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WO2019059267A1 - Marqueur de cellules myéloïdes immunosuppressives - Google Patents

Marqueur de cellules myéloïdes immunosuppressives Download PDF

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Publication number
WO2019059267A1
WO2019059267A1 PCT/JP2018/034769 JP2018034769W WO2019059267A1 WO 2019059267 A1 WO2019059267 A1 WO 2019059267A1 JP 2018034769 W JP2018034769 W JP 2018034769W WO 2019059267 A1 WO2019059267 A1 WO 2019059267A1
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Prior art keywords
cells
antibody
cell
myeloid cells
immunosuppressive
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Japanese (ja)
Inventor
一樹 平原
真梨子 久徳
潤三 ▲濱▼西
直城 堀川
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Daiichi Sankyo Co Ltd
Kyoto University NUC
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Daiichi Sankyo Co Ltd
Kyoto University NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

Definitions

  • the present invention relates to techniques for identifying immunosuppressive myeloid cells.
  • the present invention relates to a marker for immunosuppressive myeloid cells, a drug and method for identifying immunosuppressive myeloid cells, a method of screening a substance targeting immunosuppressive myeloid cells, and immunosuppressive myeloid cells. It also relates to targeted cancer treatment.
  • Bone marrow-derived immunosuppressive cells are myeloid cells whose main action is to suppress T cell proliferation. It is believed that MDSC acts to promote tumor growth by strongly suppressing the antitumor immune response (Non-patent Document 1). Peripheral blood MDSCs are reported to be more frequent in patients with poor prognosis cancer and those who are not effective in immunotherapy using immune checkpoint inhibitors etc. MDSCs are important targets for immunotherapy for cancer It is considered to be a cell group. That is, if a drug that specifically removes MDSC or a drug that inhibits the immunosuppressive function of MDSC can be developed, it is expected that anti-tumor immunity is activated to bring about a therapeutic effect on cancer.
  • a drug that specifically removes MDSC or a drug that inhibits the immunosuppressive function of MDSC can be developed, it is expected that anti-tumor immunity is activated to bring about a therapeutic effect on cancer.
  • MDSCs are immunosuppressed by inactivating T cells or inducing regulatory T cells (Treg) through the production of arginase, reactive oxygen species, nitric oxide, TGF- ⁇ , IL-10, etc. It is considered to express a function (Non-patent Document 1).
  • Non-patent Document 1 proposes that in human and mouse, a cell group expressing a specific cell surface molecule is regarded as M-MDSC and G-MDSC. ing.
  • Lineage marker CD3, CD14, CD19, CD56
  • HLA-DR negative CD11b positive
  • CD33 positive cells can be regarded as MDSC as a trait common to M-MDSC and G-MDSC. is there.
  • M-MDSCs differentiate into macrophages as the differentiation stage further progresses.
  • Macrophages that infiltrate and accumulate in tumors and are affected by the tumor microenvironment are called tumor-associated macrophages (TAM, tumor-associated macrophages), and through the production of angiogenic factors and cell growth factors, and suppression of antitumor immunity, It is believed to act as a tumor promoting agent (Non-patent Document 2).
  • TAM tumor-associated macrophages
  • Macrophages are roughly divided into M1 macrophages and M2 macrophages mainly because of differences in activation mode, and it has been hypothesized that TAM is biased to M2 macrophages.
  • TAM is a heterogeneous cell population, and it has been recognized that macrophages in vivo can not simply be classified and interpreted as M1 / M2 (Non-patent Document 3).
  • macrophages and MDSC which exhibit T cell proliferation inhibitory activity directly in particular, have high functionality in common with marker molecules, and it is considered difficult to accurately distinguish them. Therefore, in the present specification, those cell groups are collectively referred to as "immunosuppressive myeloid cells".
  • the challenge in targeting immunosuppressive myeloid cells as a therapeutic target is the lack of specific markers.
  • Human CD11b is also expressed on neutrophils, and human CD33 is a molecule widely expressed on myeloid cells. Therefore, for example, when developing antibody drugs specific to these, side effects such as neutropenia It may occur. If marker molecules with high specificity for human immunosuppressive myeloid cells can be found, they have high utility in therapeutic applications.
  • CD206 is also known as a mannose receptor. It is a C-type lectin receptor having a single transmembrane structure. Among the sugar chains expressed by cells such as macrophages and dendritic cells and possessed by foreign pathogens, they bind to mannose, N-acetylglucosamine and fucose, and the antigen is taken into the cell via endocytosis and phagocytosis By being involved in antigen presentation, it contributes to both innate immunity and acquired immunity to play a role in host infection protection (Non-patent Document 4). CD206 is known to be expressed in M2 macrophages (Non-patent Document 1). However, there is no information on whether CD206 expression correlates with immunosuppressive effects.
  • Imaging reagent As a diagnostic agent targeting CD206, there is an imaging reagent (trade name: Lymphoseek) for detecting metastatic lymph nodes in breast cancer and melanoma patients.
  • This imaging reagent is obtained by isotope labeling of mannose binding dextran having binding activity to the mannose receptor, but it is unclear whether it exhibits an antitumor effect.
