CD70 and venetoclax, BCL-2 inhibitors, combination therapy for the treatment of acute myeloid leukemia

Abstract

To provide pharmaceutical compositions for use in combination therapies, particularly combination therapies for the treatment of myeloid malignancy.SOLUTION: The present invention provides a pharmaceutical composition for administering an antibody binding to CD70 or an antigen-binding fragment thereof in combination with a BCL-2 inhibitor, wherein the pharmaceutical composition includes an antibody binding to CD70 or an antigen-binding fragment thereof, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, and the antibody binding to CD70 or an antigen-binding fragment thereof comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Field of Invention) This invention relates to combination therapy, particularly combination therapy for the treatment of myeloid malignancies. This therapy is particularly useful for treating acute myeloid leukemia (AML). This combination therapy targets CD70 The binding antibody or its antigen-binding fragment, and a BCL-2 inhibitor, such as venetoclax or It contains a medicinally acceptable salt. This combination therapy can also include additional anticancer agents, such as bruises. It may also include drugs used to treat AML, such as cytidine or decitabine. [Background technology]

[0002] (Background of the invention) In recent years, the development of new cancer treatments has focused on molecular targets, particularly proteins, that are involved in cancer progression. They've started to hit the mark. The list of molecular targets involved in tumor growth, invasion, and metastasis continues to expand. The list includes proteins overexpressed by tumor cells, as well as vascular and This includes targets related to systems that support tumor growth, such as the immune system. The number of therapeutic drugs or anticancer drugs designed to interact with each other is also continuously increasing. Many targeted cancer drugs have been approved for clinical use, and many more are still under development. It's inside.

[0003] CD70 is constitutively expressed in many types of hematological malignancies and solid tumors. It has been identified as a particularly interesting molecular target (Junker et al., (2005) J Urol. 173:2150). -3; Literature by Sloan et al., (2004) Am J Pathol. 164:315-23; Literature by Held-Feindt and Mentlein , (2002) Int J Cancer, 98:352-6; the document of Hishima et al., (2000) Am J Surg Pathol. 24:742 -6; the document of Lens et al., (1999) Br J Haematol. 106:491-503; the document of Boursalian et al., (2009) Adv Exp Med Biol. 647:108-119; the document of Wajant H., (2016) Expert Opin Ther Targets, 20(8):959-973). CD70 is a type II transmembrane glycoprotein that belongs to the tumor necrosis factor (TNF) superfamily, and mediates its effects through binding to its cognate cell surface receptor CD27. Both CD70 and CD27 are expressed by multiple cell types of the immune system, and the CD70-CD2 7 signaling pathway is involved in the regulation of several different aspects of immune responses. This reflects the fact that overexpression of CD70 occurs in various autoimmune diseases including rheumatoid arthritis, psoriatic arthritis and lupus (the document of Boursalian et al., (2009) Adv Ex p Med Biol. 647:108-119; the document of Han et al., (2005) Lupus, 14(8):598-606; the document of Lee et al., ( 2007) J Immunol. 179(4):2609-2615; the document of Oelke et al., (2004) Arthritis Rheum. 50(6): 1850-1860).

[0004] CD70 expression is associated with poor prognosis of several cancers including B-cell lymphoma, renal cell carcinoma and breast cancer (the document of Bertrand et al., (2013) Genes Chromosomes Cancer, 52(8):764- 774; Jilaveanu et al., (2012) Hum Pathol. 43(9):1394-1399; Petrau et al., (2014) J Cancer, 5(9):761-764). CD70 expression is also detected on metastatic tissue in a high proportion of cases, indicating that this molecule plays an important role in cancer progression (Jacobs et al., ( 2015) Oncotarget, 6(15):13462-13475). The constitutive expression of CD70 and its receptor CD2 7 on hematopoietic lineage tumor cells directly regulates the proliferation and survival of tumor cells, and is involved in the central role of CD70-CD27 signaling (Goto et al., (2012) Leuk Lymphoma, 53(8):1494-1 500; Lens et al., (1999) Br J Haematol. 106(2):491-503; Nilsson et al., (2005) Exp Hematol. 33(12):1500-1507; van Doorn et al., (2004) Cancer Res. 64(16):557 8-5586).

[0005] Upregulated CD70 expression on tumors, particularly solid tumors that do not co-express CD27, also contributes to immunosuppression in the tumor microenvironment in various ways. For example, CD70 bound to CD2 7 on regulatory T cells has been shown to increase the frequency of Tregs, reduce tumor-specific T cell responses , and promote tumor growth in mice (Claus et al., (2012) Cancer Re s. 72(14):3664-3676). As has been shown in cells of renal cell carcinoma, glioma and glioblastoma, CD70-CD27 signaling also contributes to immunosuppression via tumor-induced apoptosis of T lymphocytes It can also weaken the epidemic response (Chahlavi et al., (2005) Cancer Res. 65(12):5428-5438). ;Diegmann et al., (2006) Neoplasia, 8(11):933-938;Wischusen et al., (2002) Canc (er Res, 62(9):2592-2599). Finally, CD70 expression is also related to T cell depletion, which leads to Tumor cells employ a more differentiated phenotype and are unable to kill tumor cells. (Wang et al., (2012) Cancer Res, 72(23):6119-6129; Yang et al., (2014) Leukemia (28(9):1872-1884).

[0006] Given the importance of CD70 in cancer progression, CD70 is an attractive target for anti-cancer therapy. Furthermore, antibodies that target this cell surface protein are currently undergoing clinical trials (Jacob et al., (2 015) Pharmacol Ther. 155:1-10; Silence et al., (2014) mAbs, 6(2):523-532). [Overview of the project]

[0007] (Summary of the invention) The present invention relates to a combination therapy comprising an antibody that binds to CD70 or an antigen-binding fragment thereof. As such, the list of proteins involved in tumor growth continues to expand, and these two or more Combination therapies targeting proteins are becoming increasingly attractive as anti-cancer treatments. In the combination therapy of the present invention, the antibody or antigen-binding fragment thereof that binds to CD70 is BCL- 2. In combination with an inhibitor, such as venetoclax or a pharmaceutically acceptable salt thereof. Overexpression of BCL-2 in cancer cells confers resistance to apoptosis, therefore Inhibition of the venetocran protein can promote tumor cell death. Kus is an example of a potent and selective small molecule inhibitor of the BCL-2 protein. (As described herein) As described above, an antibody or its antigen-binding fragment that binds to CD70, and a BCL-2 inhibitor, for example The combination of venetoclax or its pharmaceutically acceptable salts is for cancer, particularly acute bone marrow cancer. To provide effective therapies for treating myeloid malignancies such as leukemia malformation (AML).

[0008] In a first embodiment, the present invention relates to (i) an antibody or antigen-binding fragment thereof that binds to CD70, and (ii) Provide a combination comprising a BCL-2 inhibitor. In some preferred embodiments, BCL- 2. The inhibitor is compound (I) shown below. [ka] or a salt that is acceptable as a medicine. Compound (I) is also referred to herein as venetoclax.

[0009] In some embodiments, the antibody or antigen-binding fragment that binds to CD70 is: (i) variable heavy chain It includes a (VH) domain and a variable light chain (VL) domain, and this VH domain and VL domain are Heavy chain CDRs (HCDR3, HCDR2, and HCDR1) and light chain CDRs (LCDR3, LCDR2, and LCDR1): Includes sequence number 3. HCDR3 containing or following sequence number 2; HCDR2 containing or following sequence number 2; sequence Number: HCDR1 containing or derived from 1; Sequence ID: L containing or derived from 7 CDR3; containing or derived from sequence number 6; and LCDR2; containing or derived from sequence number 5 (ii) an antibody or antigen-binding fragment containing LCDR1:, (ii) SEQ ID NO: 4 and at least 7 VH2 containing amino acid sequences that are 0%, at least 80%, at least 90%, and at least 95% identical. Main, and array number: 8 and at least 70%, at least 80%, at least 90%, at An antibody or antigen-binding fragment containing a VL domain having an amino acid sequence that is 95% identical; or (iii) ) Selected from ARGX-110. In some embodiments, the antibody is IgG, preferably IgG It is 1.

[0010] The CD70 antibody or antigen-binding fragment in this combination may also have one or more effector functions. In some embodiments, the antibody or antigen-binding fragment is ADCC (Antibody-Dependent Cell Intervention). Possesses cellular cytotoxic activity; and / or contains a defucosylated antibody domain; and / or or possesses CDC (complement-dependent cell cytotoxicity) activity; and / or ADCP (antibody-dependent cell phagocytosis) activity. It has properties. In a preferred embodiment, the CD70 antibody is ARGX-110.

[0011] In some embodiments, the CD70 antigen-binding fragment of this combination is: Antibody light chain variable domain (VL); Antibody heavy chain variable domain (VH); Single-chain antibody (scFv); F(ab')2 fragment; Fab fragment; Fd fragment; F v fragment; a single-armed (monovalent) antibody; a diabody, triabody, tetrabody, or Formed by such combinations, assemblies, or conjugations of antigen-binding fragments It is independently selected from the group consisting of any antigen-binding molecule.

[0012] In some embodiments, the CD70 antibody or its antigen-binding fragment and the BCL-2 inhibitor are individual It is formulated as a separate composition. In some embodiments, it is a CD70 antibody or its antigenic compound. The composite fragments, and venetoclax or its pharmaceutically acceptable salts, are used as separate compositions. It is then formulated into a pharmaceutical product.

[0013] The combination of the present invention includes one or more additional therapeutic agents, for example, at least one additional anticancer agent, In some embodiments, this may include a therapeutic agent for myeloid malignancies. In some embodiments, additional anticancer agents It is a therapeutic agent for acute myeloid leukemia (AML). In a preferred embodiment, the combination is low It contains a methylating agent, preferably azacitidine or decitabine.

[0014] In a further embodiment, the present invention, according to the first aspect of the present invention, is for use in therapy. The present invention provides a combination of malignant tumors in humans, preferably myeloid malignant tumors. The present invention provides a combination according to a first aspect of the present invention for use in treatment. A method for treating malignant tumors in humans, preferably myeloid malignant tumors, and for the subject, this invention The present invention provides a method comprising administering an effective amount of any combination according to the first embodiment of the present invention. .

[0015] The present invention is also for use in the treatment of malignant tumors in humans, preferably myeloid malignancies. an antibody or antigen-binding fragment thereof that binds to CD70, and is a BCL-2 inhibitor, preferably a compound Provides an antibody molecule to be administered in combination with substance (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to BCL-2 inhibitors, preferred for use in the treatment of malignant tumors in human subjects. The invention provides compound (I) or a pharmaceutically acceptable salt thereof, and a BCL-2 inhibitor thereof, preferably Compound (I) or a pharmaceutically acceptable salt thereof is an antibody or its anti-CD70 binding antibody. It is administered in combination with the original conjugated fragment.

[0016] The combination of the present invention is particularly advantageous because they exhibit synergistic effects. Therefore, the present invention In all embodiments, preferably, the CD70 antibody or its antigen-binding fragment is used in this combination. The doses administered and / or provided, and the BCL-2 inhibitor administered and / or provided in this combination. The dosages used are selected so that their combination provides a synergistic treatment.

[0017] In some preferred embodiments of the combination of the present invention, CD70 antibody or its antigen binding cleavage occurs. The sac and BCL-2 inhibitor were cultured in AML cell lines selected from NOMO-1, MOLM-13, NB4, and MV4-11. Each of these compounds present in this combination in sufficient quantities to provide synergistic cell death when this occurs. do.

[0018] With respect to malignant tumors treated using the combination of the present invention, these malignant tumors are newly diagnosed. Myeloid malignancies; relapsed or refractory myeloid malignancies; or acute myeloid leukemia ( AML); Myelodysplastic syndrome (MDS); Myeloproliferative neoplasm (MPN); Chronic myeloid leukemia (CML); and chronic Myeloid malignancies selected from myelomonocytic leukemia (CMML) may also be present. Particularly preferred In one embodiment, the combination of the present invention is for the treatment of acute myeloid leukemia (AML).

[0019] In some embodiments, the subject or patient treated according to the method of the present invention is newly This group consists of newly diagnosed AML patients who are ineligible for standard intensive chemotherapy. AML patients aged 75 and older who have been discouraged from using standard intensive chemotherapy, or who have been newly diagnosed and whose use of standard intensive chemotherapy is being hindered. AML patients with co-existing conditions are also acceptable.

[0020] In some embodiments, the CD70 antibody or its antigen-binding fragment is present in a range of 0.1 to 25 mg / kg. It is administered separately, preferably at a dose of 10 mg / kg. Separately, or in addition thereto, BCL-2 The inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof, is present in a quantity of 100 mg to 600 mg. It may be administered in doses within the range of . In a preferred embodiment, the method described herein is This includes administering a combination that additionally contains azacitidine, the azacitidine being 75 mg g / m 2 It is administered in the dose of [amount]. In a more preferred embodiment, the method described herein is [details omitted]. The treatment includes administering a combination that additionally contains cytabine, with this decitabine dose being 20 mg / m². 2 Use It is administered by dose.

[0021] In some embodiments, the method further monitors the patient's blast count. This includes the fact that the blast count in the patient's peripheral blood and / or bone marrow can be reduced, for example. If reduced to less than 25%, for example to 5%, for example to less than 5%, for example minimal residual disease It can be reduced to a bell, for example, to an undetectable level. Several embodiments In this study, the myeloblast count decreased to between 5% and 25%, and compared to before treatment, the myeloblast count decreased. The percentage of balls decreases by more than 50%.

[0022] In some embodiments, this method induces a partial response. Furthermore, this method induces a complete response and optionally involves platelet and / or neutrophil recovery. The law requires transfusions of red blood cells, platelets, or both for 8 weeks, 10 weeks, or 12 weeks or longer. It may also induce addiction withdrawal. In some embodiments, this method is used after 30 days or It reduces the mortality rate after 60 days.

[0023] In some embodiments, this method extends the lifespan. For example, this method is used in this group Standard of one or more therapeutic agents used in combination to treat certain myeloid malignancies Conversely, it can also extend survival time. This method induces a negative minimal residual disease state. Sometimes it happens.

