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WO2022083049A1 - Anticorps anti-cd73 et son utilisation - Google Patents

Anticorps anti-cd73 et son utilisation Download PDF

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WO2022083049A1
WO2022083049A1 PCT/CN2021/080517 CN2021080517W WO2022083049A1 WO 2022083049 A1 WO2022083049 A1 WO 2022083049A1 CN 2021080517 W CN2021080517 W CN 2021080517W WO 2022083049 A1 WO2022083049 A1 WO 2022083049A1
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seq
antibody
amino acid
sequence
fibrosis
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PCT/CN2021/080517
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Chinese (zh)
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夏瑜
王忠民
金小平
李百勇
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中山康方生物医药有限公司
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Definitions

  • the present invention relates to the field of immunology.
  • it relates to anti-CD73 antibodies and uses thereof.
  • Ecto-5'-nucleotidase the CD73 protein, is a multifunctional glycoprotein with a molecular weight of 70KD encoded by the NT5E gene, which is mediated by glycosylphosphatidylinositol (glyocsyl phosphatidy linositol, GPI) is anchored to the cell membrane (Zimmermann H. Biochem J. 1992;285:345-365).
  • CD73 is widely distributed on the surface of human tissue cells and is also widely expressed on the surface of immune cells, such as dendritic cells, regulatory T cells (Treg), natural killer cells (NK cells), and myeloid-derived suppressor cells (MDSC).
  • immune cells such as dendritic cells, regulatory T cells (Treg), natural killer cells (NK cells), and myeloid-derived suppressor cells (MDSC).
  • CD73 has both hydrolase activity and non-hydrolase activity.
  • One of the immunosuppressive mechanisms of the enzymatic and non-enzymatic functions of CD73 is mediated by the CD73-Adenosine metabolic signaling pathway.
  • CD39 upstream of CD73 can catalyze the production of adenosine monophosphate (AMP) from ATP, and the generated AMP is catalyzed by CD73 It is converted into adenosine, and adenosine binds to the downstream adenosine receptor (A2AR).
  • A2AR inhibits a series of immune activation-related signaling pathways such as LCK, MAPK, and PKC by activating protein kinase A (PKA) and Csk kinase.
  • PKA protein kinase A
  • CD73 is expressed in human B cells, T cells, bone marrow cells, bone marrow stromal cells and thymic epithelial cells.
  • Organ fibrosis refers to the necrosis of parenchymal cells of organs, fibrous connective tissue, necrosis of parenchymal cells due to various chronic stimuli, such as pathogenic microorganism infection, inflammation, immune response, toxins (drugs), radiation, ischemia and hemodynamic changes, etc. Pathological processes including abnormal increase and excessive deposition of cellular components and extracellular matrix (ECM).
  • pathogenic microorganism infection such as pathogenic microorganism infection, inflammation, immune response, toxins (drugs), radiation, ischemia and hemodynamic changes, etc.
  • Pathological processes including abnormal increase and excessive deposition of cellular components and extracellular matrix (ECM).
  • ECM extracellular matrix
  • organ fibrosis with unknown pathogenic mechanism called idiopathic or primary organ fibrosis, such as idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the milder degree is called fibrosis, and the severe one causes the destruction of the tissue structure
  • the fibrous connective tissue deposited in the tissues of fibrotic organs includes two major parts: cellular components and ECM. tissue parenchyma cells, fibroblasts and mononuclear phagocytes; and collagen, non-collagen glycoproteins, proteoglycans and elastic fibers.
  • transforming growth factor- ⁇ transforming growth factor- ⁇
  • CTGF connective tissue growth factor
  • PDGF platelet-derived growth factor
  • bFGF basic fibroblast growth factor
  • epidermal growth factor EGF epidermal growth factor
  • IL-1, IL-6, IL-8, TNF- ⁇ , IFN- ⁇ , etc. are also involved in the occurrence of diseases (Wynn TA.J Pathol.2008;214(2):199-210) .
  • TGF- ⁇ signaling regulates ECM deposition in breast cancer through an adenosine-dependent mechanism (Vasiukov G, et al. Cancer Res. 2020;80(12):2628-2638).
  • Tissue blood supply disorder is a risk factor for organ fibrosis, and the institutional changes caused by organ fibrosis can often lead to tissue blood supply disorder and tissue cell hypoxia.
  • hypoxia-inducible factor-1 HIF-1
  • IIF-1 Isolecular upregulation, resulting in widespread expression of CD73
  • A2B receptor A2BR
  • A2BR is more easily activated under hypoxia, and the activation of A2BR directly promotes the production of a large amount of IL-6 in related cells, which not only induces the differentiation of lung fibroblasts (Zhong HY et al. Am J Respir Cell Mol Biol, 2005, 32:2–8.).
  • Organ fibrosis can occur in a variety of tissues, such as liver, kidney, heart, lung and bone marrow.
  • the main pathological features of chronic kidney disease are excessive deposition of extracellular matrix and extensive fibrosis. A common pathway that ultimately leads to end-stage renal failure. The extent and degree of renal fibrosis is highly correlated with renal dysfunction.
  • liver fibrosis is common in liver inflammation infection (viruses, bacteria, fungi, parasites), toxin damage, changes in liver blood flow, and many congenital metabolic abnormalities cause substances to accumulate in the liver. All of the above factors can lead to liver fibrosis and damage the liver.
  • Myelofibrosis is characterized by the abnormal deposition of collagen, fibronectin, laminin and other fibrous tissues in the bone marrow, replacing the normal bone marrow hematopoietic tissue, thus seriously affecting the hematopoietic function.
  • Arteriosclerosis is a fibroproliferative disease of the arteries that results in thickening, stiffness and loss of elasticity of the vessel wall and a narrowing of the lumen.