  • the object of the present invention relates to providing a technique for identifying immunosuppressive myeloid cells.
  • the object of the present invention is to use a drug for identifying immunosuppressive myeloid cells, a method for identifying immunosuppressive myeloid cells, a method for screening a drug targeting immunosuppressive myeloid cells, and an immunosuppressive myeloid cell
  • the goal is to provide T cell proliferation agents targeting cancer and treatment techniques for cancer.
  • the present invention includes, but is not limited to, the following inventions.
  • An agent for identifying an immunosuppressive myeloid cell comprising a substance that recognizes CD206.
  • the agent according to (1) wherein the substance is an antibody or a functional fragment thereof.
  • a medicament for treating cancer comprising a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • the medicine according to (3) wherein the substance is an antibody or a functional fragment thereof.
  • the medicine according to (7), wherein the drug is a cytocidal agent.
  • the antibody or functional fragment thereof according to (12), wherein the drug is a cytocidal agent.
  • a T cell proliferation promoter comprising a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • the T cell proliferation promoter according to (15) or (16), wherein the antibody or a functional fragment thereof is linked to a cytocidal agent.
  • a method for identifying an immunosuppressive myeloid cell comprising the step of recognizing or detecting CD206 on myeloid cells.
  • a method for selecting immunosuppressive myeloid cells comprising the steps of: identifying immunosuppressive myeloid cells by recognizing or detecting CD206 on myeloid cells; and selecting the identified immunosuppressive myeloid cells. .
  • a method for screening a cancer therapeutic drug comprising the step of selecting a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • a diagnostic agent for evaluating the presence of immunosuppressive myeloid cells in a tissue comprising a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • immunosuppressive myeloid cells can be identified. Furthermore, according to the present invention, it becomes possible to screen for pharmaceuticals targeting immunosuppressive myeloid cells. Furthermore, the present invention is effective in the treatment of cancer that targets immunosuppressive myeloid cells.
  • FIG. 1 is a graph showing experimental results according to Example 2, and shows CD206 expression in CD33 positive myeloid cells derived from ascites fluid of ovarian cancer patients.
  • FIG. 2 is a graph showing the experimental results according to Example 3, and shows that CD33 positive CD206 positive cells derived from ascites fluid of ovarian cancer patients suppress T cell proliferation in a cell number dependent manner. The T cell proliferative response was measured by detecting the fluorescence of CFSE which is halved with each T cell division.
  • FIG. 3 is a graph showing the results of an experiment according to Example 4, and shows that CD33 positive cells derived from PBMC suppress T cell proliferation in a cell number dependent manner. As a control, CD33 positive cells immediately after thawing frozen PBMC were separated and used.
  • FIG. 1 is a graph showing experimental results according to Example 2, and shows CD206 expression in CD33 positive myeloid cells derived from ascites fluid of ovarian cancer patients.
  • FIG. 2 is a graph showing the experimental results according to Example 3,
  • FIG. 4 is a graph showing the results of experiments according to Example 5, and shows CD206 expression of MDSCs derived from PBMC. In the histogram on the right end, the solid line shows the result of anti-CD206 antibody, and gray shows the result of isotype control antibody.
  • FIG. 5 is a graph showing the results of an experiment according to Example 6, and shows that among the MDSCs derived from PBMC, CD206 strongly positive cells strongly suppress T cell proliferation.
  • FIG. 6 is a graph showing the results of an experiment relating to Example 7, wherein tumor CT 26.
  • FIG. 16 shows that intravenous administration of saporin-conjugated anti-CD206 antibody inhibited tumor growth in a mouse model implanted subcutaneously with WT cells.
  • the "substance” that recognizes CD206 is not particularly limited as long as it recognizes CD206, and examples include an antibody against CD206 or a functional fragment thereof, a ligand or a compound thereof.
  • the "agent" for identifying an immunosuppressive myeloid cell comprising a substance that recognizes CD206 refers to the identification of an immunosuppressive myeloid cell containing a substance that recognizes CD206, as described later.
  • cell markers and reagents may be used.
  • the agent may contain other components besides the substance that recognizes CD206.
  • drug is used to mean a drug such as a cell killing agent or an anticancer agent which is used together with a substance that recognizes CD206 on immunosuppressive myeloid cells, as described later.
  • the agent that recognizes CD206 on the immunosuppressive myeloid cells may or may not be conjugated to the drug.
  • the present invention is an agent for identifying an immunosuppressive myeloid cell, which comprises a substance that recognizes CD206 of myeloid cells.
  • the present inventors conducted intensive studies on myeloid cells that suppress T cell proliferation and found that CD206 in myeloid cells serves as a marker for immunosuppressive myeloid cells.
  • the invention also relates to methods of identifying immunosuppressive myeloid cells comprising recognizing CD206 on or in immunosuppressive myeloid cells.
