KR20190140756A - A bispecific antibody binding to natural killer cells and an use thereof - Google Patents

Abstract

The present invention relates to a bispecific antibody binding to natural killer (NK) cells, and a use thereof. The antibody of the present invention binds to antibodies associated with NK cells with low affinity to induce proliferation of human NK cells, and thus induces NK cell-mediated killing of tumor cells, abnormal cells or infected cells with high efficacy.

Description

Bispecific antibody binding to natural killer cells and an use

The present invention relates to bispecific antibodies that bind to natural killer cells and their use.

Natural killer cells (NK cells) are cytotoxic lymphocytes that make up the major components of the innate immune system. Natural killer cells are activated in response to interferon or macrophage-derived cytokines. Natural killer cells comprise two types of surface receptors that control the cytotoxic activity of cells, labeled as "activating receptors" and "inhibiting receptors."

More specifically, natural killer cells (hereinafter referred to as 'NK cells') are MHC class I of normal cells recognized by inhibitory receptors of NK cells to inhibit NK cell activity and thus are not attacked by NK cells, but MHC class I When recognizing damaged cells that lack receptors or overexpress ligands, when antibodies derived from B cells recognize and bind to antigens of target cells, these target cells are detected by CD16 receptors of NK cells and potent activity is observed. It has the surprising effect of being effectively eliminated by induced antibody dependent cell cytotoxicity (ADCC). Therapeutics are being developed using the potential of these NK cells. It prevents immune checkpoints using antibodies, or when NK cells are transplanted with NK cells, killer cell immunoglobulin-like receptors (KIR) inhibitory receptors do not recognize MHC class I molecules in heterologous tumor cells, There is a method of expressing CAR (chimeric antigen receptors) in NK cells through genetic engineering to specifically bind to ligands that tumor cells overexpress, NK cells attack tumor cells and the like.

As described above, antibodies that selectively bind to the surface of cancer cells through antibody dependent cell cytotoxicity (ADCC) as a representative cancer cell death function of an anti-cancer antibody are bound to the Fc portion and the Fc receptor present on the surface of immune cells. It serves to gather immune cells around cancer cells, and activated immune cells around cancer cells secrete various cytokines to kill cancer cells. Due to this apoptosis process, the binding capacity of the antibody to the Fc receptor may be an important factor in determining the degree of antibody-dependent cytotoxicity.

In particular, the bispecific monoclonal antibody for anticancer treatment is composed of two domains, and is composed of a domain capable of binding to a specific antigen on the surface of cancer cells and a domain capable of binding to an Fc receptor on the surface of immune cells. have. The purpose of the initially developed bispecific monoclonal antibodies was to obtain binding to Fc receptors that are stronger than the Fc portion of normal antibodies in the form of immunoglobulin (IgG). The binding capacity of IgG 1 to Fc receptors present on the surface of NK cells was about 1000 nM (dissociation constant Kd value), and bispecific monoclonal antibodies were prepared using domains exhibiting Fc receptor binding capacity 10 times higher. . In addition to Fab'-type antibody fragments, the binding domain used scFv, and bispecific monoclonal antibodies in IgG form were also initially developed. As methods for simultaneously expressing two binding domains, forms such as diabody, tandem diabody, and tandem scFv have been developed (Current Opinion in Drug Discovery & Development, 2009, 12 ( 2): 276-283, mAbs, 2009, 1 (6): 1-9).

The 2B1 antibody, developed by Chiron, USA, is in the form of a mouse IgG that can bind to NK cell surface antigens (CD16) and cancer cell surface antigens (Her2). development was discontinued due to side effects (Cancer Res. 1995, 55: 4586-4593, Immunology Letters, 2008, 116: 126-140, Cancer Immunol. Immunother. 1996, 42: 141-150). C6.5 / NM3E2 is a tandem scFv that can bind to NK cell surface antigen (CD16) and cancer cell surface antigen (Her2), and has problems such as low expression rate and low antigen affinity for CD16 (Molecular Immunology, 1999, 36: 433-446, J. of Immunology, 2001, 166: 6112-6117).