[0024] In some embodiments, the method further includes the step of providing a bone marrow transplant to the subject. Alternatively, the method may include the step of administering one or more additional anticancer drugs. It may also include one or more additional cancer agents for myeloid malignancies, preferably AML. Any drug suitable for treatment may be selected. Preferred drugs are selectin inhibitors. (e.g., GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g., Midstau); Phosphorus; cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK / STAT inhibitors; Cytarabine; anthracycline compounds (e.g., daunorubicin, idarubicin); Doki Sorbicin; hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors, Idohifa (Idhifa) (or enasidenib) or tibsovo (or ivosidenib), etc.; Smo Other inhibitors, such as glass-de-gib, BET bromodomain inhibitors, CD123 or CD33 targeting agents, H DAC inhibitors, LSC targeting agents, AML bone marrow niche targeting agents, and NEDD8 activating enzyme inhibitors, pevone You may choose from options such as Zistat. [Brief explanation of the drawing]

[0025] (drawing) [Figure 1] Co-treatment with xatuzumab and decitabine synergistically eliminates NOMO-1 AML cells. NOMO-1 AML cells were treated with vehicle, xatuzumab, venetoclax, or decitabine, either alone or in combination of fixed ratios, in the presence of carboxyfluorescein succinimimidyl ester (CFSE)-labeled NK cells (1:1 ratio). The number of NOMO-1 AML cells per well was counted after 72 hours, and the degree of viability was determined by Annexin V staining. The effect of the drug treatment was calculated as the ratio of viable cells to vehicle-treated cells. The combination index (CI) value was calculated and plotted against the fraction affected (Fa) value between 0 and 10. Fa-CI plots (Chou-Talalay plots) evaluating synergistic and / or antagonistic effects are shown. Fa values ​​of 0, 0.5, and 1 correspond to 0%, 50%, and 100% dead cells, respectively. CI less than 1, CI of 1, and CI greater than 1 represent synergistic, additive, and antagonistic effects, respectively. IC50 represents the Fa value at which the Ve / Cusa combination (low Fa) and Ve / De / Cusa combination (high Fa) reach the IC50 concentration. Ve / De, venetoclax and decitabine; De / Cusa, decitabine and xatuzumab; Ve / Cusa, venetoclax and xatuzumab; Ve / De / Cusa, venetoclax and decitabine and xatuzumab.

[0026] [Figure 2]Co-treatment with xatuzumab and decitabine synergistically eliminates NOMO-1 AML cells. Data for each combination are individually plotted using CI-Fa and are shown in Figure 1. (A) Venetoclax and decitabine; (B) Decitabine and xatuzumab; (C) Venetoclax and xatuzumab; (D) Venetoclax, decitabine, and xatuzumab.

[0027] [Figure 3] Co-treatment with xatuzumab and decitabine synergistically eliminates NB4 AML cells. NB4 AML cells were treated with a vehicle, xatuzumab, venetoclax, or decitabine, either individually or in combination at specific ratios, in the presence of CFSE-labeled NK cells (1:1 ratio). The number of NB4 AML cells per well was counted after 72 hours, and the degree of viability was determined by Annexin V staining. The effect of the drug treatment was calculated as the ratio of viable cells to vehicle-treated cells. A combination index (CI) value was calculated and plotted against the action ratio (Fa) value between 0 and 10. Fa-CI plots [Chou-Talalay plots] evaluating synergistic and / or antagonistic effects are shown. Fa values ​​of 0, 0.5, and 1 correspond to 0%, 50%, and 100% dead cells, respectively. (A) Venetoclax and decitabine; (B) Venetoclax and xatuzumab; (C) Decitabine and xatuzumab; (D) Venetoclax, decitabine and xatuzumab.

[0028] [Figure 4]Co-treatment with xatuzumab and decitabine synergistically eliminates MOLM-13 AML cells. MOLM-13 AML cells were treated with a vehicle, xatuzumab, venetoclax, or decitabine, either individually or in combination at specific ratios, in the presence of CFSE-labeled NK cells (1:1 ratio). The number of MOLM-13 AML cells per well was counted after 72 hours, and the degree of viability was determined by Annexin V staining. The effect of the drug treatment was calculated as the ratio of viable cells to vehicle-treated cells. The combination index (CI) value was calculated and plotted against the action ratio (Fa) value. Fa-CI plots [Chou-Talalay plots] evaluating synergistic and / or antagonistic effects are shown. Fa values ​​of 0, 0.5, and 1 correspond to 0%, 50%, and 100% dead cells, respectively. (A) Venetoclax and decitabine; (B) Venetoclax and xatuzumab; (C) Decitabine and xatuzumab; (D) Venetoclax, decitabine and xatuzumab.

[0029] [Figure 5] Co-treatment with xatuzumab and decitabine synergistically eliminates MV4-11 AML cells. MV4-11 AML cells were treated with a vehicle, xatuzumab, venetoclax, or decitabine, either individually or in combination at specific ratios, in the presence of CFSE-labeled NK cells (1:1 ratio). The number of MV4-11 AML cells per well was counted after 72 hours, and the degree of viability was determined by Annexin V staining. The effect of the drug treatment was calculated as the ratio of viable cells to vehicle-treated cells. The combination index (CI) value was calculated and plotted against the action ratio (Fa) value. Fa-CI plots [Chou-Talalay plots] evaluating synergistic and / or antagonistic effects are shown. Fa values ​​of 0, 0.5, and 1 correspond to 0%, 50%, and 100% dead cells, respectively.

[0030] [Figure 6]The combined treatment of venetoclax and xatuzumab synergistically eliminates leukemia stem cells (LSCs) in vitro. CD34+CD38- AML LSCs derived from patient P1-P3 cells were cultured overnight in double rows in the presence of NK cells (1:1 ratio) with either xatuzumab (Cusa: 0.3 μg / ml) or venetoclax (Ve: 6 nM), either alone or in combination, followed by seeding (plating) in methylcellulose. Colony formation was evaluated after 14 days. (A) Absolute number of colonies per well from the first seeding after treatment; (B) Cells collected from the first seeding were reseeded (second seeding), and colony formation and colonies per well were evaluated after 14 days. Data are shown as mean ± SD. Statistics: One-way ANOVA; Tukey's post-hoc test; *, P<0.05; **, P<0.01; ***, P<0.001.

[0031] [Figure 7] The combined venetoclax and xatuzumab treatment synergistically eliminates LSCs in vitro. The data shown correspond to the data in Figure 6 and were normalized to the mean number of colonies per well after vehicle treatment for each patient. (A) First dissemination; (B) Second dissemination.

[0032] [Figure 8] Combined venetoclax and xatuzumab treatment synergistically eliminates LSCs in vitro. CD34+CD38- AML LSCs from patients P4 and P5 were cultured overnight in double rows in the presence of NK cells (1:1 ratio) with either xatuzumab (Cusa: 0.3 μg / ml), venetoclax (Ve: 6 nM), or decitabine (0.01 μM), either alone or in combination, followed by seeding in methylcellulose. Colony formation was evaluated after 14 days. Data are shown as mean ± SD. (A) Results from a single patient; (B) Results from patients P4 and P5.

[0033] [Figure 9]CD70 mRNA expression (as a percentage of housekeeping genes) after 24 or 48 hours of treatment with vehicle (Veh) or venetoclax (Ven). [Figure 10] CD70 protein and CD70 mRNA expression in MOLM-13 and NOMO-1 cells in the presence (gray bars) and absence (black bars) of venetoclax. Significance was determined using Student's t-test. MFI = mean fluorescence intensity. ***P<0.001. [Modes for carrying out the invention]

[0034] (Detailed explanation) (A.Definition) Unless otherwise defined, all technical and scientific terms used herein are: This has the same meaning as that commonly understood by those skilled in the art in the field of the present invention.

[0035] "Combination therapy" - As used herein, the term "combination therapy" refers to a subject, for example This refers to a treatment in which two or more therapeutic drugs are administered to human subjects. The term "combination" as used herein refers to: It is intended for use in combination therapy. Two or more medications are typically used for a single disease. In this specification, it is administered to treat cancer or malignant tumors. Combination of the present invention Alternatively, combination therapy may involve an antibody or antigen-binding fragment that binds to CD70 and a BCL-2 inhibitor, or This specification includes the small molecule inhibitor venetoclax or a pharmaceutically acceptable salt thereof. As described, the drugs included in combination therapy are administered to the target or patient who needs them. For administration, they may be co-formulated for drug use, or, for example, individually as separate compositions. It may also be used as a substitute.

[0036] "Antibody" - As used herein, the term "antibody" refers to a full-length antibody and its Varian form. It is intended to include modified antibodies, humanized antibodies, and germline antibodies. This includes, but is not limited to, the term "anti" as typically used in this specification. "Immunoglobulin polypeptide" refers to an immunoglobulin polypeptide having a combination of two heavy chains and two light chains. The polypeptide exhibits a significant specific immune response against the target antigen (CD70 in this specification). It has reactive activity. Regarding IgG class antibodies, this antibody has a molecular weight of approximately 23,000 daltons. It contains two identical polypeptide light chains and two identical heavy chains with molecular weights of 53,000 to 70,000. These four chains are linked by disulfide bonds in a "Y" configuration, where the light chain is "Y" It starts with the mouth of " and encloses the heavy chain in brackets (bracket) over the variable region. The light chain of an antibody is classified as either kappa or lambda (κ, λ). Each heavy chain class is It will be bonded to either a kappa light chain or a lambda light chain. Generally, light chains and heavy chains They are covalently bonded to each other, and the "tails" of these two heavy chains are connected by disulfide covalent bonds. Or immunoglobulin in either hybridoma, B cell, or genetically modified host cell When produced by this method, they are linked to each other by non-covalent bonds. In the heavy chain, The mino acid sequence is arranged from the N-terminus at the branching end of the Y-shaped configuration to the C-terminus at the base of each chain.

[0037] Those skilled in the art will know that heavy chains are accompanied by several subclasses (e.g., γ1-γ4), gamma, mu, and a It is important to understand that they are classified as γ, μ, α, δ, ε. It is likely. Due to the nature of this chain, the "classes" of antibodies are, respectively, IgG, IgM, IgA, IgD, or Ig It is determined to be E. Immunoglobulin subclass (isotype), e.g., IgG1, IgG2, IgG3 IgG4, IgA1, and others are well-characterized and known to possess functional specialization. As used herein, the term "antibody" refers to an antibody derived from any class or subclass of an antibody. It encompasses the body.

[0038] "Antigen-binding fragment" - As used herein, the term "antigen-binding fragment" refers to a full-length antibody. Antibodies containing fewer amino acid residues than a complete or intact antibody, either partially or in part. It refers to a fragment of an antibody chain that maintains its antigen-binding activity. The antigen-binding fragment of an antibody is an antibody. It contains peptide fragments that exhibit specific immune response activity against the same antigen (e.g., CD70). As used herein, the term "antigen-binding fragment" refers to the antibody light chain variable domain (VL); antibody weight Chain variable domain (VH); single-chain antibody (scFv); F(ab')2 fragment; Fab fragment; Fd fragment; Fv fragment; one piece Arm (monovalent) antibody; diabody, triabody, tetrabody, or such Any antigen formed from a combination, assembly, or conjugation of antigen-binding fragments It is intended to contain selected antibody fragments from the protoconjugated molecule. The term "antigen-binding fragment" used here is similar to unibody, domain antibody, and nanobody. It may be intended to include antibody fragments selected from the group consisting of the following. The fragments are, for example, Intact or complete antibodies or antibody chains, obtained by chemical or enzymatic treatment, or by recombinant It can be obtained by step.

[0039] "Specificity" and "Multispecific antibodies" - For use in combination therapies as described herein Antibodies and antigen-binding fragments bind to specific target antigens such as CD70. It is preferable that the target antigens "specifically bind" to these target antigens, and here the term "specifically bind" "To do so" means binding any antibody or antigen that preferentially triggers an immune response with a predetermined target, such as CD70. This refers to the ability of the fragment. The antibody and antigen-binding fragments of this combination and method may not have monospecificity. This combination may contain one or more binding sites that bind well and specifically to a particular target. The antibodies and antigen-binding fragments of the method are in the "multispecific antibody" format, for example, bispecific It can also be incorporated into heterozygous antibodies, and in this case, this multispecific antibody targets two or more target antigens. They bind. To achieve multispecificity, "multispecific antibodies" typically use different VHs. - Manipulated to include different combinations or pair formation of heavy and light chain polypeptides having VL pairs. Multiple specificity, especially bispecificity antibodies, are different from naive (native) antibodies, for example, in the Fc region. The overall structure of Y-shaped antibodies, etc., having conjugated Fab arms of different specificities, is adopted. They may be manipulated to be used. Alternatively, multispecific antibodies, such as bispecific antibodies, may be used, for example. For example, multiple variable domains or pairs of variable domains with different specificities are arranged at both ends of the Fc region. It may be manipulated to adopt a non-naive structure, such as one in which it is placed.

[0040] "Modified antibody" - As used herein, the term "modified antibody" refers to an antibody that does not occur naturally. It does not include a modified antibody synthesis form, for example, one that includes at least two heavy chain moieties but two Antibodies that do not contain a full heavy chain (such as antibodies with deleted domains or mini-bodies); (two or more different antibodies) Multiple characteristics of antibodies (modified to bind to the original antigen or to different epitopes on a single antigen) Isomers (e.g., bispecificity, tripspecificity, etc.); heavy chain molecules bound to scFv molecules, etc. The scFv molecule is known in this art and is described, for example, in U.S. Patent No. 5,892,019. In addition, the term "modified antibody" refers to a polyvalent form of an antibody (for example, three or more copies of the same antigen). It includes an antibody that binds to - (trivalent, tetravalent, etc.). In another embodiment, the present invention is modified The antibody contains at least one heavy chain moiety lacking a CH2 domain, and has a receptor ligand pair. It is a fusion protein containing a polypeptide binding domain that includes a binding site for one of its members.

[0041] "Humanization substitution" - As used herein, the term "humanization substitution" refers to the VH or VL domain of an antibody. Amino acid residues located at specific positions within the domain correspond to equivalent positions in the reference human VH or VL domain. This refers to amino acid substitutions that occur when an amino acid residue is replaced by an amino acid residue in the same position. (See Human VH or VL) The main component may be a VH or VL domain encoded by a human germline. The substitution is performed in the antibody's framework region and / or CDR as defined herein. It is possible.

[0042] "Humanized variant" - The term "humanized variant" or "H" as used herein. A "humanized antibody" refers to a variant antibody that contains one or more "humanization substitutions" compared to a reference antibody. Here, the portion of this reference antibody (for example, the VH domain and / or the VL domain or at least) Some of them (including one CDR) have amino acids of non-human origin and "humanization substitution". This occurs within amino acid sequences derived from non-human species.

[0043] "Germ cell lineage variant" - a term used herein. Specifically, "ant" or "germ cell lineage antibody" is a type of antibody that undergoes "humanization substitution" within that context. One or more amino acid residues located at specific positions (multiple positions possible) within the VH or VL domain of the antibody are A occurs at the equivalent position in the reference human VH or VL domain encoded by the germline. This refers to a "humanized variant" that is substituted with a mino acid residue. Regarding the "germ cell variant," the replacement amino acid residue is that which has been substituted into the germ cell lineage variant. The base is derived exclusively or primarily from a single human germline-encoded VH or VL domain. It is common to obtain these. The terms "humanized variant" and "germline variant" are used. "T" is often used interchangeably. One or more "humanization substitutions" derived from camels (for example) When introduced into the VH or VL domain (derived from llamas), the result is a camel (llama)-derived VH or VL A "humanized variant" of the domain is created. The amino acid residues that are substituted into it are Derived primarily or exclusively from a single human germline-encoded VH or VL domain sequence. In this case, the result is the "human germline conversion" of the VH or VL domain derived from camels (llamas). It will likely be a "variant."