  • MDSCs Bone marrow-derived immunosuppressive cells
  • M-MDSC monocyte-based M-MDSC
  • G-MDSC granulocyte-based G-MDSC
  • Lineage marker CD3, CD14, CD19, CD56
  • HLA-DR negative HLA-DR negative
  • CD11b positive CD33 positive cells
  • M-MDSCs differentiate into macrophages as the differentiation stage further progresses.
  • Macrophages that infiltrate and accumulate in the tumor and are affected by the tumor microenvironment are called tumor-associated macrophages (TAMs) and act as tumor-promoting agents through the production of angiogenic factors and cell growth factors, and suppression of anti-tumor immunity. It is believed that.
  • the present inventors compare the gene expression difference of CD33 positive myeloid cells in the peritoneal fluid of ovarian cancer patient ascites and CD33 positive myeloid cells in peripheral blood mononuclear cells (hereinafter referred to as PBMC) by means of Microarray analysis. , CD206 mRNA was found to be highly expressed in the patient group.
  • PBMC peripheral blood mononuclear cells
  • amino acid and nucleotide sequences of human CD206 are available by reference to GenBank Accession Nos. NP_002429.1 and NM_002438.3 (nucleotide sequence: SEQ ID NO: 1, amino acid sequence: SEQ ID NO: 2).
  • Human CD206 also called mannose receptor, is a type I single chain transmembrane glycoprotein having a multilectin receptor structure.
  • CD206 is considered to play an important role in intracellular uptake of proteins containing sugar chains, and the CD206 antigen is expressed not only in macrophages but also in various cells such as immature dendritic cells and endothelial cells. It is known. Although not expressed on lymphocytes and monocytes, expression of CD206 is enhanced during differentiation from monocytes to macrophages. It is known that bone marrow-derived myeloid cells have cells that suppress immunity, but according to our studies, CD206 on myeloid cells is a good marker as to whether it is an immunosuppressive myeloid cell or not. It was found to be That is, it was confirmed that myeloid cells having CD206 on the cell surface have an activity to suppress the proliferation of immune cells such as T cells.
  • the invention relates to a method of identifying an immunosuppressive myeloid cell comprising recognizing or detecting CD206 on an immunosuppressive myeloid cell.
  • the recognition or detection can use an antibody against CD206 or a functional fragment thereof.
  • the method for detecting a molecule of interest using an antibody or a functional fragment thereof can be performed using methods well known to those skilled in the art, and is detected by, for example, flow cytometry or immunohistochemical analysis.
  • a functional fragment of an antibody means an antibody fragment whose function is maintained, for example, a functional fragment of an antibody against CD206 means an antibody fragment whose function of recognizing CD206 is maintained.
  • a substance that recognizes CD206 can be used.
  • a ligand for CD206 such as an antibody or a functional fragment thereof can be used.
  • the term "ligand” as used herein means any molecule that can specifically bind to a marker on the cell surface, and includes, for example, any compound, antibody and the like. When it is an antibody, it includes not only whole antibodies but also antibody fragments such as scFv and domain antibodies.
  • the ligand preferably includes an antibody or an antibody fragment thereof.
  • antibodies may be prepared by known methods.
  • an antibody against CD206 immunizes a non-human animal with a target antigen, and the lymph fluid, lymph tissue, blood cell sample or bone marrow-derived cells are collected from the immunized animal and known methods (eg Kohler and Milstein, Nature) (1975) 256, p. 495-497, Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N. Y. (1980)), and antibody-producing cells producing an antibody against CD206 A hybridoma can be established by fusing with myeloma cells to obtain a monoclonal antibody. Specific examples of such methods are described in WO 2009/48072 (published April 16, 2009) and WO 2010/17011 (published October 14, 2010).
  • the antibodies of the present invention include, in addition to monoclonal antibodies, genetically modified antibodies, such as Chimeric antibodies and Humanized antibodies, which are artificially modified for the purpose of reducing heterologous antigenicity to human etc. And human antibodies. These antibodies can be produced using known methods.
  • chimeric antibodies include antibodies in which the variable region of the antibody and the constant region are heterologous to each other, such as a chimeric antibody in which the variable region of a mouse- or rat-derived antibody is conjugated to a constant region derived from human (Proc. Natl. Acad) Sci.U.S.A., 81, 6851-6855, (1984)).
  • humanized antibody an antibody in which only a CDR is incorporated into a human-derived antibody (see Nature (1986) 321, p. 522-525), and by CDR grafting, amino acid residues of some frameworks in addition to the CDR sequences.
  • the group may also be an antibody (International Publication WO 90/07861) grafted to a human antibody.
  • the antibodies of the present invention can further include human antibodies.
  • an anti-CD206 human antibody means a human antibody having only the gene sequence of an antibody derived from a human chromosome.
  • the anti-CD206 human antibody is a method using a human antibody-producing mouse having a human chromosomal fragment containing heavy and light chain genes of human antibody (Tomizuka, K. et al., Nature Genetics (1997) 16, p. 133). Kuroda, Y. et. Al., Nucl. Acids Res. (1998) 26, p. 3447-3448; Yoshida, H. et. Al., Animal Cell Technology: Basic and Applied Aspects vol. 10, p.