In addition, HRS-3 / A9, developed by Biotest, Germany, chemically connects Fab 'to NK cell surface antigen (CD16) and Fab' to cancer cell surface antigen (Her2). In one form, the antibody was discontinued in phase 3 clinical trials due to low in vivo efficacy and side effects such as cytokine seizures. In addition, linking two Fab's using a chemical linker has shown problems of heterogeneous composition and low production yield (Cancer Immunol. Immunother. 1999, 48: 9-21, Immunology Letters, 2008, 116: 126-140, Advanced Drug Delivery Reviews, 2003, 55: 171-197). AFM-13, which is being developed by Affimed, Germany, is a CD19 / CD16 tandem diabody (US20050089519), which has a low affinity for surface antigen (CD16) of NK cells, as low as 850 nM (dissociation constant Kd). (US20050089519). Finally, French biotechnology company Innate Pharma is still studying bispecific antibodies against NKp46 receptors and anti-tumor cell molecules that are activated against viral surface antigens.

As such, domestic and foreign researchers who are studying the efficacy by administering bispecific antibodies to NK cells are far fewer than those of T cell bispecific antibodies, and in the absence of commercially available antibodies, the present inventors have found that NK cells If we make bispecific antibodies that link epitopes of ligands or antigenic proteins that cause diseases to various receptors such as CD16, and amplify potent ADCC effects specific to tumors or specific diseases, we can develop breakthrough therapeutics. I thought I could. Thus, in the present invention, the first antigen-binding domain that specifically binds human NK cells with weak binding affinity or undetectable affinity in an in vitro assay depending on the specific antibody, and human tumor, virus infected cells, autologous It provides a bispecific antigen-binding molecule comprising a second antigen-binding molecule that specifically binds to an antigen expressed in immune diseases, degenerative brain diseases, pathogens including tuberculosis, lung fibrosis, and the like.

One object of the present invention is to provide a bispecific antibody that binds to immune cell activating receptors and tumor cell surface antigens.

Another object of the present invention is to provide a composition for treating diseases comprising the bispecific antibody and a pharmaceutically acceptable carrier.

As one aspect for achieving the above object, the present invention provides a bispecific antibody that binds to immune cell activating receptor and disease cell surface antigen.

As used herein, the term "bispecific antibody" refers to an antibody capable of binding two different kinds of antigens, and includes forms produced by genetic engineering. For the purposes of the present invention the bispecific antibodies may simultaneously bind to immune cell activating receptors and disease cell surface antigens.

As used herein, the term "antibody" includes immunoglobulin molecules that are immunologically reactive with specific antigens, and include both polyclonal and monoclonal antibodies. The term also includes forms produced by genetic engineering such as chimeric antibodies (eg, humanized murine antibodies) and heterologous binding antibodies (eg, bispecific antibodies). For the purposes of the present invention, the antibody refers to a bispecific antibody that is a heterologous antibody, and in the case of an immunoglobulin (IgG) form, which is a disadvantage of the existing improved anti-cancer therapeutic antibody, the Fc portion present in the IgG is various immune cells. In order to prevent interfering with targeting around cancer cells by binding to various Fc receptors present on the surface of the Fc region, a domain that binds to the immune cell surface antigen is bound to the Fc region so that only binding with the desired immune cells can be performed. It may be, but is not limited thereto. In the present invention, the term domain can be used interchangeably with antibody fragments.

As used herein, the term “antibody fragment” includes antigen-binding forms of an antibody, including fragments having antigen-binding ability, eg, Fab ′, F (ab ′) 2, Fab, Fv and rIgG. The term also refers to recombinant single chain Fv fragments (scFv), tandem single chain Fv (scFv) 2, bispecific T-cell contributors (BiTE ^® ), dual affinity retargeting antibodies (DART ^™ ), diabodies, Tandem Diabody (TandAb ^® ), Triabody and Tetrabody (FIG. 1).

Antibodies of the present invention are in the form of IgG, bivalent to the variable region or tetravalent to the constant region, a form made by attaching a molecule, a form in which two IgG forms are linked, and a scFv (single- chain antibody fragments containing both Engager forms in which two linker peptides are linked, preferably the V _H of the antibody. It may be in the form of scFv, which is a form of connecting the region with the V _L region by a short peptide chain. It does not promote the immune response because there is no Fc site, but because it is small in molecular weight it can be used as a carrier of a specific substance through the tissue and cells. Accordingly, the bispecific antibodies of the present invention can be useful for the treatment of natural killer cells (NK cells) to target various cancer or viral diseases, tuberculosis, pulmonary fibrotic autoimmune diseases, and degenerative brain diseases. have.

When the bispecific antibody of the present invention is in the form of connecting two single-chain Fv fragments (scFv), the linker peptide may insert an interleukin that affects the differentiation and survival of natural killer cells. Specifically, IL-2 , IL-15, IL-18, IL-21 and the like can be inserted.