[0044] "CD70" - as used herein, the term "CD70" or "CD70 protein" or "CD "70 antigen" is used interchangeably and is a ligand for TNFRSF7 / CD27, a TNF ligand family. Refers to a member of the Lie family. CD70 is also known as CD27L or TNFSF7. The term "human CD70 TNFSF7" "Particle," "human CD70 antigen," or "human CD70" are used interchangeably, specifically, human Naive human CD70 protein is naturally expressed in the body and / or on the surface of cultured human cell lines. This refers to the substance, as well as human homologs including recombinant forms and fragments thereof. Specific examples of human CD70 are: The amino acid sequence indicated by NCBI reference sequence deposit number NP_001243, or the extracellular domain thereof It contains polypeptides that do so.

[0045] "BCL-2 Family" - The term "BCL-2 Family" or "BC" as used herein. The "L-2 protein family" includes pro-apoptotic proteins and apoptotic proteins related to BCL-2. This refers to a collection of cis-inhibiting proteins, as described in the literature by Delbridge et al. (2016) Na See Rev Cancer. 16(2): 99-109. This family has at least 16 members. However, there are three functional groups: (i) BCL-2-like proteins (e.g., BCL-2, BCL-X) L / BCL2L1, BCLW BCL2L 2. MCL2, BFL1 / BCL2A1); (ii) BAX and BAK; and (iii) BH3 monoprotein (e.g., BI It is classified into and exists as M, PUMA, BAD, BMF, BID, NOXA, HRK, BIK). Protein BCL-2 Millie is a member of the family of apoptosis inhibitors (e.g., BCL-2, BCL-X). L ) along with this They play an essential role in regulating qualitative apoptotic pathways and are typically apoptosis-promoting members. It antagonizes (for example, BAX and BIM). For example, it antagonizes gene translocation, amplification, overexpression and mutation. Deregulation of BCL-2 family members has been observed in many cancers. The downstream effect is often apoptosis resistance, which promotes cancer growth.

[0046] "BCL-2" - As used herein, "BCL-2" or "BCL-2 protein" refers to human protein. The first member of the BCL-2 protein family identified in B-cell lymphoma It refers to 2. The cDNA encoding human BCL-2 was cloned in 1986, and this protein is Its important role in potosis inhibition was revealed in 1988. BCL-2 is involved in several different processes. It has been confirmed that it is upregulated in certain types of cancer. For example, BCL-2, It is activated by t(14;18) chromosome translocation in follicular lymphoma. Amplification of the BCL-2 gene is also observed. Furthermore, leukemia (CLL, etc.), lymphoma (B-cell lymphoma, etc.), and several solid tumors (e.g., small cell lymphoma) It has been reported in various cancers, including genital lung cancer. Human BCL-2 is associated with the BCL-2 gene (UniProtKB-P10415 The amino acids encoded by ) and shown as NCBI reference sequences NP_000624.2 and NP_000648.2. It has an array.

[0047] "BCL-2 inhibitor" - The BCL-2 inhibitors used herein specifically inhibit the activity of BCL-2. Any drug, compound, or molecule capable of inhibiting BCL-2 apoptosis, particularly the inhibitory activity of BCL-2 This refers to drugs, compounds, or molecules that can inhibit the properties of a substance. The combinations described herein are suitable. Examples of BCL-2 inhibitors used include B-cell lymphoma homology 3 (BH3) mimetic compounds (Merino et al.) The references include (2018) Cancer Cell. 34(6): 879-891). Specific BCL-2 inhibitors are listed below. While not limited to this, Venetoclacus, ABT-737 (Oltersdorf, T et al., (2005) N ature 435: 677-681), Navitoclax / ABT-263 (Tse, C. et al., (2008) Cancer Res. 6 8: 3421-3428), BM-1197 (Bai, L. et al., (2014) PLoS ONE 9: e99404), S44563 (Nemati F. et al.'s literature, (2014) PLoS ONE 9: e80836), BCL2-32 (Adam, A. et al.'s literature, (2014) Blood 1 24: 5304), AZD4320 (Hennessy, EJ et al., (2015) ACS Medicinal Chemistry annual meeting https: / / www.acsmedchem. org / ama / orig / abstracts / mediabstractf2015.pdf abs tr. 24), and S55746 (International Standard Randomized Controlled Trial Registry Number (ISRCTN) http: / / www.isrctn. This includes ISRCTN04804337(2016)). Further examples of BCL-2 inhibitors can be found in the literature by Ashkenazi, A et al. (2017) Nature Reviews Drug Discovery 16: 273-284 is described and cited hereby reveals the true meaning. It is incorporated into the detailed instructions.

[0048] "Venetocrax" - As used herein, the term "Venetocrax" is defined as follows: This refers to compounds that possess a specific structural composition. [ka] This compound is referred to herein as "Compound (I)". Venetoclax is B It is a potent, selective, and orally bioavailable inhibitor of the CL-2 protein. The formula is C 45 H 50 Its molecular weight is C1N7O7S and it is 868.44. Venetoclax is insoluble in water. It is always low. Venetoclax is chemically 4-(4-{[2-(4-chlorophenyl)-4,4dimethyl Cyclohexa-1-en-1-yl]methyl}piperazine-1-yl)-N-({3-nitro-4-[(tetrahydro (-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine) It can be represented as -5-yloxy)benzamide). Venetoclax is also known as ABT-1. 99; Chemical name 1257044-40-8; GDC-0199 is included.

[0049] Venetoclax was approved by the U.S. Food and Drug Administration (FDA) in 2015 as requiring at least one drug administration before treatment. Regarding the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who have received the law Venetoclax was approved in the United States for use in adults aged 75 and older or for enhanced induction. In adults with comorbidities that interfere with the use of chemotherapy, newly diagnosed acute myeloid leukemia Combination of azacitidine, decitabine, or low-dose cytarabine for the treatment of AML (Amyoplastic Syndrome). It has been approved for use in [location / area].

[0050] "Myeloid malignant tumor" - As used herein, the term "myeloid malignant tumor" refers to a hematopoietic stem cell malignant tumor. This refers to any clonal disease of cells or progenitor cells. Myeloid malignant tumor or myeloid malignant disease. This includes chronic and acute symptoms. Chronic symptoms include myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPS). This includes N) and chronic myelomonocytic leukemia (CMML), and acute symptoms include acute myeloid leukemia (AML).

[0051] "Acute myeloid malignant tumor" - as used herein, "acute myeloid leukemia" or " AML refers to hematopoietic neoplasms involving bone marrow cells. AML is a type of bone marrow neoplasm with reduced differentiation potential. Characterized by the clonal proliferation of precursor cells, AML patients accumulate blast cells in the bone marrow. It exhibits accumulation. As used herein, “blast cells” or simply “blasts” are destroyed. This refers to clonal myeloid progenitor cells that exhibit differentiation potential. Blast cells are typically also found in the terminal stages of AML patients. It also accumulates in the peripheral blood. AML is usually diagnosed when a patient has 20% or more of the drug in their bone marrow or peripheral blood. This is an example showing blast cells.

[0052] "Standard intensive chemotherapy" - as used herein, "standard intensive chemotherapy" (honmyo) In the detailed text, this is also called "reinforcement induction therapy" or "induction therapy"), which is the so-called "7+3" induction therapy. This refers to a therapeutic regimen consisting of high-dose cytarabine for 7 days, followed by anthracycline for 3 days (for example) If so, it is characterized by the administration of daunorubicin or idarubicin. Standard intensive chemotherapy The law stipulates that eligible, newly diagnosed AML patients will receive treatment typically after successful chemotherapy. To administer to patients with the intention of inducing complete remission of AML, with the goal of performing stem cell transplantation. This is possible. As described herein, all newly diagnosed AML patients receive standard reinforced chemotherapy. They are not necessarily eligible for the therapy.

[0053] "Leukemia stem cells" - As used herein, "leukemia stem cells" or "LSC" refers to AML LSCs are a subset of blast cells associated with [the condition]. When transplanted into an immune-deficient recipient, LSCs are [described as follows]. LSCs are blast cells with stem cell characteristics that can cause leukemia. Although it can regenerate by causing leukemia, and although it resembles the original disease, it is self LSCs can also partially differentiate into conventional blast cells of the non-LSC type that are not regenerative. The frequency of (primary) AML blast cells ranges from 1 in 10,000 to 1 in 1,000,000. This occurs in (Pollyea and Jordan, (2017), Blood, 129:1627-1635, cited by the original source). (Included in the details). LSC is CD34+, CD38-, and optionally CD45- and / or CD LSCs can also be characterized as cells that are 123+. LSCs are also CD45dim, SSClo, CD90+CD34 They may also be characterized as +cells.

[0054] "Anticancer" - as used herein, an anticancer agent directly or indirectly promotes cancer growth. This refers to any drug that can prevent, inhibit, or treat [the condition]. Such drugs are This includes chemotherapy drugs, immunotherapy drugs, angiogenesis inhibitors, radionuclides, etc., and many examples of these are in our business. It is common knowledge among those in power.

[0055] (Combination therapy with B.CD70 antibody and BCL-2 inhibitor) The present invention comprises (i) an antibody or antigen-binding fragment thereof that binds to CD70, and (ii) a BCL-2 inhibitor. We offer a combination therapy. As described herein, CD70 is characterized as an attractive target for anticancer therapy. CD70 has been constitutively expressed in many types of hematological malignancies and solid tumors, The expression of CD70 is thought to be associated with a poor prognosis in several cancers. The body is being developed, and some of these have progressed to clinical trials.

[0056] Antibodies targeting CD70 are used in the treatment of myeloid malignancies, particularly acute myeloid leukemia (AML). It has become clear that it is particularly effective in treating the target. In AML patients, CD70 antibody, A Results from a Phase I / II clinical trial evaluating RGX-110 indicate that, in this condition, particularly in the case of standard... Newly diagnosed patients who have been classified as ineligible for intensive chemotherapy (see WO2018 / 229303) In this clinical trial, its remarkable effectiveness was revealed. CD70 antibody, when used in combination with azacitidine, targets leukemia stem cells (LSCs) in AML patients. The reduction was efficient. Tests of LSCs isolated from patients in the trial showed that they were effective against myeloid cells. This showed evidence of increased asymmetric division of LSCs showing differentiation. In summary, these results suggest that CD7 The study showed that the 0 antibody depletes the LSC pool in AML patients, thereby improving the prognosis for remission. Furthermore, the risk of recurrence is reduced.

[0057] This invention combines a CD70 antibody or its antigen-binding fragment with a BCL-2 inhibitor. The BCL-2 protein is a member of the BCL-2 family. This family comprises more than 20 proteins. It contains proteins that regulate essential apoptotic pathways. Members of the BCL-2 family regulate essential apoptotic pathways. It is involved in this process and plays a fundamental role in regulating the balance between cell survival and death.

[0058] The BCL-2 protein is an apoptosis inhibitory member of the BCL-2 family, and many different... It is upregulated in certain types of cancer. Overexpression of BCL-2 is associated with tumor cells being By capturing apoptosis-promoting proteins, it becomes possible to avoid apoptosis. BCL-2 is highly expressed in many hematological malignancies, including chronic lymphocytic leukemia (CLL) and filtration. In diseases such as cystic lymphoma and mantle cell lymphoma, the major survival-promoting protein is Yes. By inhibiting BCL-2, this protein inhibits apoptosis or promotes survival. Activity is also inhibited.

[0059] Apoptosis inhibitors of the BCL-2 family, including BCL-2, are found in primary AML samples. Overexpression has been reported (Bogenberger et al., (2014) Leukemia 28(2); 165). 7-65). Overexpression of BCL-2 has also been reported in leukemia stem cells (LSCs) obtained from AML patients. (Lagadinou et al., (2013) Cell Stem Cell 12(3); 329-341). In the in vitro LSC population. Inhibition of BCL-2 led to the selective eradication of quiescent LSCs (Lagadinou et al., (2013) Cell Stem Cell 12(3); 329-341).

[0060] While not limited by theory, the combinations of this invention involve CD70 antibody or antigen binding cleavage. Due to the therapeutic effect of combining one and a BCL-2 inhibitor, particularly the combined effect at the LSC level, It is considered particularly effective for the treatment of AML. The self-regenerative capacity of LSCs is the persistence of these cells. This means that it is the main cause contributing to the recurrence of the disease.

[0061] As shown in the examples, the combination of the present invention demonstrates synergistic therapeutic efficacy against AML cells. In other words, the inhibitory level induced by the combination is greater than the additive effect of monotherapy alone. This is shown. Methods for determining synergistic interactions are well known to those skilled in the art and are described in the examples. It is being said that a preferred method for determining whether a synergistic effect will result from a combination is Chou-Talal This is the ay method (referenced herein by reference from Chou, TC., Cancer Res. (20 10) 70(2); 440-6).

[0062] The synergistic effect of the combination of the present invention is manifested as potent inhibition of primary LSC cells from AML patients. Therefore, the combination therapy of the present invention targets both blast cells and LSC compartments. This improves the likelihood of disease remission while reducing the risk of relapse.

[0063] In some preferred embodiments of the combination of the present invention, the BCL-2 inhibitor is venetoclamo Venetoclax is a small molecule inhibitor of BCL-2. This is described in US2010 / 0305122 (which is incorporated herein by reference). By inhibiting BCL-2, venetoclax inhibits the apoptosis of this protein. Alternatively, it inhibits survival-promoting activity. Venetoclax overexpresses most CLL cells and BCL-2. It rapidly induces apoptosis in lymphoma cell lines.

[0064] Early studies have shown that venetoclax may be useful as a treatment for AML. (Konopleva et al., (2016) Cancer Discov. 6(10); 1106-17). However, Benetoc It was found that Lacus has limited activity as a monotherapy. Subsequent research Therefore, benetoc is used in combination with low-methylating agents, namely azacitidine and decitadine. The effectiveness of Lacus was investigated, and these combinations were found to be particularly effective (Bogenbe Rger et al. (2015) Leuk Lymphoma, 56(1): 226-229). Venetocracus and Azasich To investigate the combination with din, decitabine, or low-dose cytarabine, clinical The study was conducted (Dinardo et al., (2018) Lancet Oncol. 19(2): 216-228; Dinardo et al.) References, (2019) Blood 133(1); 7-17). Based on the results of these studies, adults aged 75 years or older or Newly diagnosed acute myeloid in adults with comorbidities that preclude the use of intensive induction chemotherapy. For the treatment of leukemia (AML), in combination with azacitidine, decitabine, or low-dose cytarabine. FDA approval was granted for the use of venetoclax.