  • idiopathic pulmonary fibrosis is a chronic progressive fibrotic interstitial lung disease with unknown etiology and pathogenesis.
  • the disease is mainly confined to the lungs, and it usually occurs in middle-aged and elderly men. It is mainly manifested as progressively worsening dyspnea, accompanied by restrictive ventilation dysfunction and gas exchange disorders, resulting in hypoxemia and even respiratory failure.
  • the study found a potential link between idiopathic pulmonary fibrosis and the adenosine system.
  • CD73 catalyzes the production of adenosine from AMP, which binds to the receptor A2BR and promotes the differentiation of lung fibroblasts into myofibroblasts (Della LV et al. Pharmacological research, 2013, 76: 182–189.).
  • CD73-deficient mice had less radiation-induced pulmonary fibrosis (Wirsdorfer F. et al. Cancer research, 2016, 76(10): 3045–3056.); selected Sexual antagonism of A2BR can reduce inflammation and fibrosis (Zhou Y et al. PloS one, 2010, 5(2): e9224).
  • the present inventors use a mammalian cell expression system to express recombinant human CD73 as an antigen to immunize mice, and obtain hybridoma cells by fusing mouse spleen cells with myeloma cells.
  • the inventor obtained the hybridoma cell line LT014 by screening a large number of samples (the deposit number is CCTCC NO: C2018137).
  • the hybridoma cell line LT014 can secrete and produce a specific monoclonal antibody (named 19F3) that specifically binds to human CD73. Further, the inventors have prepared a humanized antibody against human CD73 (for example named 19F3H1L1 (hG1DM), 19F3H2L2 (hG1DM) and 19F3H2L3 (hG1DM)).
  • the inventors also surprisingly found that the antibodies of the present invention, such as 19F3H1L1 (hG1DM), 19F3H2L2 (hG1DM) and 19F3H2L3 (hG1DM), can very effectively inhibit the enzymatic reaction of CD73 in a non-substrate competition manner and reduce the production of adenosine , and exhibited good pharmacological activity in a mouse model of pulmonary fibrosis.
  • the antibody of the present invention has the effect of treating tissue and organ fibrosis.
  • Another aspect of the present invention also relates to an anti-CD73 antibody, wherein the anti-CD73 antibody comprises HCDR1, HCDR2 of the heavy chain variable region shown in SEQ ID NO: 2, SEQ ID NO: 6 or SEQ ID NO: 10 and HCDR3, and LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:12 or SEQ ID NO:14;
  • the anti-CD73 antibody comprises:
  • HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 15, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% with the sequence , 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or have one or more sequences compared to said sequence (preferably 1, 2 or 3) amino acid sequences of conservative amino acid mutations (preferably substitutions, insertions or deletions), or consisting of,
  • HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 16, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% with the sequence , 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or have one or more sequences compared to said sequence (preferably 1, 2 or 3) amino acid sequences of conservative amino acid mutations (preferably substitutions, insertions or deletions), or consisting of,
  • HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 17, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% with the sequence , 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or have one or more sequences compared to said sequence (preferably 1, 2 or 3) amino acid sequences of conservative amino acid mutations (preferably substitutions, insertions or deletions), or consisting of,
  • LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 18, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% with said sequence , 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or have one or more sequences compared to said sequence (preferably 1, 2 or 3) amino acid sequences of conservative amino acid mutations (preferably substitutions, insertions or deletions), or consisting of,
  • LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 19, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% with the sequence , 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or have one or more sequences compared to said sequence (preferably 1, 2 or 3) the amino acid sequence of conservative amino acid mutations (preferably substitutions, insertions or deletions), or consisting of, and
  • LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 20, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% with the sequence , 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or have one or more sequences compared to said sequence
  • the amino acid sequence of preferably 1, 2 or 3 conservative amino acid mutations (preferably substitutions, insertions or deletions), or consisting of.
  • the heavy chain variable region of the antibody comprises or consists of the following sequence:
  • the heavy chain variable region of the antibody comprises or consists of the following sequences:
  • SEQ ID NO:2 SEQ ID NO:6 or SEQ ID NO:10, having at least 80%, 81%, 82%, 83%, SEQ ID NO:2, SEQ ID NO:6 or SEQ ID NO:10, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity
  • the sequence of SEQ ID NO: 2, SEQ ID NO: 6 or SEQ ID NO: 10 has one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acid sequences of conservative amino acid mutations (preferably substitutions, insertions or deletions); and
  • the light chain variable region of the antibody comprises or consists of the following sequences:
  • amino acid sequence of the heavy chain variable region of the antibody is set forth in SEQ ID NO:2
  • amino acid sequence of the light chain variable region of the antibody is set forth in SEQ ID NO:4 Show;
  • amino acid sequence of the variable region of the heavy chain of the antibody is shown in SEQ ID NO: 6, and the amino acid sequence of the variable region of the light chain of the antibody is shown in SEQ ID NO: 8;
  • amino acid sequence of the heavy chain variable region of the antibody is shown in SEQ ID NO: 10
  • amino acid sequence of the light chain variable region of the antibody is shown in SEQ ID NO: 12; or
  • amino acid sequence of the heavy chain variable region of the antibody is shown in SEQ ID NO:10, and the amino acid sequence of the light chain variable region of the antibody is shown in SEQ ID NO:14.
  • the heavy chain constant region of the antibody is the Ig gamma-1 chain C region, ACCESSION:P01857; the light chain constant region is the Ig kappa chain C region, ACCESSION:P01834.
  • the heavy chain constant region of the antibody is a leucine to alanine point introduced at position 234 based on the Ig gamma-1 chain C region, ACCESSION:P01857 Mutation (L234A), a point mutation (L235A) from leucine to alanine was introduced at position 235;
  • the light chain constant region is the C region of the Ig kappa chain, ACCESSION:P01834, the amino acid sequence is as shown in SEQ ID NO:21 Show.