As used herein, the term "immune cell" includes, without limitation, immune cells that act on antibody-dependent cytotoxic mechanisms, but may preferably be natural killer cells or T cells.

As used herein, the term "immune cell activating receptor" is a concept including an antigen present on the surface of immune cells, including without limitation antigens present on the surface of natural killer cells or T cells. Specifically, CD16 (FcyRIIIA), 2B4, CD2, CD3 zeta, CD27, CD56, CD57, CD62L, CD94, CD96, CD100, CD160, CD244, CEACAM1, CRACC, CRTAM, CS1, DAP10, DAP12, DNAM-1 (CD226 ), FcR gamma, KIRs (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR2DL4, KIR3DL2, KIR3DS1), LFA-1, NCRs, NKG2A, NKG2C, NKG2D, NKG2E, NKG230, NKp30H, NKp30H, NKp30H, NKp30H NTB-A, OX40, PSGL1, semaphoring 4D, SLAMF4, SLAMF6, SLAMF7, TIGIT, TLR, TRAIL and the like. The present invention may be composed of an antibody fragment comprising a domain that binds to the immune cell activating receptor or immune cell surface antigen.

As used herein, the term "disease cell surface antigen" is a concept including a ligand of a cell or an antigenic protein epitope that causes a specific disease, and refers to an antigen that is expressed by being involved in a specific disease or disease. Specifically, specific diseases include, but are not limited to, various kinds of cancers (tumors), bacterial infections including viral diseases, tuberculosis, lung fibrosis, autoimmune diseases, and degenerative brain diseases.

 Preferably the disease cell surface antigen of the invention may be a "tumor cell surface antigen". As used herein, the term "tumor cell surface antigen" includes without limitation antigens present on the surface of tumor cells. Specifically, AFP, AICL, ALK, ATM, ATPase, BAT3, BAG6, BAGE protein, BARD1, BIRC5 (survivin), BIRC7, β-catenin, B7-H6, BCA225, BFP, brc-abl, BRCA1, BRCA2 , BORIS, BRIPI, CA9, Carbonic anhydrase IX, Caspase-8, CA125, CA130, CA15-3, CA19-9, CA50, CA72-4, Calcitonin, E-, N-, R-Cadherins, CALR, CCR5, CD19, CD20 (MS4A1), CD22, CD24, CD25, CD27, CD27L, CD30, CD32, CD33, CD34, CD38, CD40, CD44, CCD45, D45R, CD47, CD48, CD54, CD56, CD58 (LFA-3 ), CD64, CD70, CD72, CD82 CD93, CD96, CD98, CD105, CD111, CD112, CD113, CD122, CD123, CD132, CD133, CD155, CD157, CD200, CD300f, CDK4, CEA, CEACAM-1, CEACAM-5 , CDH1, CHEK2, collagen, CPCAM, CpG, CRACC, CS1, CTLA4, CXCR4, Cyclin-B1, CYP1B1, Cyfra21-1, DUPAN-II, EGFR, EGFRvIII, Elastase-1, ErbB2 / Her2, ErbB3, ErbB4, ETV6 -AML, EpCAM, EphA2, FANCC, FLT3, Fra-1, FOLR1, GAGE protein (e.g. GAGE-1, -2), GD2, GD3, galecin-9, GloboH, Glypican-3, GM3, gp100 , Her2, HLA / B-raf, HLA-A, -C (2DS1), HLA class I, HLA-E, HLA-G, HLA / k-ras, HLA / MAGE-A3, HS, hTERT, la, IAP, ICAM-1, IgG-Fc, IL-1RAP, KIR 2DS2-2DS5, LMP2, L-selectin (CD62L), MAGE protein (e.g., MAGE-1 , -2, -3, -4, -6, and -12), MART-1, mesothelin, MHC Class I Ligands, MICA, MICB, MLH1, ML-IAP, MSH2, MSH6, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16 (CA-125), MUM1, NA17, NBC, NECL2 (CADM1) -IGSF4A, NECL5 (CD155, PVR), Nectin-1, Nectin-2 (CD112, PVRL2), NKp44L, NSE, NSS- ST-439, NTB-A, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PALB2, PAP, PAX3, PAX5, PCNA, PCTA-1, PD-1, PD- 1L, PIVKA-II, PLAC1, PRLR, PRAME, PSA, PSM2, PTEN, PVR, PSMA (FOLH1), RAD51C, RAD51D, RAGE Protein, Ras, RGS5, Rho, r-sm, SAIL, SART-1, SART- 3, SCC, SKT ll, SLAMF6, SLAMF7, SLX, SSX2, Span-1, STEAP1, STEAP2, STN, survivin, TAG-72, TLRL, TRAILR1, TRAILR2, thyroglobulin, TP53, TPA, U5snRNP complex, ULBP1-6, Along with VEGFR, vimentin, VLA-4 and XRCC2, viral hemagglutinins, viral antigens, mycolic acids of Mycobacterium tuberculosis, SLAMF7, Tau-protein overexpressed in degenerative brain diseases, beta-a myloid, C9orf72, Phosphorylated TDP-43, a-Synuclein, MICA overexpressed in lung fibrosis, TGF-beta and the like.