[0065] In some other embodiments of the present invention, a BCL-2 inhibitor is used to identify B-cell lymphoma homology 3 (BH 3) It is a mimic compound. In some embodiments, the BCL-2 inhibitor is ABT-737, Navito Select from Krax, BM-1197, S44563, BCL2-32, AZD4320, or S55746.

[0066] (CD70 antibody) An antibody or antigen-binding fragment that binds to CD70 and is incorporated into any of the combinations described herein. Possible substances include: (but not limited to) those that inhibit the interaction of CD70 with CD27. CD70 antibody or antigen binding fragment; CD70 antibody or antigen binding that competes with CD27 in relation to CD70 binding. Fragment; CD70 antibody or antigen-binding fragment that inhibits CD27 signaling induced by CD70; Treg activity CD70 antibodies or antigen-binding fragments that inhibit the formation and / or proliferation of CD70 cells; which deplete CD70-expressing cells. CD70 antibody or antigen-binding fragment; CD70 antibody or antigen-binding fragment that induces lysis of CD70-expressing cells; Contains a CD70 antibody or antigen-binding fragment that has ADCC and CDC functionality and / or induces ADCP. nothing.

[0067] An exemplary CD70 antibody is described in WO2012 / 123586 (incorporated herein by reference). ARGX-110, SGN-70 (WO2006 / 113909), and the literature by McEarChern et al. (2008) Clin Cancer Res. 14(23):7763 (both of which are incorporated herein by reference), and WO As described in 2006 / 044643 and WO2007 / 038637 (each incorporated herein by reference) Those are the CD70 antibodies that were developed.

[0068] WO2006 / 044643 describes a CD70 antibody containing an antibody effector domain, which is It can mediate one or more of ADCC, ADCP, or CDC, and promotes cell proliferation in cancers expressing CD70. It exerts a growth inhibitory effect or a cytotoxic effect, or inhibits immunological disorders in which CD70 is expressed. It can either exert an epidemic control effect or, if necessary, a cell proliferation inhibitor or a cell It is not necessary to conjugate to an injury agent. The antibodies exemplified herein are 1F6 and 2F2 and It is based on the antigen-binding regions of two monoclonal antibodies.

[0069] WO2007 / 038637 describes a fully human monoclonal antibody that binds to CD70. The antibodies were 1 × 10 -7 K below M D These are characterized by binding to human CD70. The body also binds to renal cell carcinoma tumor cell lines that express CD70, such as 786-O, and thereby It will be internalized.

[0070] ARGX-110 is an IgG1 anti-CD70 antibody, also known as xatuzumab. ARGX-110 is an IgG1 anti-CD70 antibody. It has been shown to inhibit the interaction of that receptor CD27 (Silence et al., (2014)). MAbs. Mar-Apr;6(2):523-32, incorporated herein by reference). In particular ARGX-11 It has been shown that 0 inhibits CD70-induced CD27 signaling. The levels are explained, for example, in the literature by Riether et al. (J. Exp. Med. (2017) 214(2); 359-380). This can be done by measuring serum soluble CD27, or by following the instructions in Silence et al.'s paper (MAbs(2014) 6(2): 523-32). It can be determined by measuring the revealed IL-8 expression. It is not constrained by theory. However, inhibition of CD27 signaling reduces the activation and / or proliferation of Treg cells, and this This is thought to reduce the inhibition of antitumor effector T cells. AGRX-110 also reduces the inhibition of CD70 cells. It was also revealed that it can deplete the tumor cells present. In particular, ARGX-110 is antibody-dependent. Tumor cells expressing CD70 via cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) It has been shown to lyse cells and increase antibody-dependent cell phagocytosis (ADCP) of CD70-expressing cells. (See Silence et al., cited above.)

[0071] The CDR, VH, and VL amino acid sequences of ARGX-110 or xatuzumab are shown in the table below. (Table 1) [Table 1]

[0072] In some embodiments, the antibody or antigen-binding fragment that binds to CD70 is a variable heavy chain. It includes a domain (VH) and a variable light chain domain (VL), where the VH domain and the VL domain are The following CDR sequence: HCDR3 containing or derived from sequence number 3; HCDR2 containing or derived from sequence number 2; HCDR1 containing or derived from sequence number 1; LCDR3 containing or containing sequence number 7; LCDR2 containing or derived from sequence number 6; and LCDR1 containing or containing sequence number 5: Includes.

[0073] In some embodiments, the antibody or antigen-binding fragment that binds to CD70 is optionally on The antibody or antigen-binding fragment having the specified CDR sequence is IgG, preferably IgG1. In this embodiment, the antibody or antigen-binding fragment that binds to CD70 is less than SEQ ID NO: 4. Both include sequences that are 70%, at least 80%, at least 90%, or at least 95% identical. or a variable heavy chain domain (VH domain) derived therefrom, and at least 70% of sequence number 8, Contains sequences that are at least 80%, at least 90%, or at least 95% identical, or It includes a variable light chain domain (VL domain) consisting of the following. In some embodiments, it connects to CD70. The antibody molecule that combines contains or is derived from Sequence ID No. 4 (VH domain). , and includes or comprises a variable light chain domain (VL domain) comprising sequence number 8. VH and Implementations in which the VL domain is identified as having a specific percentage of identity with the reference sequence. In some embodiments, the VH and / or VL domains may retain the CDR sequence of their reference sequence. The CD70 antibodies or antigen-binding fragments identified herein with respect to SEQ ID NOs. 4 and 8 are SEQ ID NOs. The CDR sequence represented by 1-3 and 5-7 may be retained.

[0074] CD70 antibodies or their antigen-binding fragments that may be incorporated into the combinations described herein are antibody drug combinations Includes a combination drug conjugate (ADC). The ADC is, for example, auristatin and mytansin or other cytotoxic agents. These are antibodies bound to active substances such as the above. Some ADCs are antibody blocking and / or It maintains effector functions (e.g., ADCC, CDC, ADCP) while also conjugating The activated substance is delivered to cells expressing the target (e.g., CD70). An example of an anti-CD70 ADC is... , borsetuzumab mahodotin (also known as SGN-75, Seattle Genetics), SGN-70A (Seat This includes Tel Genetics, and MDX-1203 / BMS936561 (Bristol-Myers Squibb), each of which This can be used in accordance with the present invention. Suitable anti-CD70 ADCs are also WO2008074004 and WO20 These are explained in 04073656, and these are also incorporated herein by reference.

[0075] (Venetocracy) In some preferred embodiments of the present invention, the CD70 antibody or antigen described herein The composite fragment is combined with venetoclax or a pharmaceutically acceptable salt thereof. Clax is a small molecule inhibitor of BCL-2, as described herein.

[0076] Venetoclax for use in combination therapy as described herein is BCL-2 It can be provided in any suitable form that effectively inhibits protein. Such forms include The following are some, but are not limited to, any appropriate polymorph, amorphous or crystalline form, or any This includes isomers or tautomers of the same name. Several embodiments are described herein. The combination therapy described in US2010 / 0305122 (incorporated herein by reference) This includes venetoclax synthesized according to Rothes. Another embodiment is described herein. The listed combination therapies are EP3333167, WO2017 / 156398, WO2018 / 029711, CN107089981(A), WO201 8 / 069941, WO2017 / 212431, WO2018 / 009444, CN107648185(A), WO2018 / 167652, WO2018 / 15 Either 7803 or CZ201769 (both incorporated herein by reference) Includes venetoclax synthesized according to the form or process described. Several embodiments In this specification, the combination therapies described herein are incorporated by reference in WO2012 / 071336 (as described herein by reference). (Included) Contains either the crystalline or salt form of venetoclax as described above.

[0077] A salt that is pharmaceutically acceptable for use in accordance with the present invention contains a salt of an acidic group or a basic group. The following are examples of acid addition salts that are acceptable as pharmaceuticals, but are not limited to those listed below, including hydrochloride salts and bromide salts. Hydrogenates, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, iso Nicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate , bitartrate, ascorbate, succinate, maleate, gentisinate (genti sinate), fumarate, gluconate, glucaronate, sugar salt, formate, Benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate 1,1'-methylene-bis-(2-hydrochloride salts, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydrochloride salts) Contains roxy-3-naphthoate). Medicinal salts are formed with various amino acids. This can be achieved. Suitable base salts include, but are not limited to, aluminum Salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, and diethanolamine salts are also included.

[0078] Venetoclax for use in combination therapies as described herein is available in hydrate and anhydrous form. Alternatively, it may be provided in the form of a solvate. Venetoclax is a registered trademark of AbbVie Inc. and Genentech. It is commercially available and sold under the trade name of ). In some embodiments, as described herein The combination includes an antibody or its antigen-binding fragment that binds to CD70 and Veneclexta®. nothing.

[0079] (Additional medications) The combination of the present invention may include one or more additional agents, for example, one or more additional anticancer agents. Cut. In some embodiments, this combination contains one or more "nucleoside metabolism inhibitors" (NMIs). Includes. NMI refers to the post-modification of nucleotides (DNA and / or RNA) (e.g., methylation, demethylation). It is a molecule that inhibits chilling, acetylation, or deacetylation. Nucleoside metabolism inhibitors. Examples include hypomethylating agents (HMAs), isocitrate dehydrogenase (IDH) inhibitors, and histone dehydrogenase inhibitors. Acetylase (HDAC) inhibitors, as well as bromodomain and extraterminal (BET) inhibitors. The agent is included. Preferred nucleoside metabolism inhibitors are hypomethylating agents. Hypomethylating agents It inhibits the normal methylation of DNA and / or RNA. An example of a low methylating agent is azacitidine. These are decitabine and guadecitabine.

[0080] In a preferred embodiment, the combination of the present invention further includes azacitidine (as specified herein). It contains azacitidine (also called AZA or aza). Therefore, in a preferred embodiment, The present invention relates to (i) an antibody or antigen-binding fragment thereof that binds to CD70; (ii) venetoclax or its (iii) Provide a pharmaceutically acceptable salt; and a combination comprising azacitidine.

[0081] In a more preferred embodiment, the combination of the present invention further comprises decitabine. In preferred embodiments, the present invention provides (i) an antibody or antigen-binding fragment thereof that binds to CD70; (ii) Venetoclax or a pharmaceutically acceptable salt thereof; and (iii) a combination containing decitabine To provide.

[0082] Azacitidine is an analog of cytidine, and decitabine is its deoxy derivative. Azacitdine and decitabine induce gene expression through promoter hypomethylation. Inhibition of DNA methyltransferase (DNMT), which is known to upregulate It is a harmful agent. Such hypomethylation disrupts cell function and, as a result, produces cytotoxic effects. To do.

[0083] In some embodiments, the combination of the present invention additionally includes cytarabine. Cytosine arabinose (also known as "ara-C") is commonly used in the treatment of AML. It is a chemotherapy drug used. High-dose cytarabine is typically used in newly diagnosed AML patients. It forms part of the standard "7+3" induction chemotherapy regimen. Low doses of cytarabine are used in standard... It may be used in AML patients who are not eligible for induction chemotherapy. For example, low doses Tarabine in combination with venetoclax was newly used to treat patients who were ineligible for standard induction chemotherapy. It is prescribed to AML patients who have been diagnosed. The combination of this invention further includes low-dose cytarabine. It is possible.

[0084] In some embodiments, the combination of the present invention includes additional anticancer agents. Select a suitable cancer drug from among those suitable for the treatment of myeloid malignancies, preferably AML. It is possible. Preferred drugs are: selectin inhibitors (e.g., GMI-1271); FMS-like tyrosine FLT3 kinase receptor 3 (FLT3) inhibitors (e.g., midostaurin or gilteritinib); cycle Phosphate-dependent kinase inhibitors; aminopeptidase inhibitors; JAK / STAT inhibitors; cytarabine; Fludarabine; anthracycline compounds (e.g., daunorubicin, idarubicin); Xorubicin; Hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors, Idohif Idhifa (or enasidenib) or Tibsovo (or ivosidenib), etc.; S Mothened inhibitors, such as Grass-Degib; BET bromodomain inhibitors; CD123 or CD33 targeting agents; HDAC inhibitors; LSC targeting agents; AML bone marrow niche targeting agents; NEDD8 activating enzyme inhibitors, pevonidonexase Stats, etc.; G-CSF, as well as topoisomerase inhibitors, mitoxantrone, selinexo You may choose from drugs such as ru and etoposide.

[0085] (Combination formulations) The combination of drugs described herein is intended for the target or patient who needs it, preferably the target. In any form that enables combination therapy to be administered to the person or patient who needs it, combination or This can be formulated into a pharmaceutical product. This combination can be formulated for single-dose or multi-dose administration. It can be transformed. In some embodiments, the combination of drugs is co-formulated, i.e., a single pharmaceutical composition. It may be formulated as such. In embodiments in which the drug is co-formulated, the combination or composition This is suitable for simultaneous administration of drugs.

[0086] In a preferred embodiment, the combination of agents described herein is a combination of individual compositions or pharmaceuticals. It is formulated as a composition. In embodiments in which the drugs are formulated separately, different drugs or The compositions may be administered simultaneously or individually. Different compositions may be administered individually. In such cases, the drugs may be administered sequentially in any order. The interval between drug administrations is at the discretion of the doctor. Any suitable time interval is acceptable. The different compositions may be administered at once (for single-dose administration), This may be performed repeatedly (for multiple dose administration).

[0087] The CD70 antibody or antigen-binding fragment combinations described herein may be used with any suitable pharmaceutical carrier, AGI The antibody may be formulated using uvant and / or excipients. The formulation technology is well known in this field, for example, the literature by Wang et al., (2007) Journal of Phar This has been verified in Maceutical Sciences, 96:1-26, and the entire content of that paper is cited. It is incorporated herein by reference. It can be used in the formulation of this antibody composition. Excipients that are acceptable as pharmaceuticals are not limited to those listed below, but include ion exchangers, aluminum Mina, aluminum stearate, lecithin, serum protein, e.g., human serum albumin Buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated ions A mixture of partial glycerides of physical fatty acids, water, salt or electrolyte, such as protamine sulfate or phosphoric acid. Disodium hydrogen, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, Magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., cellulose) Sodium methylcellulose, polyethylene glycol, polyacrylate, Polyethylene-polyoxypropylene-block polymer, polyethylene glyco Contains tallow and wool fat.

[0088] BCL-2 inhibitors (preferably venetoclax or a pharmaceutically acceptable salt thereof) are, The drug may be formulated using an appropriate pharmaceutical carrier, adjuvant, and / or excipient. Examples of such drugs include encapsulating materials, absorption enhancers, antioxidants, binders, buffers, etc. Coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, moisturizers Agents, lubricants, fragrances, preservatives, propellants, release agents, sterilizers, sweeteners, solubilizers, wetting agents and so These contain additives such as mixtures of these substances.