  • variable regions of the light and heavy chains determine antigen binding; the variable regions of each chain contain three hypervariable regions, called complementarity determining regions (CDRs) (the CDRs of the heavy chain (H) include HCDR1, HCDR2, HCDR3 , the CDRs of the light chain (L) comprise LCDR1, LCDR2, LCDR3; it is named by Kabat et al., see Bethesda M.d., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 1991; 1-3:91-3242.
  • CDRs complementarity determining regions
  • the CDRs can also be defined by the IMGT numbering system, see Ehrenmann, Francois, Quentin Kaas, and Marie-Paule Lefranc.
  • IMGT/3Dstructure-DB and IMGT/DomainGapAlign a database and a tool for immunoglobulins or antibodies, T cell receptors , MHC, IgSF and MhcSF. Nucleic acids research 2009;38(suppl_1):D301-D307.
  • amino acid sequences of the CDR regions of the monoclonal antibody sequences are analyzed according to the IMGT definitions by technical means well known to those skilled in the art, for example, by the VBASE2 database.
  • antibody CDR regions Given the known sequences of antibody heavy and light chain variable regions, there are currently several methods for determining antibody CDR regions, including the Kabat, IMGT, Chothia and AbM numbering systems.
  • variable region amino acid sequence of the antibody Given the variable region amino acid sequence of the antibody, one skilled in the art can generally determine which residues comprise a particular CDR, without relying on any experimental data other than the sequence itself.
  • the antibodies 19F3, 19F3H1L1 (hG1DM), 19F3H2L2 (hG1DM), and 19F3H2L3 (hG1DM) involved in the present invention have the same CDRs:
  • amino acid sequences of the three CDR regions in the variable region of its heavy chain are as follows:
  • HCDR1 GYSFTGYT (SEQ ID NO: 15),
  • HCDR2 INPYNAGT (SEQ ID NO: 16),
  • HCDR3 ARSEYRYGGDYFDY (SEQ ID NO: 17);
  • amino acid sequences of the three CDR regions of the light chain variable region are as follows:
  • LCDR1 QSLLNSSNQKNY (SEQ ID NO: 18),
  • LCDR3 QQHYDTPYT (SEQ ID NO:20).
  • the antibody is a monoclonal antibody.
  • the antibody is a humanized antibody, a chimeric antibody, a multispecific antibody (eg, a bispecific antibody).
  • the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab') 2 , Fd, Fv, dAb, Fab/c, complementarity determining region fragments, single chain antibodies (eg, scFv ), humanized antibodies, chimeric antibodies or bispecific antibodies.
  • Another aspect of the invention pertains to isolated polypeptides selected from the group consisting of:
  • An isolated polypeptide comprising the sequences shown in SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17, wherein the polypeptide, as part of an anti-CD73 antibody, specifically binds to CD73, the antibody also comprise the sequence shown in SEQ ID NO: 18; SEQ ID NO: 19; SEQ ID NO: 20;
  • An isolated polypeptide comprising the sequence shown in SEQ ID NO: 2, SEQ ID NO: 6 or SEQ ID NO: 10 or having at least 80%, 81%, 82%, 83%, 84% with the sequence %, 85%, 86%, 87%, 88%, 89%, 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in sequence or have one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence
  • the amino acid sequence of the polypeptide, wherein the polypeptide is used as a part of an anti-CD73 antibody that specifically binds to CD73, and the antibody also corresponds to the sequence shown in SEQ ID NO: 4, SEQ ID NO: 8 or SEQ ID NO: 12 or with Said sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%
  • An isolated polypeptide comprising or having at least 80%, 81%, 82%, 83%, 84% with the sequence shown in SEQ ID NO:4, SEQ ID NO:8 or SEQ ID NO:12 %, 85%, 86%, 87%, 88%, 89%, 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in sequence or have one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence
  • the amino acid sequence of the polypeptide, wherein the polypeptide is used as a part of an anti-CD73 antibody that specifically binds to CD73, and the antibody also corresponds to the sequence shown in SEQ ID NO: 2, SEQ ID NO: 6 or SEQ ID NO: 10 or with Said sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,
  • An isolated polypeptide comprising or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% with the sequence shown in SEQ ID NO: 10 %, 89%, 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or compared to said sequence
  • polypeptide comprising or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% with the sequence shown in SEQ ID NO: 14 %, 89%, 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or compared to said sequence
  • the antibody also comprises the sequence shown in SEQ ID NO: 10 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, or to the The sequences are
  • Another aspect of the present invention pertains to an isolated nucleic acid molecule encoding an antibody or antigen-binding fragment thereof of any one of the present invention, or the isolated polypeptide.
  • Yet another aspect of the present invention relates to a vector comprising the isolated nucleic acid molecule of the present invention.
  • Yet another aspect of the present invention relates to a host cell comprising an isolated nucleic acid molecule of the present invention, or a vector of the present invention.
  • Yet another aspect of the present invention relates to a conjugate comprising an antibody and a coupling moiety, wherein the antibody is the antibody or antigen-binding fragment thereof of any one of the present invention, and the coupling moiety is a purification tag (such as His tag), a detectable label or a small molecule drug; preferably, the coupling moiety is a radioisotope, a fluorescent substance, a chemiluminescent substance, a colored substance, polyethylene glycol or an enzyme; preferably, the small
  • the molecular drug is a small-molecule cytotoxic drug; more preferably, the small-molecule drug is a tumor chemotherapy drug, more preferably, the antibody or its antigen-binding fragment is linked to the small-molecule drug through a linker; for example, the linker is a hydrazone bond, a disulfide bond or a peptide bond; more preferably, the antibody or its antigen-binding fragment is linked with the small molecule drug in a certain molar ratio; for
  • Yet another aspect of the present invention relates to a fusion protein or a multispecific antibody (preferably a bispecific antibody) comprising the antibody or antigen-binding fragment thereof of any one of the present invention.