  • HAC human artificial chromosome
  • Mouse artificial mouse artificial chromosome
  • eukaryotic cells are transformed with a cDNA encoding each of heavy and light chains of such human antibody, preferably a vector containing the cDNA, by genetic recombination technology to produce a recombinant human monoclonal antibody.
  • This antibody can also be obtained from the culture supernatant by culturing transformed cells.
  • eukaryotic cells preferably CHO cells
  • mammalian cells such as lymphocytes and myelomas can be used as lymphocytes and myelomas.
  • a method for obtaining a phage display-derived human antibody selected from a human antibody library (Wormstone, IM et al., Investigative Ophthalmology & Visual Science. (2002) 43 (7), p. 2301-2308; Mé, S. et. Al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p. 189-203; Siriwardena, D. et. Al., Ophthalmology (2002) 109 (3), p. 427-431, etc.) are also known.
  • a phage display method (Nature Biotechnology (2005), 23, (9), p. 1105) in which the variable region of human antibody is expressed on the phage surface as a single chain antibody (scFv) and phages that bind to the antigen are selected. -1116) can be used.
  • the DNA sequence encoding the variable region of human antibody binding to the antigen can be determined.
  • a human antibody can be obtained by preparing an expression vector having the sequence and introducing it into a suitable host for expression (WO 92/01047, WO 92 / 20791, WO 93/06213, WO 93/11236, WO 93/19172, WO 95/01438, WO 95/15388, Annu. Rev. Immunol (1994) 12, p. 433-455, Nature Biotechnology (2005) 23 (9), p. 1105-1116).
  • Substances that recognize specific proteins on immunosuppressive myeloid cells include, for example, ligands such as antibodies or functional fragments thereof that can bind to proteins.
  • An agent that recognizes a particular protein on an immunosuppressive myeloid cell may comprise more than one ligand for another marker / receptor.
  • a ligand for CD33 may be included.
  • the invention is a diagnostic for evaluating the presence of immunosuppressive myeloid cells, which comprises a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • the invention is a method of selecting immunosuppressive myeloid cells, the method comprising identifying and identifying immunosuppressive myeloid cells by recognizing CD206 on the immunosuppressive myeloid cells. Selecting the selected immunosuppressive myeloid cells.
  • immunosuppressive myeloid cells are involved in the suppression of proliferation of T cells which are immune cells, they suppress the proliferation suppression of T cells by controlling the immunosuppressive myeloid cells, and thus an antitumor immune response is achieved.
  • the activation can kill cancer cells.
  • the present invention can be used in the treatment of any tumor, including but not limited to melanoma, cancer in the prostate, intestine, breast and lung.
  • the invention can also be used in the treatment of leukemia and lymphoma.
  • the invention can be used to treat tumors in any mammal, but is particularly suitable for treating tumors in humans.
  • tumor refers to benign and malignant solid tumors as well as solid and non-solid cancers.
  • the site of the tumor or cancer is not particularly limited, and examples include ovary, brain, breast, uterus, endometrium, pancreas, kidney, peritoneum and lung.
  • the invention is a medicament for treating cancer comprising a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • a substance that recognizes CD206 on immunosuppressive myeloid cells as described above, ligands such as antibodies and functional fragments thereof can be used.
  • the medicament according to the present invention has a T cell proliferation promoting action, and the proliferation of T cells which are immune cells is promoted by inhibiting the function of the immunosuppressive myeloid cells.
  • the medicament according to the present invention has a cytotoxic effect on immunosuppressive myeloid cells, for example, antibody-dependent-cellular cytotoxicity (hereinafter referred to as ADCC) activity, complement dependence Immune cells by damaging immunosuppressive myeloid cells, such as by Complement-dependent cytotoxicity (hereinafter referred to as CDC activity) and / or antibody-dependent cellular phagocytosis (hereinafter referred to as ADCP) activity T cell proliferation is promoted.
  • ADCC antibody-dependent-cellular cytotoxicity
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCC antibody-dependent cellular cytotoxicity
  • Complement dependent cytotoxicity (CDC) activity can be evaluated by measuring cell death that occurs when contacting complement contained in blood, antibody and target cells.
  • Antibody-dependent cellular phagocytosis (ADCP) activity can be measured by dual fluorescence labeling of phagocytosis caused by contacting a phagocytotic immune cell, an antibody and a target cell.
  • the medicament according to the present invention may further comprise not only substances that recognize CD206 on immunosuppressive myeloid cells, but also drugs such as cytocidal agents and anticancer agents.
  • drugs such as cytocidal agents and anticancer agents.
  • the ligand for CD206 and the drug may or may not be conjugated.
  • a drug for example, a drug having a cytotoxic activity
  • the antibody is preferably an antibody having internalization activity.
  • the linker for binding the antibody and the drug through the linker is not particularly limited as long as it binds the anti-CD206 antibody and the drug in such a form that the activity of the drug is maintained (Protein Cell, 14 October 2016, Kyoji Tuchikama et al. (PROTEIN CELL. 2018 Jan; 9 (1): 33-46, Kyoji Tsuchikama et al.)).