[0089] In some embodiments, the composition is administered to a subject via any suitable route of administration formulated for administration, including, but not limited to, intramuscular, intravenous , intradermal, intraperitoneal injection, subcutaneous, epidural, nasal, oral, rectal, topical, inhalation, buccal (e.g. sublingual), and transdermal administration. In some embodiments, the composition is an aqueous solution , formulated as tablets, capsules, powders or any other suitable dosage form.

[0090] Excipients for the preparation of a composition comprising a BCL-2 inhibitor (preferably venetoclax) administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alco hol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulo se, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidon e, diglycerides, ethanol, ethyl cellulose, ethyl laureate , ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, pea nut (groundnut) oil, hydroxypropyl methyl cellulose, isopropanol, isotonic saline water, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, mono glycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidon , propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellu lose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soy bean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacan th, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof A composition comprising a BCL-2 inhibitor (preferably venetoclax) administered orally in liquid dosage form. Excipients for the preparation include, for example, 1,3-butylene glycol, castor oil, corn oil, and cotton. Fruit oil, ethanol, sorbitan fatty acid ester, germ oil, soybean oil, glycerol, isopodium Lopanol, olive oil, polyethylene glycol, propylene glycol, sesame oil, water , and mixtures thereof. BCL-2 inhibitors administered osmotically (preferably venetin) Excipients for the preparation of compositions containing clax include, for example, chlorofluorocarbons. It contains ethanol, water, and mixtures thereof. Parenterally administered BCL-2 inhibitors (preferably) Excipients for the preparation of compositions containing venetoclax include, for example, 1,3-butanediol Ingredients: Castor oil, corn oil, cottonseed oil, glucose, wheat germ oil, soybean oil, liposomes, oleic acid Olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, United States Pharmacopeia (USP) or This includes isotonic sodium chloride solution, water, and mixtures thereof.

[0091] In embodiments in which the combined drugs are formulated separately, i.e., as individual compositions, The individual compositions can be formulated for administration via the same route. This combination of drugs In embodiments in which the agents are formulated separately, i.e., as individual compositions, the individual compositions The substance can also be formulated for administration via different routes. For example, CD70 antibody or antigen. The conjugated fragment may be formulated for intravenous administration, and may contain a BCL-2 inhibitor (preferably venetoclax). ) may be formulated for oral administration.

[0092] As described above, the combination therapy of the present invention may include Benecrexta®. Necrexta® is marketed and sold by AbbVie Inc. and Genentech. This is a venetoclax product. Venetoclax® oral tablets contain the following active ingredient: It is offered as a pale yellow or beige tablet containing 10, 50, or 100 mg of venetoclax. Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate. It contains Rubate 80, stearyl sodium fumarate, and dibasic calcium phosphate. Furthermore, the 10 mg or 100 mg coated tablets contain the following: yellow iron oxide, polyvinyl alcohol Contains 50 mg of coating, polyethylene glycol, talc, and titanium dioxide. The following are also included in the ing tablets: yellow iron oxide, red iron oxide, black iron oxide, polyvinyl alcohol. Contains talc, polyethylene glycol, and titanium dioxide. CD70 antibody or antigen binding cleavage. As an embodiment combining the fragment and Veneclexta®, a CD70 antibody or antigen-binding fragment is used. While it may be formulated for intravenous administration, Venclexta (registered trademark) may be in the above tablet form. It can also be offered as one or more items.

[0093] In addition to a CD70 antibody or antigen-binding fragment and a BCL-2 inhibitor (preferably venetoclax), a drug The present invention includes or comprises one or more additional agents. Compared to pharmaceuticals, it may be formulated for administration via the same or different routes. For example, This combination is (i) an antibody or its antigen-binding fragment that binds to CD70; (ii) venetoclax or its (iii) Pharmaceutically acceptable substances; and in preferred embodiments comprising azacitidine, This antibody or antigen-binding fragment may be administered intravenously, as venetoclax or its pharmaceutical product. The acceptable salt may be administered orally, while azacitidine may be administered by subcutaneous injection. The combination comprises (i) an antibody that binds to CD70 or an antigen-binding fragment thereof; (ii) venetoclax or its pharmaceutically acceptable form; and (iii) decitabine. In this preferred embodiment, the antibody or antigen-binding fragment may be administered intravenously, and venetoclax or the pharmaceutically acceptable salt thereof may be administered orally, while decitabine may be administered by subcutaneous injection.

[0094] (C. Method of Treatment) The combination therapy described according to the first aspect of the present invention is useful for malignant tumors in human subjects, particularly myeloid it can be used in a method for treating malignant tumors.

[0095] The present invention provides an antibody that binds to CD 70, or an antigen-binding fragment thereof, for use in the treatment of malignant tumors, particularly myeloid malignant tumors, in a human subject, wherein the antibody or antigen-binding fragment thereof is administered in combination with a BCL-2 inhibitor. The present invention also relates to malignant tumors in human subjects, particularly myeloid malignant tumors, which is a BCL-2 inhibitor for use in the treatment of tumors, wherein the BCL-2 inhibitor is administered in combination with an antibody that binds to CD70 or an antigen binding fragment thereof. There is provided a BCL-2 inhibitor administered in combination with the original binding fragment.

[0096] In a preferred embodiment, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. The present invention further provides a combination for use in the treatment of malignant tumors, particularly myeloid malignant tumors, in a human subject according to the first aspect of the present invention. The combination according to the first aspect of the present invention is provided.

[0097] In a further aspect, the present invention provides a method for treating a malignant tumor, particularly a myeloid malignant tumor, in a human subject The present invention provides a method comprising administering a combination according to the first aspect of the present invention to a subject. The present invention also relates to a method for treating malignant tumors in humans, particularly myeloid malignancies, and (i) (ii) administering an antibody that binds to CD70 or an antigen-binding fragment thereof to an elephant; and (ii) administering BCL to the subject. -2 Inhibitors, preferably venetoclax or a pharmaceutically acceptable salt thereof, are administered. A method is provided that includes the steps (i) and (ii) of this method can be performed in any order. That's good too.

[0098] All embodiments described above with respect to a combination of the first aspects of the present invention are similar to those described above. This can be applied to the methods described in the detailed document. The term "malignant tumor" refers to a disease in which abnormal cells proliferate uncontrollably and invade surrounding tissues. It includes malignant cells that enter the body's blood and lymphatic systems migrate to distal parts of the body. It can be transferred to a second site. In some embodiments, the method described herein The treatment of malignant tumors, including the production of cancer progenitor cells or stem cells expressing CD70, CD27, or both. Regarding treatment. As described herein, upregulated CD70 expression is used in renal cells. Different types of cancer odor, including cancer, metastatic breast cancer, brain tumors, leukemia, lymphoma, and nasopharyngeal cancer. It is detected as follows. Co-expression of CD70 and CD27 is also associated with acute lymphoblastic lymphoma and T-cell lymphoma. It is detected in malignant tumors of the hematopoietic system, including tumors. In some embodiments, as specified herein The described method is for any of the aforementioned malignancies that are associated with CD70 expression, CD27 expression, or both. Regarding the treatment of...

[0099] In certain embodiments, the method described herein is for treating myeloid malignancies. Therefore, here, myeloid malignancies refer to any clonal disease of hematopoietic stem cells or progenitor cells. Myeloid malignancies treated according to the method of the present invention are newly diagnosed as myeloid malignancies. It may also be a recurrent / refractory myeloid malignancy.

[0100] In some embodiments, myeloid malignancies include acute myeloid leukemia (AML); myelodysplastic syndromes. Myeloproliferative Neoplasms (MDS); Myeloproliferative Neoplasms (MPN); Chronic Myeloid Leukemia (CML); and Chronic Myelomonocytic Leukemia A selection is made from hematological malignancies (CMML). In a preferred embodiment, myeloid malignancies are acute myeloid leukemia. It is a disease (AML).

[0101] Myeloid malignancies are classified according to the WHO 2008 classification and the 2016 revision of this classification. It can be classified and diagnosed, in particular by reference to Arber et al., which are incorporated herein by reference. See reference (2016) Blood, 127(20):2391-2405.

[0102] Acute myeloid leukemia (AML) refers to hematopoietic neoplasms related to bone marrow cells. AML is a condition in which the amount of bone marrow cells decreases. It is characterized by the clonal proliferation of blast cells in the bone marrow. AML patients have blast cells in their bone marrow. This shows cell accumulation. Blast cells also accumulate in the peripheral blood of AML patients. Typical AML is characterized by... The diagnosis is made when a person shows 20% or more blast cells in their bone marrow or peripheral blood.

[0103] According to the WHO classification, AML generally has the following subtypes: AML with recurrent genetic abnormalities; bone malformation. AML with myelodysplastic changes; treatment-related myeloid neoplasms; myelosarcoma; Down syndrome-related myeloproliferation Macroplasia; blastocyte plasmacytoid dendritic cell neoplasm; and unclassifiable AML (e.g., acute megakaryoblastic leukemia) This includes diseases such as acute basophilic leukemia.

[0104] AML can also be classified according to the French-American-British (FAB) classification, which is Subtypes: M0 (Acute myeloblastic leukemia, minimally differentiated); M1 (Acute myeloblastic leukemia, naive) Mature type); M2 (Acute myeloblastic leukemia, granulocyte mature type); M3 (Promyelocytic leukemia, or acute) Promyelocytic leukemia (APL); M4 (acute myelomonocytic leukemia); M4eo (myelomonocytic, myeloeosinophilic leukemia). (acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)); M6 (acute red and white leukemia) Hematological diseases, including erythroleukemia (M6a) and rare pure erythroleukemia (M6b); or M7 (acute megakaryoblastic leukemia) Includes.

[0105] As used herein, "AML" refers to the WHO classification and / or FAB classification unless otherwise specified. It refers to any of the symptoms encompassed by [the term]. Some AML subtypes have a relatively good prognosis. Some are considered to have an intermediate prognosis, and some have a poor prognosis. Those skilled in the art can determine which of the following... I know whether the type falls into the risk category.

[0106] Myelodysplastic syndrome (MDS) is a condition characterized by dysplasia, cytopenia, and / or bone marrow cell density and / or characterized by abnormal changes in myeloid cell differentiation, such as increased blast cell infiltration. According to the WHO classification, MDS generally falls under the following subtypes: MD with monocytic lineage dysplasia. S (formerly called "refractory cytopenia with dysplasia of a single blood cell lineage," also known as refractory anemia or refractory anemia) Including sexual neutropenia and refractory thrombocytopenia; MDS with ring sideroblasts, monocytic lineage This includes subtypes with dysplasia of the ring and subtypes with dysplasia of the polycythic lineage (formerly known as "ring"). This was called "refractory anemia with sideroblasts"); MDS with polycythemia (formerly called "polycythemia"). This was referred to as "refractory cytopenia with cytoplasmic dysplasia"; MDS with blast cell proliferation (MDS-EB, etc.) Previously called "refractory anemia with increased blast cells," this is based on the blast cell percentage. It can be further subdivided into MDS-EB-1 and MDS-EB-2; MDS with a single missing chromosome (5q); and classification This includes non-functional MDS.

[0107] MDS can also be classified according to the French-American-British (FAB) classification, which is Subtypes: M9980 / 3 (Refractory Anemia (RA)); M9982 / 3 (Refractory Anemia with Ring Sideroblasts (RARS)); M9983 / 3 (Refractory anemia with blast cell proliferation (RAEB)); M9984 / 3 (Refractory anemia with blast cell proliferation during the transitional phase) This includes blood (RAEB-T); and M9945 / 3 (chronic myelomonocytic leukemia (CMML)).

[0108] As used herein, "MDS" refers to the WHO classification and / or FAB classification unless otherwise specified. This refers to any of the symptoms encompassed by AML and MDS. In this specification, WHO Categorization in classification is preferable.

[0109] Myeloproliferative neoplasms (MPNs) are similar to MDS, but according to the WHO classification, MPNs are generally classified as follows: The following subtypes: Chronic myeloid leukemia (CML); Chronic neutrophilic leukemia (CNL); Polycythemia vera (PV); Primary myelofibrosis (PMF); Essential thrombocythemia (ET); Chronic eosinophilic leukemia, unspecified type ; and also include unclassifiable MPNs.

[0110] Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are classified as M according to the WHO classification. These fall under the category of DS / MPN disorders, because they overlap clinically between MDS and MPN. This is because it presents with bone marrow tumors that possess specific characteristics, clinical examination characteristics, and morphological characteristics.

[0111] (Patient characterization) Patients or subjects treated according to the methods described herein, in particular AML patients or subjects, are newly They may also have a diagnosed illness, a relapsed illness, or a primary intractable disease.

[0112] The standard approach to treating newly diagnosed AML patients is high-dose citarabi. 7 days of anthracycline (e.g., daunorubicin or idarubicin) followed by 3 days This is a "standard 7+3 intensive chemotherapy" approach characterized by intermittent administration. This is administered with the aim of inducing complete remission of AML, typically after successful chemotherapy in patients. This involves the intention to undergo stem cell transplantation.

[0113] Standard intensive chemotherapy is associated with significant toxicity and side effects, and it is difficult to tolerate these effects. This means it is inappropriate for patients who cannot tolerate it. These patients are "standard intensive chemotherapy This is referred to as "not eligible under the law." Patients may be ineligible for standard intensive chemotherapy, for example. For example, if the patient has one or more comorbidities that make them unable to tolerate the toxicity, or if those conditions are particularly severe The characteristic prognostic factors may indicate unfavorable outcomes with standard intensive chemotherapy. The determination of individual patient eligibility for targeted intensive chemotherapy depends on the individual patient's medical history and clinical guidelines. (For example, the National Comprehensive Cancer Information Network (NCCN) guidelines, which are cited herein by reference.) This will be done by a clinician, taking into consideration the (integrated) components. AML patients over 60 years of age. The patient should consider other factors, including cytogenetic and / or molecular abnormalities of the AML being treated. When accompanied by underlying causes, patients are often deemed ineligible for standard intensive chemotherapy.

[0114] Patients who are unsuitable for standard intensive chemotherapy may instead receive low-dose cytarabine (LDAC) or other low-intensity chemotherapy. You may receive chemotherapy. You are ineligible for standard intensive chemotherapy and also ineligible for LDAC. The patient should receive best supportive care (BSC), including hydroxyurea (HU) and blood transfusion support. can.

[0115] Patients or subjects treated according to the methods described herein are those who are "not receiving standard intensive chemotherapy." It may be classified as "eligible." The combination of the present invention has fewer side effects. This includes targeted therapies that may be expected to be performed. Thus, any of the principles identified above Patients deemed ineligible for standard intensive chemotherapy for the reasons described herein can be treated with the combination of the present invention. It is possible.