  • kits comprising the antibody or antigen-binding fragment thereof of the present invention, the conjugate, fusion protein or multispecific antibody of the present invention; preferably, the kit further comprises A second antibody that specifically recognizes the antibody; optionally, the second antibody further includes a detectable label, such as a radioisotope, fluorescent substance, chemiluminescent substance, colored substance, or enzyme.
  • a detectable label such as a radioisotope, fluorescent substance, chemiluminescent substance, colored substance, or enzyme.
  • kits comprising an effective amount (eg, 0.001 mg-1000 mg) of the antibody or antigen-binding fragment thereof of the present invention, the conjugate, fusion protein or multispecific antibody of the present invention , and optionally, an effective amount of one or more anti-fibrotic drugs (eg, 100-2400 mg).
  • the kit further comprises immunosuppressive and/or anti-inflammatory agents and/or DNA methylation regulators.
  • the anti-fibrotic drug may be a modulator of RhoA, RhoAGTPases, TGF- ⁇ 1 or any other member of the CTGF or RhoA signaling pathway, or may modulate inhibitor of cytokine signaling 1 (SOCS1 ), inhibitors of cytokine signaling 3 (SOCS 3) or modulators of TLR9, nintedanib, pirfenidone, angiogenic factor antagonists, drugs that inhibit myocardial remodeling (eg, ACE inhibitors, captopril, Enalapril, fosinopril, benazepril, lisinopril, etc.; ARBs include losartan, valsartan, olmesartan, irbesartan, candesartan, etc.), beta receptors Body blockers (such as propranolol, metoprolol, atenolol, bisoprolol, carvedilol, etc.), or stat
  • a further aspect of the present invention relates to the use of the antibody or antigen-binding fragment thereof, conjugate, fusion protein or multispecific antibody of the present invention in the preparation of a kit for use in The presence or level of CD73 in the sample is detected.
  • compositions comprising the antibody or antigen-binding fragment thereof of any one of the present invention, the conjugate, fusion protein or multispecific antibody of the present invention; optionally, the
  • the pharmaceutical composition also includes a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical composition is in a form suitable for administration by subcutaneous injection, intradermal injection, intravenous injection, intramuscular injection or intralesional injection.
  • Another aspect of the present invention relates to the antibody or antigen-binding fragment thereof, the conjugate or the fusion protein or the multispecific antibody of the present invention, for treating and/or preventing tissue and organ fibrosis, or Use in the preparation of a medicament or a kit for treating and/or preventing tissue and organ fibrosis.
  • Yet another aspect of the present invention relates to a method for treating and/or preventing tissue and organ fibrosis, comprising administering to a subject or patient an effective amount of said antibody or antigen-binding fragment thereof, said conjugate or said Fusion proteins or multispecific antibodies.
  • the tissue organ fibrosis is selected from the group consisting of: idiopathic pulmonary fibrosis; skin fibrosis, such as scleroderma or skin scarring after trauma and surgery; ocular fibrosis, such as ocular sclerosis disease, scarring on the conjunctiva and cornea, and pterygium arising on the conjunctiva; cystic fibrosis of the pancreas and lung; endomyocardial fibrosis; idiopathic cardiomyopathy; cirrhosis; mediastinal fibrosis; progressive mass Fibrosis; proliferative fibrosis; tumor fibrosis; pulmonary fibrosis due to tuberculosis.
  • the method comprises concurrently or sequentially administering to the subject or patient an anti-fibrotic drug (such as a statin), preferably, the anti-fibrotic drug is selected from lovastatin, pravastatin, Fluvastatin, cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, or a combination thereof.
  • an anti-fibrotic drug such as a statin
  • the anti-fibrotic drug is selected from lovastatin, pravastatin, Fluvastatin, cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, or a combination thereof.
  • the effective amount of the antibody or antigen-binding fragment thereof, the antibody drug conjugate or the bispecific antibody of the present invention is 0.001 mg-1000 mg, more preferably 0.001 mg-900 mg, 0.001 mg -800mg, 0.001mg-700mg, 0.001mg-600mg, 0.001mg-500mg, 0.001mg-400mg, 0.001mg-300mg, 0.001mg-200mg, 0.001mg-100mg, most preferably 100mg, 200mg, 300mg, 400mg, 500mg , 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or, based on the body weight of the subject or patient, the effective amount is 0.1-100 mg/kg, preferably 1-90 mg/kg, 1-80 mg/kg, 1-70 mg/kg kg, 1-60 mg/kg, 1-50 mg/kg, 1-40 mg/kg, 1-30 mg/kg, 1-20 mg/kg or 1-10 mg/
  • the effective amount of one or more anti-fibrotic drugs is 100-2400 mg, preferably 100-2300 mg, 100-2200 mg, 100-2100 mg , 100mg-2000mg, 100mg-1900mg, 100mg-1800mg, 100mg-1700mg, 100mg-1600mg, 100mg-1800mg, 100mg-1800mg, 100mg-1800mg, 100mg-1800mg, 100mg-1800mg, more preferably 100mg, 200mg, 300mg, 200mg 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg.
  • statins described above is 100-2400 mg, preferably 100-2300 mg, 100-2200 mg, 100-2100 mg , 100mg-2000mg, 100mg-1900mg, 100mg-1800mg, 100mg-1700mg, 100mg-1600mg, 100mg-1800mg, 100mg-1800mg, 100mg-18
  • the effective amount of the anti-fibrotic drug is 0.1-100 mg/kg, preferably 1-90 mg/kg, 1-80 mg/kg, based on the body weight of the subject or patient , 1-70 mg/kg, 1-60 mg/kg, 1-50 mg/kg, 1-40 mg/kg, 1-30 mg/kg, 1-20 mg/kg or 1-10 mg/kg.
