism of lysis of effector cells via CD64, the latter being saturated in the presence of polyvalent IgGs.
  • the monoclonal antibody is not displaced by the polyvalent IgGs in the case of the addition of human plasma IgG. Due to the high affinity of the Fc region of the antibody for CD16, the monoclonal antibody binds the effector cells, and this binding is not displaced by human polyvalent plasma IgG even at high serum concentrations. Accordingly, the set of means of the invention allows optimal lysis of the target cells even at low concentrations of the monoclonal antibody.
  • the concentration of the monoclonal antibody of the set of means is less than the concentration of an antibody of the same specificity, traditionally used as monotherapy, for the treatment of malignant diseases, autoimmune or infectious diseases.
  • the Fc region of the monoclonal antibody of the invention has a CD16 association constant of at least 2.10 6 M -1 .
  • association constant of the antibody of the invention is measured according to the method described in FIG. Maenaka et al. (Katsumi Maeneka, P. Anton van der Merwe, David I. Stuart, E. Yvonne Jones, and Peter Sondermann, The Human Low Affinity Fc7 receptors IIa, Hb and III Bind IgG with Fast Kinetics and Distinct Thermodynamic Properties, J. Biol. Chem., Vol 276, Issue 48, 44898-44904, November 30, 2001).
  • the monoclonal antibody of the invention may be prepared using the method described in patent application WO 01/77181.
  • This process for the preparation of a monoclonal antibody capable of activating the effector cells expressing CD16 comprises the following steps: a) purification of monoclonal antibodies obtained from different clones originating from cell lines selected from hybridomas, in particular hetero-hybridomas and animal or human cell lines transfected with a vector comprising the gene coding for said antibody; b) adding each antibody obtained in step a) to a separate reaction mixture comprising: i. the target cells of said antibodies, ii. effector cells comprising cells expressing Fc ⁇ RIII, iii. polyvalent IgG, c) determination of the percentage of lysis of the target cells and selection of the monoclonal antibodies which activate the effector cells causing significant lysis of the target cells (Fc ⁇ RIII dependent ADCC activity).
  • the monoclonal antibody composition is produced by a cell having a low enzymatic activity allowing the addition of fucose to N-acetylglucosamine of the reducing end, such an enzyme being preferably the fucosyltransferase.
  • an enzyme for example fucosidase, so to obtain a composition of monoclonal antibodies comprising such a fucose level.
  • the monoclonal antibody composition is produced in YB2 / 0 (ATCC CRL-1662).
  • the effector cells are administered at a dose of between 10 4 and 10 9 effector cells per injection.
  • the effector cells are administered repeatedly up to 10 times, the time interval between each administration being between 2 days and 12 months.
  • the monoclonal antibody is administered repeatedly up to 10 times, the time interval between each administration being between 2 days and 12 months.
  • the monoclonal antibody and the effector cells are administered simultaneously.
  • the macrophages are incubated with varying concentrations (0 to 83 ⁇ g / ml) of anti-CD20 antibodies (EMAB6, EMAB603 or rituximab) and anti-CD16 3G8 antibody coupled to a fluorochrome (3G8-PE) at a fixed concentration.
  • EMAB6, EMAB603 or rituximab anti-CD20 antibodies
  • 3G8-PE fluorochrome
  • the binding of the 3G8-PE antibody to the CD16 receptor of the macrophages is evaluated by flow cytometry.
  • Antibodies with the ability to bind to CD16 compete with the binding of the 3G8 antibody and, therefore, induce a decrease in the MFI (Mean Fluorescence Intensity or Mean Fluorescence Intensity).
  • MFI mean Fluorescence Intensity or Mean Fluorescence Intensity
  • Example 4 Activity ADCC anti-D / Rh + red blood cells / macrophages. Role of polyvalent IVIg (Tegeline). The cytotoxic capacity of the anti-D antibodies is studied by the ADCC technique. Anti-D antibodies, macrophages
  • the two anti-D antibodies, EMABling R297 and AD1 have an ADCC activity of the order of 29%.
  • the EMABling antibody appears at least 20 times more active (23% lysis per 1% with AD1). This advantage persists at higher concentrations of polyvalent immunoglobulins (25 mg / ml), the respective percentages of lysis for the EMABling antibody and AD1 being 16 and 1%.
  • the percentage of doubly labeled macrophages PKH67 / PKH26 increases in the absence of IVIg for the two antibodies tested, R297 EMABling and AD1. In the presence of IVIg, only the EMABling antibody has the capacity to phagocyte red blood cells
  • PKH67 / PKH26 increases in the absence of IVIg for the two antibodies tested, R603 anti-CD20 and Rituxan.
  • the EMABling antibody has a higher capacity, of the order of

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EP08805512A 2007-04-25 2008-04-25 Ensemble de moyens pour le traitement d'une pathologie maligne, d'une maladie auto- immune ou d'une maladie infectieuse Withdrawn EP2152311A1 (fr)

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CN110279714A (zh) * 2019-06-21 2019-09-27 安徽瑞达健康产业有限公司 一种nk细胞和vegf靶点抗体的组合物及在肝癌上应用
FR3112939B1 (fr) * 2020-07-31 2024-01-05 Univ Montpellier Produit universel de thérapie cellulaire et son utilisation
CN113009130B (zh) * 2021-02-10 2022-08-23 中国医学科学院北京协和医院 一种用于诊断原发性干燥综合征的生物标志物及其用途
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