The dissociation constant (K _D value) for the immune cell or disease cell surface antigen of the bispecific antibody of the present invention is preferably, but not limited to, 100 nM or less. The anti-cancer therapeutic improved antibody under development improved the antigen affinity for immune cells by modifying the Fc amino acid sequence or the sugar chain structure, in which case the affinity for CD16 was reported to be up to 50 nM. When using immune cells as T cells (MT101), the affinity for CD3 was reported to be about 100 nM.

As used herein, the term "cytotoxicity" refers to a phenomenon in which an immune cell or the like kills its own cells infected with a virus or a parasitic organism, and in the present invention, mainly antibody-dependent cell-mediated cytotoxicity (ADCC). Means. Antibody-dependent cytotoxicity refers to a mechanism in which macrophages or leukocytes recognize an antibody bound to an antigen and destroy the antigen. Antibody-dependent cytotoxic mechanism is the action of T cells that are too large to be ingested by phagocytosis, such as parasites or alien solidified tumors, and directly recognize and attack the antigen as the antibody covers the surface of the antigen. It plays an important role in the case of being inhibited. In the present invention, the ADCC mechanism produces an anticancer effect using an immune response using a cancer cell surface protein as an antigen.

In one embodiment of the present invention, the first antigen may be a CD16 receptor and an NK cell-specific activating receptor that relays the ADCC effect of NK cells, and the second antigen may be an example of a cell or an antigen substance to be treated. For example, ligands expressed in abnormal cells such as tumor cells, surface antigens of viruses or bacteria, and protein antigens that accumulate in the brain and cause degenerative brain diseases. Thus, if the second antigen is targeted to a disease specific ligand, a disease specific bispecific antibody can be produced.

As another aspect, the present invention provides a composition for treating diseases comprising the bispecific antibody as an active ingredient and a pharmaceutically acceptable carrier.

As used herein, the term “disease” includes various kinds of cancers (tumors), bacterial infections including viral diseases, tuberculosis, and the like, lung fibrosis, autoimmune diseases, and degenerative brain diseases, but are not limited thereto.

As used herein, the term "cancer" includes, without limitation, esophageal cancer, stomach cancer, colon cancer, rectal cancer, oral cancer, pharyngeal cancer, laryngeal cancer, lung cancer, colon cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer , Prostate cancer, testicular cancer, bladder cancer, kidney cancer, liver cancer, pancreatic cancer, bone cancer, connective tissue cancer, skin cancer, brain cancer, thyroid cancer, leukemia, Hodgkin's disease, lymphoma, multiple myeloma or hematologic cancer.

The bispecific antibody of the present invention is confirmed to have an antibody-dependent cytotoxicity (ADCC) effect, which is a function of an antibody that kills cancer cells superior to conventional anticancer antibodies or Fc engineering anticancer antibodies, and thus used as an anticancer composition. It can be confirmed that. In addition, by confirming the anti-cancer therapeutic effect in the xenograft mouse anti-cancer model administered with Daudi cells, lymphoma, it can support that the composition comprising the bispecific antibody of the present invention can be used as a composition for treating cancer.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate an organism and does not inhibit the biological activity and properties of the administered compound. Acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterile and physiologically compatible, including saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.

Compositions comprising the bispecific antibodies according to the present invention, oral formulations, external preparations, suppositories or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, respectively, according to conventional methods Formulated in the form of can be used.

In another aspect, the present invention provides a method of treating a disease using the bispecific antibody.

Specifically, the bispecific antibody of the present invention is administered to a natural killer cell medium in which the activating receptor is well expressed and cultured in vitro, and then the antibody of the present invention is well supported by the natural killer cell, and then administered in a human body by a self-administration regimen. Disease specific effects may be seen.