  • a single pharmaceutical dosage unit comprising 0.001 mg-1000 mg of the antibody or antigen-binding fragment thereof of the invention, preferably 0.001 mg-900 mg, 0.001 mg-800 mg, 0.001 mg-700 mg, 0.001 mg - 600mg, 0.001mg-500mg, 0.001mg-400mg, 0.001mg-300mg, 0.001mg-200mg, 0.001mg-100mg, more preferably 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg or 1000mg
  • the antibody or antigen-binding fragment thereof of the present invention preferably 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg or 1000mg
  • the antibody or antigen-binding fragment thereof of the present invention preferably 0.001 mg-1000 mg of the antibody or antigen-binding fragment thereof of
  • hybridoma cell line LT014 which was deposited in China, Wuhan, China on June 21, 2018, China Collection Center for Type Cultures (CCTCC), and the deposit number is CCTCC NO: C2018137.
  • the antibody or antigen-binding fragment, conjugate, fusion protein or multispecific antibody thereof is administered (preferably intravenously) one or more times.
  • EC 50 refers to the concentration for 50% of maximal effect, which refers to the concentration that elicits 50% of the maximal effect.
  • antibody refers to an immunoglobulin molecule generally composed of two pairs of polypeptide chains, each pair having one "light” (L) chain and one "heavy” (H) chain.
  • Antibody light chains can be classified as kappa and lambda light chains.
  • Heavy chains can be classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are linked by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 3 or more amino acids.
  • Each heavy chain consists of a heavy chain variable region ( VH ) and a heavy chain constant region ( CH ).
  • the heavy chain constant region consists of 3 domains ( CH1 , CH2 and CH3 ).
  • Each light chain consists of a light chain variable region ( VL ) and a light chain constant region ( CL ).
  • the light chain constant region consists of one domain, CL .
  • the constant regions of the antibodies mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.
  • the VH and VL regions can also be subdivided into regions of high variability called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs).
  • CDRs complementarity determining regions
  • Each VH and VL consists of 3 CDRs and 4 FRs arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from amino terminus to carboxy terminus.
  • the assignment of amino acids to regions or domains follows the Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda Md (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 1987; 196:901-917; Chothia et al.
  • IMGT/3Dstructure-DB and IMGT/DomainGapAlign a database and a tool for immunoglobulins or antibodies, T Definition of cell receptors, MHC, IgSF and MhcSF.” Nucleic acids research 2009;38(suppl_1):D301-D307.
  • antibody is not limited by any particular method of producing an antibody. For example, it includes, in particular, recombinant antibodies, monoclonal antibodies and polyclonal antibodies.
  • Antibodies can be of different isotypes, eg, IgG (eg, IgGl, IgG2, IgG3, or IgG4 subtype), IgAl, IgA2, IgD, IgE, or IgM antibodies.
  • IgG eg, IgGl, IgG2, IgG3, or IgG4 subtype
  • IgAl IgA2, IgD, IgE, or IgM antibodies.
  • the terms “monoclonal antibody” and “monoclonal antibody” refer to an antibody or a fragment of an antibody from a population of highly homologous antibody molecules, that is, excluding natural mutations that may arise spontaneously, A population of identical antibody molecules.
  • Monoclonal antibodies are highly specific for a single epitope on an antigen.
  • Polyclonal antibodies are relative to monoclonal antibodies, which generally comprise at least two or more different antibodies that generally recognize different epitopes on an antigen.
  • Monoclonal antibodies can usually be obtained using the hybridoma technology first reported by Kohler et al. ( G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. nature, 1975; 256(5517): 495), but can also be obtained using recombinant DNA techniques (eg see US Patent 4,816,567).
  • humanized antibody refers to the replacement of all or part of the CDR regions of a human immunoglobulin (acceptor antibody) with the CDR regions of a non-human antibody (donor antibody)
  • the antibody or antibody fragment of which the donor antibody can be a non-human (eg, mouse, rat or rabbit) antibody with the desired specificity, affinity or reactivity.
  • some amino acid residues in the framework region (FR) of the acceptor antibody can also be replaced by amino acid residues of corresponding non-human antibodies, or by amino acid residues of other antibodies, to further improve or optimize the performance of the antibody.
  • isolated refers to artificially obtained from the natural state. If an "isolated” substance or component occurs in nature, it may be due to a change in its natural environment, or separation of the substance from its natural environment, or both. For example, a certain unisolated polynucleotide or polypeptide naturally exists in a living animal, and the same polynucleotide or polypeptide with high purity isolated from this natural state is called isolated of.
  • isolated or isolated
  • the term "vector” refers to a nucleic acid delivery vehicle into which a polynucleotide can be inserted.
  • the vector can express the protein encoded by the inserted polynucleotide, the vector is called an expression vector.
  • the vector can be introduced into a host cell by transformation, transduction or transfection, so that the genetic material elements carried by it can be expressed in the host cell.
  • Vectors are well known to those skilled in the art and include, but are not limited to: plasmids; phagemids; cosmids; artificial chromosomes, such as yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs) or P1 derived artificial chromosomes (PACs) ; Phage such as ⁇ phage or M13 phage and animal viruses.
  • YACs yeast artificial chromosomes
  • BACs bacterial artificial chromosomes
  • PACs P1 derived artificial chromosomes
  • Animal viruses that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (eg, herpes simplex virus), poxviruses, baculoviruses, papillomaviruses, papillomaviruses Polyoma vacuolar virus (eg SV40).