  • An antibody-drug complex is one in which an antibody and a drug are linked by a linker, and is also referred to as ADC (Antibody-drug conjugates).
  • ADC Antibody-drug conjugates
  • Multiple drug linkers can be linked to the antibody, for example, an ADC with two drug linkers bound, an ADC with four drug linkers linked, an ADC with six drug linkers linked, eight drug linkers linked ADCs and the like can be suitably used, and mixtures of these can also be used.
  • the ratio of drug to antibody is also called DAR (Drug to Antibody Ratio), and means the average number of drugs bound to one antibody molecule.
  • DAR can be, for example, 1 to 10, preferably 2 to 9, and more preferably 3 to 8.
  • the drug used for ADC is not particularly limited, as long as it has a substituent or a partial structure capable of binding to the linker structure.
  • part or all of the linker is cleaved in the cell to produce a cytotoxic effect and the like.
  • a drug is linked to an antibody via a linker, but a drug linker including this drug and a linker moiety may be referred to as a drug.
  • the linker used for ADC is not particularly limited, and any of a cleavable linker and a non-cleavable linker can be used.
  • a linker having an N-substituted maleimidyl group can be mentioned as a particularly preferred example.
  • the cleavable linker can include, for example, a peptide linker that is cleaved by an intracellular protease such as lysosomal protease and endosomal protease.
  • the ADC according to the present invention can also be produced using a drug linker intermediate. That is, for example, the carboxyl group of the linker compound and the amino group of the drug are reacted using a condensing agent or the like to obtain a drug linker intermediate, and this intermediate is reacted with an interchain thiol of an antibody for use can do.
  • the drug linker intermediate according to the present invention has an N-substituted maleimidyl group, but is not limited thereto, and preferably used as long as it has a functional group that allows the reaction of the antibody with interchain thiol to proceed. be able to.
  • the ADC can be produced, for example, by reducing the disulfide of an antibody to convert it into a thiol group, and then reacting the antibody having a thiol group with a drug linker.
  • the drug antibody ratio is 2, 4, 6 or It will be eight.
  • the heavy chain-light chain thiol may be linked to a drug linker, and the heavy chain-heavy chain thiol may be linked to a drug linker.
  • ADCs are manufactured under defined reaction conditions such as the amounts of starting materials and reagents to be reacted so that the number of drugs bound is controlled, but are usually obtained as a mixture in which different numbers of drugs are bound. . Therefore, unless otherwise stated, DAR is described as the average value of the number of drugs bound to one antibody molecule.
  • the ADC can be used alone or in combination with other therapies in adjuvant therapy, and can be combined with surgery, radiation therapy, hormonal therapy and the like. Furthermore, it can also be used as a drug for drug therapy in neoadjuvant therapy. Also, the ADC according to the present invention may be administered locally as a systemic therapy to patients. In a preferred embodiment of the present invention, parenteral administration can be carried out, and parenteral routes of administration may include intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous routes, and examples of administration methods include: Infusion, bolus injection and the like can be mentioned.
  • the drug not only anticancer agents, but also antibacterial, antiprotozoa, other active substances having antiviral or antifungal activity and the like can be suitably used.
  • the drug is a cytotoxic agent comprising a cytocidal agent.
  • drugs for example, doxorubicin, epirubicin, 5-fluorouracil, cytosine arabinoside, cyclophosphamide, thiotepa, busulfan, cytoxin, paclitaxel, doxetaxel, taxotere, methotrexate, cisplatin, vinblastine, bleomycin, etoposide , Ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycin, esperamycin, 6-thioguanine, 6-mercaptopurine, actinomycin D, VP -16, chlorambucil and melphalan can be mentioned.
  • drugs for example, doxorubicin, epirubicin, 5-fluorouracil, cytosine arabinoside, cyclophos
  • cytocidal agent for example, saporin, curcin, crotin, gelonin, miterin, restrictocin, phenomycin, enomycin, trichothecene, diphtheria A chain, non-binding active fragment of diphtheria toxin, cholera toxin, botulinum toxin Exotoxin A chain, ricin A chain, abrin A chain, modexin A chain, alpha-sarcin, aleurites foody protein, diantin protein, calicheamicin, maytansinoid, palytoxin, CC1065, etc. .
  • the anti-CD206 antibody of the present invention can also be administered two, three or more other therapeutic agents depending on the therapeutic purpose, and those other therapeutic agents can be simultaneously administered by encapsulating them in the same formulation. can do.
  • the other therapeutic agent and the anti-CD206 antibody can also be administered simultaneously by encapsulating them in the same formulation.
  • the anti-CD206 antibody and the other therapeutic agent can be enclosed in separate formulations and administered simultaneously.
  • the other drug and the anti-CD206 antibody can be administered separately in tandem.
  • a therapeutic agent containing an anti-CD206 antibody or an antigen-binding fragment of the antibody as an active ingredient is administered, or an anti-CD206 antibody or an antigen-binding fragment of the antibody is contained as an active ingredient
  • Other therapeutic agents may be administered after administering the therapeutic agent.