[0116] As mentioned above, venetoclax is not suitable for individuals aged 75 or older or those with comorbidities that preclude the use of intensive induction chemotherapy. For the treatment of newly diagnosed AML in adults with the disease, azacitidine, decitabine or low dose It is approved in the United States to be used in combination with cytarabine. Therefore, several practices In some embodiments, the BCL inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In this embodiment, the patient or subject treated according to the method described herein is 75 years of age or older. These are newly diagnosed AML patients. Further embodiments of the method described herein Patients or subjects treated according to this method have comorbidities that interfere with the use of intensive induction therapy. The patient is newly diagnosed with AML and has comorbidities that prevent the use of intensive induction chemotherapy. Patients must meet at least one of the following criteria: Baseline US East Coast Cancer Group (ECOG) Performance status of 2-3, severe heart or lung disease, moderate liver impairment. They can be classified based on CLcr < 45 ml / min. Such embodiments are in accordance with the present invention. When the combination BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof Particularly preferable.

[0117] Patients or subjects treated according to the methods described herein should not be subjected to other treatments, such as standard treatments. While they may be eligible for intensive chemotherapy, the combination described herein is an alternative treatment option. Combination therapy may be used. For example, patients or others being treated according to the method described herein. The elephant may be a newly diagnosed AML patient who is also eligible for standard intensive chemotherapy.

[0118] (Additional treatment) The methods described herein include the administration of one or more additional therapeutic agents, such as additional anticancer agents. This can be done. In some embodiments, this method can be used in the treatment of myeloid malignancies. This includes the administration of one or more drugs for use, for example, drugs suitable for use in the treatment of AML. Drugs such as the following are examples, but are not limited to: selectin inhibitors (e.g., GMI-1271) ); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g., midostaurin or gilte) Litinib; cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK / STAT inhibitors Harmful agents; cytarabine; fludarabine; anthracycline compounds (e.g., daunorubicin) Idalubicin; Doxorubicin; Hydroxyurea; Vyxeos; IDH1 or IDH 2. Inhibitors, Idhifa (or enasidenib) or Tibsovo (or Ivosidenib, etc.; Smoothened inhibitors, Grasdecib, etc.; BET bromodomain inhibitors, CD123 Alternatively, CD33 targeting agents; HDAC inhibitors; LSC targeting agents, AML bone marrow niche targeting agents; NEDD8 activating enzymes. Inhibitors, such as pevonesistat; G-CSF, as well as topoisomerase inhibitors, mitoxant Includes ron, selinexol, and etoposide, etc.

[0119] In preferred embodiments, the methods described herein are nucleoside metabolism inhibitors, preferably This includes the administration of further drugs, such as hypomethylating agents. Particularly preferred hypomethylating agents are those that cause birthmarks. These are cytidine and decitabine. As described above, in this specification, several embodiments are described. (i) CD70 antibody or its antigen-binding fragment; and (ii) BCL-2 inhibitor, preferably venetoclacin. The present invention, which includes salts that are pharmaceutically acceptable, may include additional agents, such as bruises. The formulation may include cytidine or decitabine.

[0120] Alternatively, this combination may consist of (i) an antibody or antigen-binding fragment that binds to CD70; and (ii) a BCL-2 inhibitor. Preferably, embodiments comprising venetoclax or a pharmaceutically acceptable salt thereof. The method of administering that combination to the target involves an additional drug, such as azacitidine or The procedure may also include a further step of administering decitabine. Therefore, in a preferred embodiment, The present invention relates to a method for treating myeloid malignancies, preferably AML, in humans, and To the elephant: (i) an antibody or antigen-binding fragment thereof that binds to CD70; (ii) a BCL-2 inhibitor, preferably a bell Netoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine or de The present invention provides a method comprising administering cytabine. Similarly, the present invention provides: A combination for use in the treatment of myeloid malignancies in humans, preferably AML: (i (ii) an antibody or antigen-binding fragment thereof that binds to CD70; (ii) a BCL-2 inhibitor, preferably venetoclamoblastic (iii) kus or a pharmaceutically acceptable salt thereof; and (iii) azacitidine or decitabine It is a combination that includes ,.

[0121] (Dosage) As shown in the examples, the combination of the present invention exhibits a synergistic therapeutic effect on AML cells—that is The level of inhibition induced by this combination is greater than the additive effect of monotherapy alone.

[0122] The method for determining synergistic interactions is known to those skilled in the art and is described in the examples. Synergistic effect in combination A preferred method for determining whether or not a result has occurred is the Chou-Talalay method (Chou, TC., Cancer R). es.2010 Jan 15;70(2):440-6, incorporated herein by reference.

[0123] In the Chou-Talalay method, CI < 1 indicates a synergistic effect, CI = 1 indicates an additive effect, and CI > 1 indicates an additive effect. It exhibits antagonistic effects. As shown in Figure 1, the existence of synergistic effects arising from the combination of the present invention and The range changes according to the strength of the inhibitory effect of the combination. The strength of the inhibitory effect of the combination itself is It depends on the total concentration of the combination.

[0124] Therefore, preferably, in embodiments of the present invention, CD70 antibody or its antigen The combined fragment is administered and / or provided in this combination, and the BCL-2 inhibitor is in this combination The doses administered and / or provided, in combination, provide a synergistic treatment. - That is, the combination is selected such that it shows a CI of less than 1, as determined by the Chou-Talalay method. The preferred dosage is one in which the combination shows a confidence interval of less than 0.5.

[0125] Preferably, in some embodiments, the CD70 antibody or its antigen-binding fragment is combined with this combination The dose administered and / or provided, and the BCL-2 inhibitor administered and / or provided in this combination The doses provided are those where the combination is determined by the Chou-Talalay method, where CI is less than 1 and Fa is > 0 Each is selected to represent 0.5.

[0126] As shown in this embodiment, synergistic effects are also observed with anti-CD70 antibody (ARGX-110) and BCL-2 inhibitor (Bene). This was observed with a combination of tocrax and HMA (decitabine). Therefore, from the standpoint of the present invention, In several preferred embodiments, when this combination includes HMA, CD70 antibody or its antigenic compound The combined fragment is administered and / or provided in this combination, and the BCL-2 inhibitor is administered in this combination. and / or the doses provided, and the HMA administered and / or provided in this combination. The dosages are selected so that the combination provides a synergistic effect in the treatment.

[0127] CD70 antibodies, particularly ARGX-110, are effective even at relatively low doses in the treatment of myeloid malignancies, especially AML. It was found that... Therefore, in some embodiments of the whole method of the present invention, CD70 anti The body or its antigen-binding fragments are administered in a range of 0.1 mg / kg to 25 mg / kg per dose, for example, 0.1 mg / kg It is administered in doses ranging from ~20 mg / kg. In some embodiments, CD70 antibody or its The antigen-binding fragment is administered in doses ranging from 1 mg / kg to 20 mg / kg per dose. The stated range includes the endpoint unless otherwise specified. For example, a dosage in the range of 0.1 to 25 mg / kg. The administration includes administration at a dose of 0.1 mg / kg and administration at a dose of 25 mg / kg, and at two endpoints. This includes administration at all intermediate doses.

[0128] In some embodiments of the method of the present invention, the CD70 antibody or its antigen-binding fragment is 0.1 It is administered in doses ranging from mg / kg to 15 mg / kg. In some embodiments, CD70 antibody or The antigen-binding fragment is administered in doses ranging from 0.5 mg / kg to 2 mg / kg. Several implementations In this embodiment, the CD70 antibody or its antigen-binding fragment is administered in doses of 1 mg / kg, 3 mg / kg, 10 mg / kg, or It is administered at a dose of 20 mg / kg. In some preferred embodiments, CD70 antibody or The antigen-binding fragment is administered at a dose of 1 mg / kg. In some preferred embodiments... The CD70 antibody or its antigen-binding fragment is administered at a dose of 10 mg / kg.

[0129] In some embodiments, multiple doses of CD70 antibody or antigen-binding fragments are administered. In some such embodiments, each of the CD70 antibody or its antigen-binding fragment Dosage administration should be spaced 10 to 20 days apart, or optionally 12 to 18 days apart. In some embodiments, Each dose administration of the anti-CD70 antibody is spaced at an interval of 14 to 17 days.

[0130] The BCL-2 inhibitor of the combination, preferably venetoclax or a pharmaceutically acceptable salt thereof can be administered according to any regimen determined to be effective for the compound. AM According to the information specified by the FDA for the use of Venclexta® in the treatment of AML, a dose escalation phase proposes a dosing schedule with a subsequent maintenance phase. When Venclexta® is prescribed in combination with azacitidine or decitabine, the dosing schedule is: on day 1, 100 mg of Venclexta® is administered; on day 2, 200 mg of Venclexta® is administered; on day 3, 400 mg of Venclexta® is administered; and thereafter, 400 mg of Venclexta® daily is combined with 75 mg / m 2 of azacitidine or 20 mg / m 2 of decitabine , and it is recommended that the administration consists of continuing administration until disease progression or unacceptable toxicity is observed . When Venclexta® is prescribed in combination with low-dose cytarabine, the dosing sche dule is: on day 1, 100 mg of Venclexta® is administered; on day 2, 200 mg of Venclex ta® is administered; on day 3, 400 mg of Venclexta® is administered; and thereafter, 600 mg of Venclexta® daily is combined with 20 mg / m 2 , and administration is continued until disease progression or unacceptab le toxicity is observed, and this dosing regimen is recommended.

[0131] In some embodiments, the individual dose of venetoclax or a pharmaceutically acceptable salt thereof The dosage, for example, the oral dosage, is in the range of 100 mg to 600 mg. In a particular manner, venetoclax or a pharmaceutically acceptable salt thereof may be administered at a dose of 400 mg per day. It is administered in doses. In some embodiments, it is permitted as venetoclax or its pharmaceutically acceptable form. The salt that can be administered is given at a dose of 600 mg per day. As described above, venetoclax A fixed daily dose can be administered with, for example, a 3-day dose escalation period beforehand. During this period, the patient's venetoclax dose will be increased until the daily maintenance dose is reached. Administer to [the appropriate location].

[0132] This combination includes a nucleoside metabolism inhibitor, or this method involves the administration of a nucleoside metabolism inhibitor. In embodiments of the present invention, which include administering 20 to 1 nucleoside metabolism inhibitor per day, the nucleoside metabolism inhibitor is administered. 00 mg / m 2 It may be administered in doses within the range described herein. As already stated, within the range described herein Unless otherwise specified, the range includes the endpoint. For example, 20-100 mg / m² per day. 2 Dosage within the range The dosage is 20 mg / m² per day. 2 Dosage-based administration and 100 mg / m² per day 2 Including administration in doses, This includes administration at all doses between the two endpoints.

[0133] In some embodiments, the nucleoside metabolism inhibitor is azacitidine, and 1 day 70-80 mg / m² 2 It is administered in doses within the range of . In some preferred embodiments, nu The cleoside metabolism inhibitor is azacitidine, administered at a dose of 75 mg / m² per day. 2 It is administered in the following dosage.

[0134] In some embodiments, the nucleoside metabolism inhibitor is decitabine, and per day 15-25 mg / m² 2 It is administered in doses within the range of . In some preferred embodiments, nuk The reoside metabolism inhibitor is decitabine, administered at a dose of 20 mg / m² per day. 2 It is administered in the following dosage.

[0135] The combination of the present invention includes a nucleoside metabolism inhibitor, or the method of this invention inhibits nucleoside metabolism. In embodiments of the present invention, which include administering the agent, the nucleoside metabolism inhibitor is administered for 5 to 10 days. It may be administered at a daily dose during the treatment period. That is, one nucleoside inhibitor The dosage is administered daily for a certain period or for a length of 5, 6, 7, 8, 9, or 10 days. In several preferred embodiments, the nucleoside metabolism inhibitor is administered in a daily dose for 7 days. It is administered throughout the course of treatment. The preferred nucleoside metabolism inhibitor is azacitidine. .

[0136] In some embodiments, nucleoside metabolism inhibitors are administered at the end of a single drug administration period. And at the start of the next medication period, follow a medication regimen of repeated dosing periods with an interval of 18 to 25 days. It is administered as follows: That is, the drug regimen is administered as a single dose of nucleoside inhibitor daily. For example, including at least two medication periods (5, 6, 7, 8, 9, or 10 days), at the end of one medication period. At the end of one course of medication and at the start of the next, an interval of 18, 19, 20, 21, 22, 23, 24, or 25 days is observed. In some embodiments, at the end of one medication period and at the start of the next medication period. A 21-day interval is observed.

[0137] In some embodiments, each medication period is of the same length (e.g., 7 days). In some embodiments, at the end of each medication period and at the start of the next medication period An interval of the same number of days (for example, 21 days) is placed between them.

[0138] In some embodiments, the initial dose of a nucleoside metabolism inhibitor is a CD70 antibody Alternatively, it is administered 7 to 21 days after the initial dose of the antigen-binding fragment. Several embodiments In this study, the initial dose of a nucleoside metabolism inhibitor is CD70 antibody or its antigen-binding fragment. It is administered 10 to 17 days after the first dose. The initial dose of the metabolic inhibitor is 14 times the initial dose of the CD70 antibody or its antigen-binding fragment. It will be administered a few days later.

[0139] In some embodiments, one of the daily doses of a nucleoside metabolism inhibitor is CD70 The antibody or its antigen-binding fragment is administered on the same day as the target. That is, the target receives the CD70 antibody (or An embodiment of the present invention, which involves administering both the antigen-binding fragment and a nucleoside metabolism inhibitor. In this case, the drug regimen of both CD70 antibody and nucleoside metabolism inhibitor was used, and the CD70 antibody At least one of the prescribed dose administrations is the scheduled daily dose administration of a nucleoside metabolism inhibitor. It is the same day as one of the given days. That day is the first day of the nucleoside metabolism inhibitor administration period. It may be the 2nd, 3rd, 4th, 5th, 6th, or 7th day.

[0140] In some embodiments, the dose of CD70 antibody or its antigen-binding fragment is 14 to 14 minutes daily. The medication is administered for 17 days, and the nucleoside metabolism inhibitor is administered in a repeated dosing period of 7 days at a daily dose. It is administered according to the regimen, where at the end of one treatment period and at the start of the next treatment period, it is administered twice. With a one-day interval, the first daily dose of the initial treatment period is anti-CD70 antibody or its antigenicity. It is administered 14 days after the initial dose of the composite fragment.