  • retroviruses including lentiviruses
  • adenoviruses eg, adeno-associated viruses
  • herpesviruses eg, herpes simplex virus
  • poxviruses baculoviruses
  • papillomaviruses papillomaviruses
  • Polyoma vacuolar virus eg SV40
  • a vector may contain a variety of elements that control expression, including, but not limited to, promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and
  • the term "host cell” refers to a cell that can be used to introduce a vector, including, but not limited to, prokaryotic cells such as Escherichia coli or Bacillus subtilis, fungal cells such as yeast cells or Aspergillus, etc., Insect cells such as S2 Drosophila cells or Sf9, or animal cells such as fibroblasts, CHO cells, COS cells, NSO cells, HeLa cells, GS cells, BHK cells, HEK 293 cells or human cells.
  • prokaryotic cells such as Escherichia coli or Bacillus subtilis
  • fungal cells such as yeast cells or Aspergillus, etc.
  • Insect cells such as S2 Drosophila cells or Sf9
  • animal cells such as fibroblasts, CHO cells, COS cells, NSO cells, HeLa cells, GS cells, BHK cells, HEK 293 cells or human cells.
  • an antibody that specifically binds to an antigen refers to an antibody that is less than about 10-5 M, such as less than about 10-6 M, 10-7 M, Binds the antigen with an affinity (K D ) of 10-8 M, 10-9 M, or 10-10 M or less.
  • KD refers to the dissociation equilibrium constant for a particular antibody-antigen interaction, which is used to describe the binding affinity between an antibody and an antigen.
  • antibodies exhibit a dissociation equilibrium constant (K D ) of less than about 10-5 M, eg, less than about 10-6 M, 10-7 M, 10-8 M, 10-9 M, or 10-10 M or less Binds antigen (eg, PD-1 protein).
  • KD can be determined using methods known to those skilled in the art, eg, using a Fortebio Molecular Interactometer.
  • amino acids are generally represented by one-letter and three-letter abbreviations well known in the art.
  • alanine can be represented by A or Ala.
  • the term "pharmaceutically acceptable carrier and/or excipient” refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, It is well known in the art (see e.g. Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995) and includes, but is not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers agent.
  • pH adjusting agents include but are not limited to phosphate buffers; surfactants include but are not limited to cationic, anionic or nonionic surfactants such as Tween-80; ionic strength enhancers include but are not limited to sodium chloride.
  • the term "single drug dosage unit” refers to the antibody or antigen-binding fragment thereof, the antibody-drug conjugate of the present invention to be administered to a subject or patient at the moment of the dosing regimen Or a single-dose pharmaceutical dosage form of the bispecific antibody (or a pharmaceutical composition comprising the same), such as in one ampoule.
  • the term "effective amount” refers to an amount sufficient to obtain, or at least partially obtain, the desired effect.
  • an effective amount for preventing a disease refers to an amount sufficient to prevent, prevent, or delay the occurrence of a disease
  • an effective amount for treating a disease refers to an amount sufficient to cure or at least partially prevent an existing The disease and the amount of its complications in the patient with the disease.
  • the monoclonal antibody of the present invention can well specifically bind to CD73, and can very effectively inhibit the enzymatic reaction of CD73 in a non-substrate competition manner, and can effectively treat tissue and organ fibrosis diseases.
  • FIG. 1 The effect of 19F3H2L3 (hG1DM) on the rate of change from baseline in enhanced expiratory interval values in a hCD73 transgenic mouse model of pulmonary fibrosis.
  • T and C are the administration group and the same type control group, respectively
  • FIG. 3 The effect of 19F3H2L3 (hG1DM) on the total number of inflammatory cells in the bronchoalveolar lavage fluid of hCD73 transgenic mice model of pulmonary fibrosis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, VS normal group; # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001, VS isotype control group (t-test).
  • Figure 4 The effect of 19F3H2L3(hG1DM) on the number of inflammatory cells in the bronchoalveolar lavage fluid of hCD73 transgenic mice model of pulmonary fibrosis. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, VS normal group; # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001, VS isotype control group (t-test).
  • FIG. 5 The effect of 19F3H2L3 (hG1DM) on the content of hydroxyproline (HYP) in the lung tissue homogenate of hCD73 transgenic mouse pulmonary fibrosis model.
  • the BALB/c mice used were purchased from the Guangdong Provincial Medical Laboratory Animal Center;
  • hCD73 transgenic mice used were purchased from Jiangsu Biositu Experimental Animal Co., Ltd.;
  • the used positive control antibody MEDI9447 (Oleclumab) was produced from Zhongshan Kangfang Bio-Pharmaceutical Co., Ltd., and its sequence was the same as the amino acid sequence of Oleclumab disclosed by Medlmmune Limited in the WHO drug information database and related patents. The full length is consistent (https://www.who.int/medicines/publications/dr ⁇ ginformation/innlists/en/), which is marked as MEDI9447 or MEDI9447 (Akeso) in the embodiment of the present invention;
  • the isotype control antibody used is the sequence of human anti-Hen Egg Lysozyme IgG (anti-HEL antibody, or human IgG, hIgG for short, or isotype control) Variable region sequence from Fab F10.6.6 sequence in Affinity maturation increases the stability and plasticity of the Fv domain of anti-protein antibodies published by Acierno et al. (Acierno et al. J Mol Biol. 2007; 374(1): 130-146.);
  • bovine serum albumin used is from Sigma, article number: V900933-1KG;
  • the RPMI 1640 used was derived from Gibco, article number: 22400-089;
  • the fetal bovine serum used is derived from Excell bio, article number: FSP500;
  • the sodium pyruvate used is derived from Gibco, article number: 11360-070;
  • non-essential amino acids used are derived from Gibco, item number: 11140-050;
  • the L-glutamine used is from Gibco, article number: 25030-081.
  • the MDA-MB-231 used is derived from ATCC, item number: HTB-26;
  • the CTG color developing solution used is One Solution Assay kit, from promega, catalog number: G8461;
  • Alexa was used 647-labeled mouse anti-human IgG secondary antibody was obtained from Southern Biotech, catalog number: 9040-31.