  • an immune checkpoint inhibitor refers to an agent that inhibits signal transduction by the immune checkpoint by inhibiting the binding of the immune checkpoint and its ligand.
  • an immune checkpoint and its ligand for example, PD-1, PD-L1, PD-L2, CTLA-4, TIM3, LAG3, BTNL2, B7-H3, B7-H4, CD48, CD80, BT80, BTLA, 2B4, CD160 , CD60, CD86, VISTA, etc., but it is not limited thereto.
  • the immune checkpoint inhibitor examples include, for example, Pembrolizumab (CAS number: 1374853-91-4), PD-1 antibody such as Nivolumab (CAS number: 946414-94-4), and Atezolizumab (CAS number: 1380723).
  • PD-L1 antibodies such as -44-3
  • Avelumab CAS number: 1537032-82-8
  • Durvalumab CAS number: 1428935-60-7)
  • chemotherapeutic agents such as angiogenesis inhibitors, antimetabolites, plant alkaloids, platinum preparations and the like can be suitably used.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of an anti-CD206 antibody and additives such as a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and / or adjuvant. Also provide goods.
  • the pharmaceutical composition may further contain an active ingredient other than the anti-CD206 antibody.
  • the pharmaceutical composition of the present invention changes or holds pH, osmotic pressure, viscosity, transparency, color, isotonicity, sterility, stability, dissolution rate, sustained release rate, absorption rate, permeability. It can contain substances for formulation of The addition amount of the substance for these preparations is preferably 0.01 to 100 times the weight of the anti-CD206 antibody.
  • the composition of a suitable pharmaceutical composition in a preparation can be appropriately determined by those skilled in the art according to the disease to be applied, the administration route of application, and the like.
  • the excipient or carrier in the pharmaceutical composition may be liquid or solid. Suitable excipients and carriers may be water or saline for injection, artificial cerebrospinal fluid, or other substances commonly used for parenteral administration. Neutral saline or saline containing serum albumin can also be used as a carrier.
  • the pharmaceutical composition can include Tris buffer of pH 7.0-8.5, acetate buffer of pH 4.0-5.5, citrate buffer of pH 3.0-6.2. These buffers can also include sorbitol and other compounds.
  • the pharmaceutical composition of the present invention can include a pharmaceutical composition containing an anti-CD206 antibody, and a pharmaceutical composition containing an anti-CD206 antibody and at least one anti-tumor therapeutic agent, and the pharmaceutical composition of the present invention is selected It is prepared as a lyophilizate or liquid as a drug having a composition and required purity.
  • Pharmaceutical compositions comprising the anti-CD206 antibody, and pharmaceutical compositions comprising the anti-CD206 antibody and at least one anti-cancer drug therapeutic agent can also be formulated as a lyophilizate using appropriate excipients such as sucrose.
  • the pharmaceutical composition of the present invention can be prepared for parenteral administration or can be prepared for oral gastrointestinal absorption.
  • the composition and concentration of the formulation can be determined by the method of administration.
  • the antibody of the present invention is administered to humans, about 0.1 to 100 mg / kg may be administered one or more times in 1 to 180 days.
  • the dose and the number of doses should generally be determined in consideration of the patient's sex, weight, age, symptoms, severity, side effects, etc., they are not limited to the above dose or usage. I assume.
  • Examples of the form of the pharmaceutical composition of the present invention include an injection containing a drop, a suppository, a nasal agent, a sublingual agent, a percutaneous absorption agent and the like.
  • the administration route is an oral route or a parenteral route, and a parenteral route includes, for example, intravenous, intraarterial, intramuscular, intrarectal, transmucosal, intradermal and the like.
  • cancer therapeutic agents can be screened. That is, in one embodiment, the present invention is a method for screening a cancer therapeutic drug, which comprises the step of selecting a substance that recognizes CD206 on immunosuppressive myeloid cells.
  • test substance to be subjected to screening is not particularly limited, and may be either an organic compound or an inorganic compound.
  • organic compound in addition to low molecular weight organic compounds, screening can be performed using any organic compound such as amino acids, oligopeptides, polypeptides, saccharides, lipids, nucleic acids and the like as a test substance.
  • Example 1 Gene Expression Analysis of Ascites Fluid Myeloid Cells in Ovarian Cancer Patients Microarray analysis was used to compare gene expression differences between CD33 positive myeloid cells in the ascites fluid of ovarian cancer patients and CD33 positive myeloid cells in peripheral blood mononuclear cells (hereinafter referred to as PBMC) in healthy individuals.
  • PBMC peripheral blood mononuclear cells
  • CD33 positive cells were separated by MACS method.
  • PBMC peripheral blood of 10 healthy individuals by Ficoll density gradient centrifugation, and CD33 positive cells were further separated by MACS.
  • MACS method CD33 microbeads (Miltenyi Biotec) and an automatic magnetic cell separator (autoMACS, Miltenyi Biotec) were used.
  • Example 2 Analysis of protein expression in ascites fluid myeloid cells of ovarian cancer patients
  • CD33 positive myeloid cells were separated into a CD206 positive fraction and a CD206 negative fraction.