[0141] In some embodiments, one patient treatment cycle consists of 28 days, and the nucleoside treatment cycle is 28 days long. An antiretrogestant, preferably azacitidine or decitabine, is administered starting on day 1 of the cycle. It is administered daily for 6, 7, 8, 9, or 10 days. The therapeutic method described herein is a multiple therapeutic method. It may include cycles. Each treatment cycle may be a copy of the previous treatment cycle. Good. In some embodiments, a CD70 antibody, a BCL inhibitor (preferably venetoclax or Patients treated with azacitidine (a medicinally acceptable salt) and azacitidine will receive a 28-day course of treatment. The treatment involves ikul, with azacitidine administered daily for the first seven days of the 28-day cycle. In some embodiments, a CD70 antibody, a BCL inhibitor (preferably venetoclax or so) are used. Patients treated with a medicinal salt (and decitabine) in a 28-day cycle The patient is treated with decitabine administered daily for the first five days of the 28-day cycle. In an 8-day cycle, a CD70 antibody, a BCL inhibitor (preferably venetoclax or a similar drug) (a salt that can be tolerated) and a nucleoside metabolism inhibitor (preferably azacitidine or decita) In some cases, the CD70 antibody is treated with a vial, on the third day and / or of its 28-day cycle. It may be administered on the 17th day. In a preferred embodiment, the CD70 antibody is ARGX-110. In a preferred embodiment, the CD70 antibody (e.g., ARGX-110) is administered at a dose of 10 mg / kg. It can be done.

[0142] A further advantage of the present invention is the use of NMI (e.g., azacitidine) following the initial period of combination therapy. The ability to gradually reduce or discontinue administration. Accumulated toxicity resulting from long-term NMI treatment, e.g. For example, there is a possibility of cytopenia resulting from the effects of NMI on non-blast cell types. Therefore, the risk of such toxicity is reduced or discontinued by gradually reducing the dose of NMI after the initial period. This will reduce the number of non-blast cell types, and the non-blast cell type will be able to recover. In some embodiments of the present invention, The prescribed treatment involves administering CD70 antibodies, BCL-2 inhibitors (e.g., venetoclax), and NMI to the patient as described above. As a combination therapy according to any of the embodiments described, in the first stage (induction therapy) In the next second stage, the patient will be given CD70 antibodies and BCL-2 inhibitors (e.g., venetoclax). This includes administering NMI as a combination therapy, but the dosage of NMI in the second stage (maintenance therapy) This is less than the dose of NMI administered in the first stage. The dose of NMI in the second stage is zero. But that's fine.

[0143] In this embodiment, the CD70 antibody administered in the second stage (i.e., maintenance therapy) The dose is any dose according to the embodiments already described. That is, in some embodiments In this case, the dosage is 0.1 mg / kg to 25 mg / kg, for example 0.1 mg / kg to 20 mg / kg, for example 1 mg / kg The range is ~20 mg / kg. In some embodiments, the dose is 0.1 mg / kg per dose. The range is from kg to 15 mg / kg. In some embodiments, the dosage is 0.5 mg / kg to 2 mg / kg The range is in the kg range. In some embodiments, the dosage is 1 mg / kg, 3 mg / kg, 10 mg / kg , or 20 mg / kg. In some embodiments, the dose is 1 mg / kg. In this embodiment, the dosage is 10 mg / kg.

[0144] The duration of the first stage (i.e., induction therapy), and the timing of the transition to the second stage (i.e., maintenance therapy) The limits for gradually reducing or completely discontinuing the dose of ing and NMI are adjusted on an individual patient basis. It is determined by the clinician, depending on the individual patient's response to therapy and medical history. Therefore, the following embodiments are provided as non-limiting embodiments. In some embodiments, induction therapy delivers the patient's bone marrow and / or peripheral hematopoietic cells to the bone marrow and / or peripheral hematopoietic cells. - The process is carried out until the concentration is less than 10%, and optionally less than 5%. In some embodiments... Induction therapy involves at least 5 NMI medication periods, optionally at least 6, 7, 8, 9, or fewer. It is administered over a period of at least 10 NMI treatments.

[0145] In some embodiments, the dose of NMI during the maintenance period is 50 mg / m² per day. 2 exceeding In addition, optionally 40 mg / m² per day 2 Not exceeding 30 mg / m² per day (optional). 2 Not exceeding one day at a time. 20 mg / m² 2 Not exceeding. In some embodiments, the dose of NMI during the maintenance period. It is zero.

[0146] As described elsewhere in this specification, the drugs in this combination may be administered via any preferred route of administration. It may be formulated for administration. Therefore, administration of the drug according to the method of the present invention is optional. They can travel through a suitable route, and individual drugs do not need to travel through the same route. For example In addition, a CD70 antibody or its antigen-binding fragment is administered intravenously, while a BCL-2 inhibitor (e.g., venetoclamo) is administered. (Cus) may be administered orally. Azacitidine or decitabine, etc., may be given to the patient or subject. In embodiments where the activating agent is administered, these drugs are administered intravenously or subcutaneously by injection. It is also possible.

[0147] (Therapeutic effect) In some embodiments, the method described herein involves counting the blast cells of a patient, i.e., blast cells This includes monitoring the number of cells. As used herein, “blast cells” or “blasts” are This refers to myeloblasts or myeloid blasts, which are myeloid progenitor cells in the bone marrow. In healthy individuals, blasts are Blast cells are not found in peripheral blood circulation, but less than 5% are present in the bone marrow. Myeloid malignancy Increased production of abnormal blast cells with destroyed differentiation ability in patients with ulcers, particularly those with AML and MDS. There are large cases, and the overproduction of these abnormal blast cells is transmitted to the patient's peripheral blood circulation or bone marrow, or both. It can be detected by monitoring the blast cell count inside.

[0148] The ratio of blast cells in bone marrow or peripheral blood is determined by methods known in the art, for example, the bone of the subject. Flow cytometry evaluation of cells obtained from spinal biopsy or peripheral blood smear, or cell detail It can be evaluated by cellular morphology. The proportion of blast cells is determined relative to the total number of cells in the sample. It is determined. For example, using flow cytometry, the CD45 of the total number of cells is determined. dim SSC lo w The proportion of blast cells can be determined using the number of cells. As a further example, the shape of the cells. Morphological evaluation is used to determine the number of morphologically identified blast cells relative to the total number of cells in the examination field. It can be used for that purpose.

[0149] In some embodiments, the proportion of blast cells in the bone marrow is less than 25%, less than 20%, for example A method is provided to reduce the number to less than 10%. In some embodiments, buds in the bone marrow A method is provided for reducing the proportion of globular cells to less than 5%. In some embodiments... A method is provided to reduce the proportion of blast cells in the bone marrow to approximately 5% to approximately 25%, and here again , the percentage of myeloblast cells compared to the percentage of myeloblast cells before performing this method (or before treatment) The percentage of cells decreases by more than 50%.

[0150] In some embodiments, the percentage of blast cells in peripheral blood is less than 25%, less than 20%, for example. For example, a method is provided to reduce it to less than 10%. In some embodiments, peripheral blood A method is provided to reduce the proportion of blast cells to less than 5%. Several embodiments In this study, a method was provided to reduce the proportion of blast cells in peripheral blood to approximately 5% to 25%. Furthermore, the percentage of peripheral blast cells before performing this method (or before treatment) is compared to this percentage. The decrease in the percentage of peripheral hematopoietic blast cells is greater than 50%. For the clinical determination of blast cell percentage, the morphology of the cells is typically used (cell morphology). (It is also known that) the evaluation is favorable.

[0151] In certain embodiments, the methods described herein induce complete response. In pulse therapy, complete response or "complete remission" is defined as: myeloblasts < 5%; circulating blasts and Auer's bodies. Absence of blast cells associated with [unclear]; absence of extramedullary disease; ANC ≥ 1.0 × 10 9 / L (1000μL); Platelet count ≥100 × 10 9 It is defined as / L (100,000 μL), and this is discussed in Dohner et al.'s literature, (2017) B See Lood, 129(4):424-447.

[0152] This method aims for complete response with platelet recovery, i.e., a platelet count of >100 × 10 9 / L (100,000 / A response of (μL) can be achieved. These methods can achieve a complete response with neutrophil recovery. That is, a neutrophil count > 1.0 × 10 9 A response of / L (1000 / μL) can be achieved. Alternatively, or in addition to that, this method may be used for 8 weeks or longer, 10 weeks or longer. For longer than 12 weeks or longer, the transfusion of red blood cells or platelets or both. It can induce withdrawal from blood dependence.

[0153] In certain embodiments, the method described herein is for negative minimal residual disease or measurable It induces residual encephalopathy (or MRD), as described in the literature by Schuurhuis et al., (2018) Bl. See ood, 131(12): 1275–1291. In some embodiments, the methods described herein result in a complete response with minimal residual disease. Effectiveness (CR) MRD- This induces [a certain condition], for which you should refer to the aforementioned Dohner et al.

[0154] This method can achieve a partial response or induce partial remission in the treatment of AML. In this context, partial response or partial remission is defined as a 5% to 25% reduction in the percentage of myeloblasts. This includes a reduction of at least 50% in the pre-treatment myeloblast percentage, and For further information, please refer to the aforementioned literature by Dohner et al.

[0155] The methods described herein can extend the survival period. The term "survival" refers to overall survival, survival period of 1 year, survival period of 2 years, and survival period of 5 years. This refers to event-free survival and progression-free survival. The methods described herein are for the specific diseases being treated. Alternatively, it can extend survival time compared to the gold standard treatment for symptoms. Gold standard treatment also means best practice, standard care, standard medical care or standard therapy. It can also be defined as: for any given disease, different clinical practices in various countries, for example. There will likely be one or more gold standard treatments depending on the practice. Regarding myeloid malignancies, The treatments available to them are diverse, including chemotherapy, radiation therapy, stem cell transplantation, and This includes several targeted therapies. Furthermore, clinical guidelines in both the United States and Europe for myeloid malignancies, for example. For example, they manage the standard treatment for AML, as described in the literature by O'Donnell et al., (2017) Journal. l of the National Comprehensive Cancer Network, 15(7):926-957, and the text by Dohner et al. References, (2017) Blood, 129(4):424-447, both of which are incorporated by citation. ru. The method of the present invention is more effective than in patients receiving any standard treatment for myeloid malignancies. This can extend or improve the survival period.

[0156] The methods described herein may include a further step of providing the patient or subject to bone marrow transplantation. can. The methods described herein also prepare patients or subjects with myeloid malignancies for bone marrow transplantation. It can also be used to provide. As described above, the method of the present invention is bone marrow or This can be done to reduce the absolute or relative number of blast cells in peripheral blood. In several embodiments, this method involves collecting blast cells in the bone marrow and / or peripheral blood before transplantation. This method is performed to reduce the number of patients or subjects in preparation for bone marrow transplantation. It can be used to reduce the blast cell count to less than 5%.

[0157] (D. Kit) The combinations described herein are provided in the form of a kit packaged to include instructions for use. That's fine.

[0158] (Inclusion of references) Various publications have been cited in the above description and through the following examples, and Each of these is incorporated herein by reference in its entirety. [Examples]

[0159] (Examples) In a recent Phase I clinical trial, elderly and unsuitable AML patients were treated with ADCC-enhanced humanized monophosphate. Clonal anti-CD70 antibody (mAb) xatuzumab (also known as ARGX-110 herein) combined with HMA Combined treatment has been shown to promise clinical activity and a favorable tolerability profile. .

[0160] Venetoclax, a BCL-2 antagonist, is used in Phase I and II of care standards. In clinical trials, leukemia stem cells (LSCs) were identified in elderly AML patients by suppressing oxidative phosphorylation. It targeted and eliminated the target, showing very promising activity (Pollyea et al., Nature Medicine (2018) 2 4; 1859-1866). However, even with the use of novel drugs such as venetoclax, the condition remains refractory or relapses. There are still patients who are sexually affected. Venetoclax has different but complementary effects. It is hypothesized that combining it with xatuzumab, which has a specific mechanism, may make LSC elimination successful. It was done.

[0161] (method) To test this hypothesis, drug combination studies were conducted using the Chou-Talalay method (Chou TC literature, Cancer According to Research (2010) 70(2); 440-6), CD70 expression A in MOLM-13, NB-4, and NOMO-1 cells, etc. The procedure was performed in vitro in ML cell lines. MOLM-13 AML cells express FLT3-ITD and NOMO-1 The cells express t(9; 11)(p22; q23). Each of these genetic abnormalities predicts the patient's outcome. It leads to complications later on. NB-4 is an acute promyelocytic leukemia (APL) cell line, and this APL is used in AML patients. It is a subset of the above. Notably, NOMO-1 cells and MOLM-13 cells have mRNA and tannins. MOLM-13 AML cells express high levels of CD70 as measured by protein concentration. It is expressed and sensitive to BCL-2 inhibition (Lin et al., Scientific Reports (2016) 6; 27696).

[0162] MOLM-13 cells (Matsuo et al., Leukemia (1997) 11 (9): 1469-77), NOMO-1 cells (Kato (Lanotte et al., Acta Haematol Jpn, 1986), MV4-11 cells and NB4 cells (Lanotte et al., Blood (1991) 77 (5); 1080-86) was purchased from ATCC. The cell line was tested for mycoplasma-free properties. In the FCS-containing medium recommended by ATCC, GlutaMAX supplement, 100 U / mL penicillin, 100 μg The cells were cultured and grown at 37°C in a humid atmosphere of 95% air and 5% CO2 containing g / mL streptomycin.

[0163] First, cells from each AML cell line were treated with decitabine, xatuzumab, or benetoc Lux performed the procedure alone, and IC for each procedure 50 This decision was made. 10 5 Individual AML cells, In the presence of CFSE-labeled NK cells derived from healthy individuals (1:1 ratio), xatuzumab (0.1, 1.0, and 10 μg / m²) was used. l) Concentration range of venetoclax (0.5 and 200 nM), decitabine (0.01-1 μM), or bihik The procedure was performed using a rubbing agent. This assay was performed in a triple-cycle setup.

[0164] I C 50 The decision identified the following working concentrations for the subsequent synergistic effect experiment: (1) IC 50 MOLM-13 cells: (decitabine: 0.01 nM, venetoclax: 0.42 nM, *Phragmites australis*) (B: 0.68 μg / ml) (2) IC 50 NOMO-1 cells: (decitabine: 0.001 nM, venetoclax: 3.4 nM, *Phragmites australis*) (B: 0.14 μg / ml) (3) IC 50 NB4 cells: (decitabine: 4.8 nM, venetoclax: 17.3 nM, xatuzumab: 0 0.3 μg / ml) (4) IC 50 MV4-11 cells: (decitabine: 2.36 nM, venetoclax: 5 nM, xatuzumab: 1.2 μg / ml).

[0165] To determine the synergistic effect, the equipotency ratio (IC501 / IC502, or IC501 / IC502 / IC503) of each drug is used. Experiments were conducted to determine a specific combination ratio in which each agent contributed equally to cell death. As has already been explained (Riether et al., Sci Transl Med (2015) 7(298); 298) ra119), all dose / dose combinations were evaluated using dual technical replication.