  • the bleomycin used is from Hanhui Pharmaceutical Co., Ltd., article number: 19012311;
  • trypan blue used is derived from Sigma; batch number: MKCF8888; article number: T6146;
  • the phosphate buffer used is from Fuzhou Maixin Biotechnology Development Co., Ltd.;
  • the methacholine used is derived from sigma; batch number: MKCF3289; article number: A2251;
  • the hydroxyproline used is derived from hydroxyproline, HYP;
  • the detection kit is derived from QuiekZyme Biosciences, product number: QZBTOTCOL1;
  • the used sutai originates from Virbac S.A of France Vik Co., Ltd., article number: BN 6ALU;
  • the isoflurane used comes from Shenzhen Ruiwo De Life Technology Co., Ltd.;
  • the sodium chloride injection used is derived from Jiangxi Kelun Pharmaceutical Co., Ltd.
  • CD73 (5'-nuclease) specific inhibitor APCP (alpha, beta-methylene adenosine-5'-diphosphate, 5'- ⁇ , ⁇ -methylene-diphosphate, Adenosine Phosphate) from sigma, catalog number: M3763-10MG.
  • the antigen used to prepare the anti-CD73 antibody was human NT5E-His (NT5E is Genbank ID: NP_002517.1, position: 1-552).
  • the spleen cells of the immunized mice were fused with mouse myeloma cells to prepare hybridoma cells.
  • human NT5E (NT5E is GenbankID: NP_002517.1, position: 1-552)-Biotin as an antigen
  • the hybridoma cells were screened by indirect ELISA to obtain hybridoma cells that can secrete antibodies that specifically bind to CD73.
  • the hybridoma cells obtained by screening were subjected to a limiting dilution method to obtain stable hybridoma cell lines.
  • the above hybridoma cell line was named as hybridoma cell line LT014, and the monoclonal antibody secreted by it was named 19F3.
  • Hybridoma cell line LT014 also known as CD73-19F3
  • CTCC China Center for Type Culture Collection
  • the deposit number is CCTCC NO: C2018137
  • the deposit address is China. Wuhan. Wuhan University , Zip Code: 430072.
  • the LT014 cell line prepared above was cultured with CD medium (Chemical Defined Medium) (CD medium containing 1% penicillin streptomycin, cultured in 5% CO 2 , 37° C. cell incubator). After 7 days, the cell culture supernatant was collected, subjected to high-speed centrifugation, vacuum filtration through a microporous membrane, and purified using a HiTrap protein A HP column to obtain antibody 19F3.
  • CD medium Chemical Defined Medium
  • CD medium containing 1% penicillin streptomycin cultured in 5% CO 2 , 37° C. cell incubator
  • mRNA was extracted from the LT014 cell line cultured in Example 1 according to the method of the cultured cell bacterial total RNA extraction kit (Tiangen, Cat. No. DP430).
  • the PCR amplification product was directly cloned by TA, and the specific operation was carried out by referring to the instructions of the pEASY-T1Cloning Kit (Transgen CT101).
  • the nucleic acid sequence of the heavy chain variable region is shown in SEQ ID NO: 1, and the fragment is 351 bp long.
  • sequence of heavy chain CDR1 is shown in SEQ ID NO:15
  • sequence of heavy chain CDR2 is shown in SEQ ID NO:16
  • sequence of heavy chain CDR3 is shown in SEQ ID NO:17.
  • the nucleic acid sequence of the light chain variable region is shown in SEQ ID NO: 3, and the length is 321 bp.
  • sequence of light chain CDR1 is shown in SEQ ID NO:18
  • sequence of light chain CDR2 is shown in SEQ ID NO:19
  • sequence of light chain CDR3 is shown in SEQ ID NO:20.
  • variable region sequences are as follows:
  • the nucleic acid sequence of the heavy chain variable region is shown in SEQ ID NO: 5, and the length is 363 bp.
  • SEQ ID NO:6 Its encoded amino acid sequence is shown in SEQ ID NO:6, and the length is 121aa, wherein the sequence of heavy chain CDR1 is shown in SEQ ID NO:15, the sequence of heavy chain CDR2 is shown in SEQ ID NO:16, and the heavy chain CDR3 The sequence is shown in SEQ ID NO: 17.
  • the nucleic acid sequence of the light chain variable region is shown in SEQ ID NO: 7, and the length is 339 bp.
  • the encoded amino acid sequence is as shown in SEQ ID NO:8, and the length is 113aa, wherein the sequence of light chain CDR1 is as shown in SEQ ID NO:18, the sequence of light chain CDR2 is as shown in SEQ ID NO:19, and the light chain CDR3 The sequence is shown in SEQ ID NO:20.
  • the nucleic acid sequence of the heavy chain variable region is shown in SEQ ID NO: 9, and the length is 363 bp.
  • SEQ ID NO:10 Its encoded amino acid sequence is shown in SEQ ID NO:10, and the length is 121aa, wherein the sequence of heavy chain CDR1 is shown in SEQ ID NO:15, the sequence of heavy chain CDR2 is shown in SEQ ID NO:16, and the heavy chain CDR3 The sequence is shown in SEQ ID NO: 17.
  • the nucleic acid sequence of the light chain variable region is shown in SEQ ID NO: 11, and the length is 339 bp.
  • SEQ ID NO:12 Its encoded amino acid sequence is shown in SEQ ID NO:12, and the length is 113aa, wherein the sequence of light chain CDR1 is shown in SEQ ID NO:18, the sequence of light chain CDR2 is shown in SEQ ID NO:19, and the light chain CDR3 The sequence is shown in SEQ ID NO:20.
  • the nucleic acid sequence of the heavy chain variable region is shown in SEQ ID NO: 9, and the length is 363 bp.