  • the cell suspension was stained using a cell sorter (FACS ARIA IIu, Becton Dickinson) to CD33 positive CD206 positive cells and CD33 positive CD206 negative cells Separated.
  • CD3 positive T cells were separated from healthy human peripheral blood PBMC by MACS method, and the separated T cells were labeled with a fluorescent dye CFSE.
  • the T cell proliferative response can be measured by detecting by flow cytometry the fluorescence of CFSE which is halved with every cell division.
  • CD33 positive CD206 positive cells or CD33 positive CD206 negative cells were seeded at 2 ⁇ 10 4 cells / well, 4 ⁇ 10 4 cells / well, or 8 ⁇ 10 4 cells / well .
  • CFSE-labeled CD3 positive T cells were added at 1.6 ⁇ 10 5 cells / well.
  • Dynabeads Human T-Activator CD3 / CD28 (ThermoFisher Scientific) was added to 4 ⁇ 10 4 beads / well.
  • the medium used was RPMI 1640 adjusted to 5% human type AB serum, Penicillin / Streptomycin, 1 ⁇ MEM NEAA, 1 mM Sodium Pyruvate, and 5 mM Hepes (hereinafter referred to as “co-culture medium”).
  • DAPI negative cells were gated as live cells, and the ratio of the division peak was quantified among the histogram peaks of CFSE (FITC) in CD3 positive T cells, and the inhibitory activity on T cell proliferation was compared.
  • CD33 positive CD206 positive cells (CD33 + CD206 + ) strongly suppress the proliferative response of T cells, compared to CD33 positive CD206 negative cells (CD33 + CD206 ⁇ )
  • the ratio of dividing cells was 45.3% at 8: 1, 27.7% at 4: 1, and 8.67% at 2: 1 ). This result indicates that CD33 positive CD206 positive cells are involved in T cell suppression, and removal of CD33 positive CD206 positive cells makes it possible to release T cell suppression.
  • Example 4 MDSC Preparation by Induction from PBMCs
  • PBMC Cellular Technology Limited
  • CD3 positive cells and CD3 negative cells were separated by MACS method.
  • CD3 positive cells were cryopreserved again at -80.degree. C. using Servanker (Nippon Zenyaku Kogyo Co., Ltd.).
  • CD3 negative cells were prepared by adding 20% of culture supernatant of human renal cell carcinoma cell line 786-O (ATCC Inc. CRL-1932) and co-culture medium (hereinafter referred to as induction medium) to which 10 ng / mL human GM-CSF was added.
  • induction medium co-culture medium
  • the expression analysis of the surface marker used FITC-labeled anti-CD3 antibody, FITC-labeled anti-CD19 antibody and FITC-labeled anti-CD56 antibody as Lineage markers.
  • PerCP-Cy5.5-labeled anti-HLA-DR antibody, Pacific Blue-labeled anti-CD11b antibody and PE-labeled anti-CD33 antibody were used. Cells were stained with these antibodies, and dead cell staining was performed using LIVE / DEAD Fixable Aqua Dead Cell Stain Kit (ThermoFisher Scientific). Stained cells were measured using a flow cytometer (FACS Canto II, Becton Dickinson) and analyzed using FlowJo. In the cells after induction culture, it was confirmed that there were cells expressing Lineage negative HLA-DR negative and weak positive CD11b positive CD33 positive MDSC markers.
  • CD33 positive cells contained in the cells after induction culture had inhibitory activity on T cell proliferation As control cells for CD33 positive cells after induction, CD3 negative CD33 positive cells separated by MACS immediately after thawing frozen PBMC were used (referred to as untreated CD33 positive cells).
  • the CD3 positive T cells stored by selvan were thawed and CFSE labeled.
  • CD33 positive cells were seeded at 4 ⁇ 10 4 cells / well, 8 ⁇ 10 4 cells / well, or 1.6 ⁇ 10 5 cells / well. Thereto, CFSE-labeled CD3 positive T cells were added to give 1.6 ⁇ 10 5 cells / well.
  • Dynabeads human T-Activator CD3 / CD28 was added to 3.2 ⁇ 10 4 beads / well. After culturing the plate for 72 hours at 37 ° C., 5% CO 2 , cells were recovered. Dead cells were stained using the LIVE / DEAD Fixable Aqua Dead Cell Stain Kit. Aqua (Amcyan) negative cells were gated as live cells, and the ratio of the division peak was quantified among the histogram peaks of CFSE labeled CD3 positive T cells to compare the inhibitory activity on T cell proliferation reaction.
  • CD33 positive cells after induction suppress T cell proliferation, and the suppression activity is the number of CD33 positive myeloid cells to be cocultured.
  • the proportion of dividing cells was 81.0% at a T cell: CD33 positive ratio of 8: 1, 66.5% at 4: 1, 39.0% at 2: 1) .
  • CD33 positive myeloid cells obtained by induction culture of cancer culture supernatant and GM-CSF from PBMC contain cells expressing MDSC markers and have T cell proliferation inhibitory activity. It was shown that MDSC having an immunosuppressive function could be induced.