The method may be a method for treating a particular disease to be treated, more specifically cancer, comprising administering the pharmaceutical composition to a subject in need thereof, wherein the bispecific antibody, carrier, used The types of diseases, cancers and cancers are the same as described above.

The composition may be administered in single or multiple amounts in a pharmaceutically effective amount. In this case, the composition may be administered in the form of a liquid, powder, aerosol, capsule, enteric skin tablets or capsules or suppositories. Routes of administration include, but are not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, endothelial administration, oral administration, topical administration, intranasal administration, pulmonary administration, rectal administration, and the like. However, upon oral administration, since the peptide is digested, the oral composition must be formulated to coat the active agent or to protect it from degradation in the stomach. In addition, the pharmaceutical composition may be administered by any device in which the active agent may migrate to the target cell. In addition, the composition for treating diseases of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.

Compositions comprising such bispecific antibodies of the invention are administered in a pharmaceutically effective amount. “Pharmaceutically effective amount” means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention, wherein an effective dose level is the severity of the disease, the activity of the drug, the age of the patient, Body weight, health, sex, sensitivity to the drug of the patient, time of administration of the composition of the invention used, route of administration and rate of release, duration of treatment, elements including drugs used or combined with the composition of the invention used and other medical fields Can be determined according to well-known factors.

The bispecific antibodies of the present invention are useful for the prevention or treatment of various diseases related to immunomodulation by immunotherapy, specifically cancer, viral diseases, bacterial infections including tuberculosis, lung fibrosis, autoimmune diseases, degenerative brain diseases, and the like. . In particular, the bispecific antigen-binding molecules of the present invention can inhibit the growth of tumors that express target antigens (eg HER2) and thus can be utilized as anticancer therapeutics.

Figure 1 shows several kinds of recombinant antibody fragments using the variable region of the antigen, which can be applied to the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Example  One: Bispecific  Preparation of Antibodies

Example  2: Determination of avidity of target immune cells to activating receptors (CD16 antigen)

Example 2-1: Cultivation method of immune cells containing cultured activated natural killer cells

Example 2-2: Pre-incubation of the cultured activated natural killer cells with the purified bispecific antibody for interaction

Example 2-3 Method of Promoting Cultured Activated Natural Killer Cells and Purified Bispecific Antibody Without Pre-incubation

Example  3: Identification of Antibody-Dependent Cytotoxicity

Example  4: Pharmacokinetics ( Pharmacokinetics ) analysis

Experimental Example  1: Confirm disease treatment effect

Experimental Example 1-1: Measurement of the amount of secretion of interferon-gamma in the cell medium

Experimental Example 1-2: Cytotoxicity Measurement-Lactate dehydrogenase

Experimental Example 1-3: Degranulation phenomenon of granzyme B, perforin and other substances in natural killer cells

Experimental Example 1-4: Measurement of therapeutic effect in disease-induced animal models (immune tissue staining, etc.)

Claims (13)