  • SEQ ID NO:10 Its encoded amino acid sequence is shown in SEQ ID NO:10, and the length is 121aa, wherein the sequence of heavy chain CDR1 is shown in SEQ ID NO:15, the sequence of heavy chain CDR2 is shown in SEQ ID NO:16, and the heavy chain CDR3 The sequence is shown in SEQ ID NO: 17.
  • the nucleic acid sequence of the light chain variable region is shown in SEQ ID NO: 13, and the length is 339 bp.
  • SEQ ID NO:14 Its encoded amino acid sequence is shown in SEQ ID NO:14, and the length is 113aa, wherein the sequence of light chain CDR1 is shown in SEQ ID NO:18, the sequence of light chain CDR2 is shown in SEQ ID NO:19, and the light chain CDR3 The sequence is shown in SEQ ID NO:20.
  • the light chain constant region of the antibodies of 19F3H1L1 (hG1DM), 19F3H2L2 (hG1DM) and 19F3H2L3 (hG1DM) is the Ig kappa chain C region, ACCESSION:P01834, see SEQ ID NO:22.
  • the heavy chain constant region is based on the Ig gamma-1chain C region, ACCESSION:P01857, a leucine to alanine point mutation (L234A) was introduced at position 234, and leucine was introduced at position 235.
  • Acid to alanine point mutation (L235A) resulting in humanized antibodies designated 19F3H1L1 (hG1DM), 19F3H2L2 (hG1DM) and 19F3H2L3 (hG1DM), see SEQ ID NO:21.
  • the 19F3H1L1 (hG1DM) heavy chain cDNA and light chain cDNA, 19F3H2L2 (hG1DM) heavy chain cDNA and light chain cDNA, and 19F3H2L3 (hG1DM) heavy chain cDNA and light chain cDNA were cloned into pUC57simple (GenScript). Company provided) vectors, respectively obtained pUC57simple-19F3H1 (hG1DM), pUC57simple-19F3L1; pUC57simple-19F3H2 (hG1DM), pUC57simple-19F3L2 and pUC57simple-19F3L3.
  • the recombinant plasmids containing the corresponding light and heavy chains were designed to combine the genes (pcDNA3.1-19F3H1(hG1DM)/pcDNA3.1-19F3L1, pcDNA3.1-19F3H2(hG1DM)/pcDNA3.1-19F3L2, and pcDNA3.1- 19F3H2(hG1DM)/pcDNA3.1-19F3L3) were co-transfected into 293F cells, respectively, and the culture medium was collected for purification. After the sequencing was verified to be correct, an endotoxin-free expression plasmid was prepared and the plasmid was transiently transfected into HEK293 cells for antibody expression. After 7 days of culture, the cell culture medium was collected, and a Protein A column was used for affinity purification to obtain humanized antibodies.
  • the experimental steps are as follows: take log-phase MDA-MB-231 cells in good condition, resuspend and count the cells with serum-free RPMI-1640 medium; inoculate MDA-MB-231 cells into 96-well plates, 3*10 4 cells/100 ⁇ l/well; dilute the antibody with serum-free RPMI-1640 medium, the initial concentration is 200 ⁇ g/ml, and carry out a 2.5-fold gradient dilution; add the antibody to a 96-well plate, 50 ⁇ l per well, and incubate at 37°C for 1 hour.
  • mice were nebulized in PBS solution, followed by continuous nebulization at concentrations of 1.5625, 3.125, 6.25, 12.5, 25 and 50 mg /mL of methacholine (Mch), measure the enhanced expiratory interval value at the corresponding concentration, stimulate for 90 seconds at each concentration, draw the rate of change of the enhanced expiratory interval value relative to the baseline-Mch concentration curve, and calculate the curve under the curve area.
  • Mch methacholine
  • the BALF was centrifuged at 300 g for 5 minutes at 4°C, and the cell pellet obtained after centrifugation was resuspended in 1.5 mL of PBS for smear preparation.
  • the total number of cells in the BALF was counted using a hemocytometer and stained with Wright-Giemsa staining solution to differentiate eosinophils, neutrophils, macrophages and lymphocytes. Count under a light microscope. Collect the remaining BALF fluid. After lavage, the animals were euthanized by cervical dissection, and the lung tissues were collected and cryopreserved at -80°C for the detection of hydroxyproline content after homogenization.
  • hydroxyproline content was performed using a hydroxyproline (HYP) detection kit (QuiekZyme Biosciences) according to the kit instructions.
  • the experimental data are expressed as the mean ⁇ standard error (Mean ⁇ SEM), the comparison between groups was processed by GraphPad statistical processing software, and the results were evaluated by one-way analysis of variance or t-test. 0.01 is a very significant difference.
  • HCDR1 GYSFTGYT (SEQ ID NO: 15)
  • HCDR3 ARSEYRYGGDYFDY (SEQ ID NO: 17)
  • LCDR1 QSLLNSSNQKNY (SEQ ID NO: 18)

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Abstract

La présente invention concerne un anticorps anti-CD73 et son utilisation. Spécifiquement, une région variable de chaîne lourde de l'anticorps contient HCDR1 à HCDR3 ayant des séquences d'acides aminés telles que représentées dans SEQ ID NO : 15-17. En outre, une région variable de chaîne légère de l'anticorps contient LCDR1 à LCDR3 ayant des séquences d'acides aminés telles que représentées dans SEQ ID NO : 18-20.
PCT/CN2021/080517 2020-10-19 2021-03-12 Anticorps anti-cd73 et son utilisation WO2022083049A1 (fr)

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WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2
WO2024040195A1 (fr) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditionnement pour l'ingénierie de cellules immunitaires in vivo

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2
WO2024040195A1 (fr) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditionnement pour l'ingénierie de cellules immunitaires in vivo
WO2024040194A1 (fr) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditionnement pour l'ingénierie de cellules immunitaires in vivo

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