  • Example 5 CD206 expression analysis in MDSC derived from PBMC was analyzed.
  • the surface markers of cells obtained by culturing CD3 negative cells separated from commercially available frozen PBMC in the presence of cancer cell culture supernatant and GM-CSF are analyzed by flow cytometry. did.
  • APC-labeled anti-CD206 antibody Stained using Dead cell staining was also performed using the LIVE / DEAD Fixable Aqua Dead Cell Stain Kit.
  • Example 6 Relationship Between CD206 Expression and Immunosuppressive Function of Myeloid Cells Containing MDSC Derived from PBMC The suppressive activity on T cell proliferation was examined as an indicator whether the immunosuppressive activity of CD33 positive myeloid cells containing MDSCs derived from PBMC is related to the expression of CD206.
  • CD33 positive CD206 strongly positive cells CD33 positive CD206 weak Positive cells
  • CD33 positive CD206 negative cells were separated.
  • CD3 positive T cells were CFSE labeled in the same manner as in Example 3 and Example 4. In a 96-well round bottom plate, CD33 positive CD206 strongly positive cells, CD33 positive CD206 weakly positive cells or CD33 positive CD206 negative cells were seeded at 8 ⁇ 10 4 cells / well. Thereto, CFSE-labeled CD3 positive T cells were added to give 1.6 ⁇ 10 5 cells / well.
  • Dynabeads human T-Activator CD3 / CD28 was added to 3.2 ⁇ 10 4 beads / well. The plates were cocultured for 72 hours at 37 ° C., 5% CO 2 . The cells were collected and dead cell staining was performed using LIVE / DEAD Fixable Aqua Dead Cell Stain Kit. Aqua (Amcyan) negative cells were gated as live cells, and the ratio of the division peak was quantified among the CFSE (FITC) positive CD3 positive T cell histogram peaks, and the inhibitory activity on T cell proliferation was compared.
  • FITC CFSE
  • CD33 positive CD206 weakly positive cells CD33 + CD206 low , percentage of dividing cells 64.6% showed T cell growth inhibitory activity, T cell proliferation inhibitory activity is weak when compared to CD33 positive CD206 strongly positive cells.
  • CD206 expression intensity in CD33 positive MDSCs is correlated with the immunosuppressive activity, and it was shown that CD206 can be an excellent surface marker of inhibitory myeloid cells.
  • Example 7 Antitumor Effect of Antibody Drug Targeting CD206 From the findings obtained in Examples 1 to 6, it was suggested that a drug targeting CD206 may release the immunosuppressive state and contribute to the improvement of the pathological condition. Therefore, the anti-tumor effect was examined using an anti-CD206 antibody.
  • An antibody drug complex was prepared in which a cytocidal drug was linked to an anti-CD206 antibody, using a CD206 positive cell as an antibody model capable of selectively removing it.
  • saporin was used. Saporin is a toxin contained in the seeds of Saponaria officinalis and causes cell death by directly inactivating ribosomes. Therefore, the complex in which the antibody and saporin are bound can be taken into the cell via the antigen on the target cell membrane and induce cell death.
  • Efficacy can be evaluated by administering this antibody drug complex to a tumor-bearing mouse model.
  • Mouse colon cancer cell line CT26 Evaluation was performed in a model in which WT (ATCC CRL-2638) was subcutaneously implanted in BALB / c mice.
  • CT 26 In tumors in WT tumor-bearing mice, it was confirmed that CD206 positive G-MDSC and CD206 positive M-MDSC were present. 5 ⁇ 10 5 CT26. 5 mice / mouse in the right axilla of BALB / c mice (11 females / group). WT cells were implanted subcutaneously.

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Abstract

L'invention a pour objet de fournir une technique destinée à identifier des cellules myéloïdes immunosuppressives. Selon l'invention, il est possible d'identifier des cellules myéloïdes immunosuppressives en reconnaissant un ＣＤ２０６ dans les cellules myéloïdes.
PCT/JP2018/034769 2017-09-21 2018-09-20 Marqueur de cellules myéloïdes immunosuppressives Ceased WO2019059267A1 (fr)

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WO2017027247A1 (fr) * 2015-08-07 2017-02-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Photoimmunothérapie à infrarouge proche (nir-pit) de lymphocytes suppresseurs pour le traitement du cancer
JP2017507990A (ja) * 2014-03-19 2017-03-23 インフィニティー ファーマシューティカルズ， インコーポレイテッド Ｐｉ３ｋ−ガンマ媒介障害の治療で使用するための複素環式化合物

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WO2016201388A2 (fr) * 2015-06-12 2016-12-15 Alector Llc Anticorps anti-cd33 et leurs procédés d'utilisation
WO2017027247A1 (fr) * 2015-08-07 2017-02-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Photoimmunothérapie à infrarouge proche (nir-pit) de lymphocytes suppresseurs pour le traitement du cancer

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022244852A1 (fr) * 2021-05-19 2022-11-24 国立大学法人富山大学 Composition pharmaceutique pour prévenir ou traiter un cancer

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