Bispecific antibodies that bind to immune cell activating receptors and disease cell surface antigens.
The bispecific antibody of claim 1, wherein the immune cells are natural killer cells.
The method of claim 1, wherein the immune cell activating receptor is CD16 (FcyRIIIA), 2B4, CD2, CD3 zeta, CD27, CD56, CD57, CD62L, CD94, CD96, CD100, CD160, CD244, CEACAM1, CRACC, CRTAM, CS1, DAP10, DAP12, DNAM-1 (CD226), FcR gamma, KIRs (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR2DL4, KIR3DL2, KIR3DS1), LFA-1, NCRs, NKG2A, NKG2C, NKG2D, NKG2D , b, NKp44, NKp46, NKp80, NTB-A, OX40, PSGL1, semaphoring 4D, SLAMF4, SLAMF6, SLAMF7, TIGIT, TLR and TRAIL.
The bispecific antibody of claim 1, wherein the diseased cell is a ligand of the cell causing the disease, or an antigenic protein epitope.
The bispecific antibody of claim 1, wherein the disease cell surface antigen is a tumor cell surface antigen.
The method according to claim 5, wherein the tumor cell surface antigen is AFP, AICL, ALK, ATM, ATPase, BAT3, BAG6, BAGE protein, BARD1, BIRC5 (survivin), BIRC7, β-catenin, B7-H6, BCA225, BFP, brc-abl, BRCA1, BRCA2, BORIS, BRIPI, CA9, Carbonic anhydrase IX, Caspase-8, CA125, CA130, CA15-3, CA19-9, CA50, CA72-4, Calcitonin, E-, N-, R-Cadherins, CALR, CCR5, CD19, CD20 (MS4A1), CD22, CD24, CD25, CD27, CD27L, CD30, CD32, CD33, CD34, CD38, CD40, CD44, CCD45, D45R, CD47, CD48, CD54, CD56, CD58 (LFA-3), CD64, CD70, CD72, CD82 CD93, CD96, CD98, CD105, CD111, CD112, CD113, CD122, CD123, CD132, CD133, CD155, CD157, CD200, CD300f, CDK4, CEA, CEACAM-1, CEACAM-5, CDH1, CHEK2, collagen, CPCAM, CpG, CRACC, CS1, CTLA4, CXCR4, Cyclin-B1, CYP1B1, Cyfra21-1, DUPAN-II, EGFR, EGFRvIII, Elastase-1, ErbB2 / Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, FANCC, FLT3, Fra-1, FOLR1, GAGE protein (e.g. GAGE-1, -2), GD2, GD3, galecin-9, GloboH , Glypican-3, GM3, gp100, Her2, HLA / B-raf, HLA-A, -C (2DS 1), HLA class I, HLA-E, HLA-G, HLA / k-ras, HLA / MAGE-A3, HS, hTERT, la, IAP, ICAM-1, IgG-Fc, IL-1RAP, KIR 2DS2- 2DS5, LMP2, L-selectin (CD62L), MAGE protein (e.g., MAGE-1, -2, -3, -4, -6, and -12), MART-1, mesothelin, MHC Class I Ligands , MICA, MICB, MLH1, ML-IAP, MSH2, MSH6, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16 (CA-125), MUM1, NA17, NBC, NECL2 (CADM1) -IGSF4A, NECL5 (CD155, PVR ), Nectin-1, Nectin-2 (CD112, PVRL2), NKp44L, NSE, NSS-ST-439, NTB-A, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53 , PALB2, PAP, PAX3, PAX5, PCNA, PCTA-1, PD-1, PD-1L, PIVKA-II, PLAC1, PRLR, PRAME, PSA, PSM2, PTEN, PVR, PSMA (FOLH1), RAD51C, RAD51D, RAGE protein, Ras, RGS5, Rho, r-sm, SAIL, SART-1, SART-3, SCC, SKT ll, SLAMF6, SLAMF7, SLX, SSX2, Span-1, STEAP1, STEAP2, STN, survivin, TAG- 72, TLRL, TRAILR1, TRAILR2, thyroglobulin, TP53, TPA, U5snRNP complex, ULBP1-6, VEGFR, vimentin, VLA-4, XRCC2 viral antigens viral hemagglutinins, Mycolic acids of Mycobacterium tuberculosis, SLAMF7, Standing overexpression Tau- protein, beta-amyloid, C9orf72, Phosphorylated TDP-43, a-Synuclein, is overexpressed in lung fibrosis and MICA is selected from the group consisting of TGF-beta, bispecific antibodies.
The antibody of claim 1, wherein the antibody is a Fab, Fab ', F (ab') 2, Fv fragment, rIgG, single chain Fv fragment (scFv), tandem single chain Fv fragment (scFv) 2, bispecific T-cell Selected from the group consisting of Participants (BiTE ^® ), dual affinity retargeting antibodies (DART ^™ ), Diabodies, Tandem Diabodies (TandAb ^® ), Triabodies and Tetrabodys , Bispecific antibodies.
The bispecific antibody of claim 7, wherein the antibody is a single chain Fv fragment (scFv).
The bispecific antibody of claim 8, comprising an interleukin in a linker connecting said single chain Fv fragment.
The bispecific antibody of claim 9, wherein the interleukin is selected from the group consisting of IL-2, IL-15, IL-18, and IL-21.
A composition for treating a disease comprising the bispecific antibody of any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
The composition of claim 11, wherein the disease is cancer.
The method of claim 12, wherein the cancer is esophageal cancer, stomach cancer, colon cancer, rectal cancer, oral cancer, pharyngeal cancer, laryngeal cancer, lung cancer, colon cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer. , Liver cancer, pancreatic cancer, bone cancer, connective tissue cancer, skin cancer, brain cancer, thyroid cancer, leukemia, Hodgkin's disease, lymphoma, multiple myeloma and hematologic cancer.

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