[0166] AML cell lines NOMO-1, MOLM-13, NB-4, or MV4-11 are used with vehicle, decitabine, and kusatsuzuma Venetoclax alone, venetoclax and decitabine, decitabine and kusat Zumab, or a combination of two types each of venetoclax and kusatuzumab, or decitabine Treatment was performed with a combination of three drugs: n, xatuzumab, and venetoclax. All combinations were performed with three drugs. High concentration and three types of low concentration (specified IC) 50 Tested at a constant ratio (higher and lower concentrations than) The experiment was conducted. Cells were cultured in the presence of CFSE-labeled NK cells (1:1 ratio). Annexin V staining for 72 hours. Later, the number of viable AML cells was evaluated, and the effect of drug treatment was compared to the number of viable cells treated with the vehicle. This was calculated as a cell ratio.

[0167] The combination index (CI) is calculated using CompuSyn software to obtain the action ratio (Fa) value. The plot was generated against the given parameters. The combination index (CI) for all combinations was used as the action ratio (Fa). The plotted results are shown in Figure 1, and the individual combinations are shown in Figure 2.

[0168] Fa values ​​of 0, 0.5, and 1 correspond to 0%, 50%, and 100% dead cells, respectively. CI less than 1, CI 1 CI values ​​greater than 1 represent synergistic, additive, and antagonistic effects, respectively. 50 That is, Each IC 50 This represents the Fa value reached by a combination of concentrations. The Fa-CI plot method is used to evaluate synergistic effects. The principles and advantages are described, for example, in the literature of Chou TC, Cancer Research (2010) 70(2); 440-6 and Zhao These are provided in the literature, Front Biosci (Elite ed.). (2010) 2; 241-249 (each of these (This entirety is incorporated herein by reference.)

[0169] In addition to the above, xatuzumab / venetoclax combination and xatuzumab / venetoclax / H The efficacy of MA combination was tested in primary LSCs derived from AML patients. Primary CD34 + CD38 - leukemia stem cell LSCs are isolated from newly diagnosed AML patients and treated with xatuzumab, decitabine, or Treatment involved venetoclax monotherapy or a combination thereof. Next, the colonization ability of LSCs and regeneration were assessed. The effect on seeding ability was evaluated.

[0170] In particular, CD34 derived from three AML patients (P1, P2, and P3) + CD38 - AML LSCs are treated with NK cells (1:1 ratio). In the presence of either cusazumab (Cusa: 0.3 μg / ml) or venetoclax (Ve: 6 nM), In a two-stage culture, the individual or combined agent is cultured overnight, followed by sowing on methylcellulose. Furthermore, CD34 cells derived from two AML patients (P4 and P5) were found. + CD38 -AML LSCs in the presence of NK cells (1:1 ratio) Underlying this, cusatuzumab (Cusa: 0.3 μg / ml), decitabine (0.01 μM), or venetoclax (Ve The cells were cultured overnight, either alone or in combination, with (6 nM) the active ingredient. Colony formation was evaluated after 14 days. .

[0171] (result) (1. When xatuzumab is used in combination with venetoclax and / or decitabine, (Showed a synergistic effect when eliminating AML cell lines in vitro.) Venetoclax and / or decitabine in combination with xatuzumab promotes CD70 expression in NOMO-1 AM L cells were synergistically eliminated across a wide dose range (see Figures 1 and 2B-D).

[0172] With a higher efficacy level associated with tumor death (Fa>0.7) (Chou's literature, 2010), this combination This showed a powerful synergistic effect. Importantly, venetoclax and xatuzumab (Ven / C) The CI for venetoclax, xatuzumab, and decitabine (Ven / Cusa / Dec) is close to 0.1. Furthermore, it showed a very strong synergistic effect. Venetoclax and decitabine (Ven / Dec) and cu Saturazumab and decitabine (Cusa / Dec) also have a maximum CI of approximately 0.5, indicating a high level of efficacy. A synergistic effect was achieved. The synergistic effect of the Ven / Cusa combination was the same as the synergistic effect observed in the Ven / Cusa / Dec combination. The effect was similar.

[0173] Similar results were observed in NB4 and MV4-11 AML cell lines, with all xatuzumab combinations showing high efficacy. A strong synergistic effect was observed at an effective level (Fa > 0.5) (see Figures 3 and 5).

[0174] In the MOLM-13 cell line, all two combinations showed a synergistic effect at a lower efficacy level. Venetoclax / decitabine and cusatuzumab / decitabine are each 0. The synergistic effect was observed only at drug concentrations below Fa 4 and Fa 0.6. At the appropriate efficacy level (Fa is approximately 0.7-0.8), cusatuzumab / venetoclax The combination showed a strong synergistic effect (see Figure 4), but there was some antagonism at the maximum effect level. The effects were observed. All combinations of venetoclax, decitabine, and xatuzumab showed effects. It showed a low level of antagonistic effect at the efficacy level.

[0175] (2. When xatuzumab is used in combination with venetoclax and / or decitabine, (Synchronous effect was shown when eliminating primary human AML leukemia stem cells (LSCs) in vitro.) To evaluate the efficacy of the xatuzumab / venetoclax combination against primary human AML, LSCs and CD34 derived from 5 AML patients (P1-P5) + CD38 - LSC was treated. Patient characteristics are shown below. vinegar.

[0176] (Table 2: Characteristics of patients P1-P5) [Table 2]

[0177] The results for patients P1, P2, and P3 are shown in Figures 6 and 7. Figure 6 shows the well formed after the procedure. This shows the absolute number of colonies per unit and is an indicator of the LSC count. Figure 7 shows the vehicle for each patient. The same data is shown as the ratio of the mean colony values ​​per well in the treatment group.

[0178] Figures 6 and 7 show the synergistic effect between xatuzumab and venetoclax observed in AML cell lines. The effect manifests as a powerful and significant reduction in LSC count compared to either treatment alone. As shown (Figures 6A and 7A). Figures 6B and 7B show the effect of reducing the number of LSCs, and the reseeding of the first colony in the absence of the treatment molecule. This indicates that the plants were maintained even after sowing.

[0179] The results for patients P4 and P5 are shown in Figure 8. In these patients, xatuzumab, decitabine and The combination of three venetoclax drugs is as effective as the combination of xatuzumab and two venetoclax drugs. This demonstrated that the three combinations showed an increased synergistic effect compared to the Ven / Cusa combination (Figure 1). This is consistent with the fact that it was not observed.

[0180] (3. Venetoclax increases CD70 expression.) Evaluate the effect of venetoclax on CD70 expression at both mRNA and protein levels. The results are shown in Figures 9 and 10. In the presence of venetoclax, CD70 activity decreased in AML cells. It was clearly shown that the current system has been upregulated.

[0181] (Conclusion) This experiment involves xatuzumab and venetoclax and / or hypomethylating agents (e.g., bruises). Combination therapy with cytidine or decitabine is more effective than each monotherapy alone. This was conducted to determine whether we could provide AML treatment. Furthermore, this combination therapy is synergistic We also explored whether it could demonstrate a specific therapeutic effect.

[0182] The combination index (CI) value is provided by the Chou-Talalay method, indicating the synergistic effect of drug combinations. , established means for determining whether they interact in an additive or antagonistic manner. This suggests the hypothesis that venetoclax and xatuzumab may act synergistically. However, the reason for this is that, mechanistically, treatment with venetoclax upregulates CD70 in AML cells. This is because we were able to show that venetocracus provides rations (Figures 9 and 10). This would mean that SCs would be more susceptible to cytolytic death by xatuzumab. , Chou's literature, 2010 (Chou Cancer Res. (2010) Jan 15; 70(2):440-6, cited in this specification) As described in the book, the mechanism of action of each drug Even with a certain level of knowledge, predicting synergistic effects between drugs is difficult.

[0183] The data shown in Figures 1-5 indicates that the Ven / Cusa combination exhibits a particularly high level of efficacy against AML cells. The study revealed that a strong synergistic effect was observed in the low methylating agent. The regimen was maintained using a combination of three formulations, including decitabine.

[0184] This synergistic effect is achieved when these drugs are combined, in order to achieve the same effect as monotherapy. This indicates that significantly lower concentrations of each drug can be used compared to the concentration required. This is particularly advantageous.

[0185] Cell line experiments showed a strong synergistic effect of the venetoclax / xatuzumab combination, therefore The combination was tested in primary AML LSC. Primary LSC is more clinically rigorous in terms of potential therapeutic effects. While it provides relevant assessments, it does not indicate that these cells promote the abnormal proliferative characteristics of AML. Therefore.

[0186] The synergistic effect of Ven / Cusa combination therapy observed in cell lines is in primary AML leukemia derived from human patients. This manifested as a sharp decrease in disease stem cells (LSCs) (Figures 6-8). These data were obtained from all patient samples. Regarding pull, combination therapy is significantly more effective than either therapy alone in LSC colonization. - This indicates that the formation was inhibited. This data shows a synergistic effect between the components of the Ven / Cusa combination. It is clear that (due to the limited number of available primary cells, the Chou-Talalay method was used to determine the phase (It was not possible to test the multiplicative effect.)

[0187] The effect of xatuzumab / venetoclax treatment on LSC function was evaluated in vitro through sequential re-examination. When analyzed using a more rigorous method in seed experiments, the combined treatment observed after the first sowing was observed. The colony formation disorder persisted even during subsequent reseeding. This was due to the effects of kusatsumab and ve Despite the absence of Netoclacus during reseeding, the effective reduction of LSC and its reproductive capacity was observed. This is a case that shows a small number.

[0188] The combination of three drugs, xatuzumab / venetoclax / decitabine, is xatuzumab / venetoclax It reduces the colonies of primary human LSCs to a similar extent as combination therapy with Krax, and also reduces re-dissemination ability. It reduced the amount of HMA such as decitabine. Therefore, xatuzumab and venet are not required to contain HMA such as decitabine. Effective treatment of AML can be achieved using a combination of Krax, thereby treating the patient's toxicity This could reduce exposure to the law. This application provides the invention in the following embodiments. (Aspect 1) (i) an antibody or its antigen-binding fragment that binds to CD70, and (ii) a combination comprising a BCL-2 inhibitor. . (Aspect 2) (i) an antibody or antigen-binding fragment thereof that binds to CD70, and (ii) the embodiment of 1 comprising a BCL-2 inhibitor. The combinations listed, wherein the BCL-2 inhibitor is compound (I) shown below, (chemical 1) The combination thereof, which is TIFF0007927043000005.tif94170 or a pharmaceutically acceptable salt thereof. (Aspect 3) The antibody or antigen-binding fragment that binds to CD70 has a variable heavy chain domain (VH) and a variable light chain domain. It includes a chain domain (VL), where the VH domain and VL domain are defined by the following CDR sequence: HCDR3 containing or derived from sequence number 3; HCDR2 containing or derived from sequence number 2; HCDR1 containing or derived from sequence number 1; LCDR3 containing or containing sequence number 7; LCDR2 containing or derived from sequence number 6; and LCDR1 containing or containing sequence number 5: A combination of the above, including the combination of the above, according to Embodiment 1 or Embodiment 2. (Aspect 4) The antibody or antigen-binding fragment that binds to CD70 is at least 70% identical to that of SEQ ID NO: 4. A VH domain containing a certain amino acid sequence and amino acids that are at least 70% identical to SEQ ID NO: 8. The combination according to embodiment 3, comprising a VL domain containing a sequence. (Appendix 5) The antibody or antigen-binding fragment that binds to the aforementioned CD70 has an amino acid sequence represented by SEQ ID NO: 4. A form comprising a VH domain containing and a VL domain containing the amino acid sequence represented by SEQ ID NO: 8 The combinations listed in 4. (Aspect 6) The combination according to any one of embodiments 1 to 5, wherein the antibody is IgG. (Aspect 7) The antibody has ADCC activity, CDC activity, or ADCP activity, as described in any one of embodiments 1 to 6. combination. (Pattern 8) The combination of the antibody described above, comprising a defucosylated antibody domain, according to any one of embodiments 1 to 7. (Aspect 9) The antibody is ARGX-110 (xatuzumab), a combination according to any one of embodiments 1 to 6. (Aspect 10) The antigen-binding fragment comprises: antibody light chain variable domain (VL); antibody heavy chain variable domain (VH); single-chain antibody (scFv); F(ab')2 fragment; Fab fragment; Fd fragment; Fv fragment; one-armed (monovalent) antibody; diabody, Triabodies, tetrabodies, and combinations, assemblies, of such antigen-binding fragments Selected from the group consisting of any antigen-binding fragment formed by conjugation. or a combination described in any one of the descriptions in 1 to 9. (Aspect 11) The aforementioned antibody or its antigen-binding fragment and the BCL-2 inhibitor are formulated as separate compositions. , a combination of any one of the descriptions in Actuals 1 to 10. (Aspect 12) The aforementioned combination includes at least one additional anticancer agent, preferably an agent for the treatment of myeloid malignancies. The combination described in any one of the descriptions in Actuals 1 to 11. (Aspect 13) The combination according to embodiment 12, wherein the anticancer agent is a therapeutic agent for acute myeloid leukemia (AML). (Aspect 14) The combination described above further comprises a low-methylating agent, as described in any one of embodiments 1 to 13. (Aspect 15) The combination according to embodiment 14, wherein the low-methylating agent is azacitidine. (Aspect 16) The combination according to embodiment 14, wherein the low-methylating agent is decitabine. (Aspect 17) The aforementioned CD70 antibody or its antigen-binding fragment and BCL-2 inhibitor are used in human subjects of acute myeloid leukemia. When administered, they are present in a sufficient amount to provide synergistic treatment, and each is present in the combination. The combination described in any one of the embodiments 1 to 16. (Aspect 18) The CD70 antibody or its antigen-binding fragment and the BCL-2 inhibitor are NOMO-1, MOLM-13, NB4 and M It is used to provide synergistic cell death when cultured with AML cell lines selected from V4-11. A combination described in any one of the embodiments 1 to 17, each existing within the combination in a certain quantity. (Aspect 19) A combination according to any one of embodiments 1 to 18 for use in therapy. (Aspect 20) For use in the treatment of malignant tumors in humans, preferably myeloid malignancies, Embodiments 1-1 Any combination of the items listed in item 9. (Aspect 21) For use in the treatment of malignant tumors in humans, preferably myeloid malignancies, linked to CD70. A binding antibody or its antigen-binding fragment, which is administered in combination with a BCL-2 inhibitor, the aforementioned antibody A body or its antigen-binding fragment. (Aspect 22) The antibody or its antigen-binding fragment is compound (I), (Case 2) For use as described in Embodiment 21, administered in combination with TIFF0007927043000006.tif96170 or a pharmaceutically acceptable salt thereof. an antibody or its antigen-binding fragment that binds to CD70. (Aspect 23) In the aforementioned subjects, azacitidine or decitabine is administered in addition, as in embodiment 21 or An antibody or its antigen-binding fragment for use as described in Model 22. (Aspect 24) BCL-2 inhibitors for use in the treatment of malignant tumors in humans, preferably myeloid malignancies. A drug which is administered in combination with an antibody that binds to CD70 or an antigen-binding fragment thereof, the BCL- 2. Inhibitors. (Aspect 25) The BCL-2 inhibitor is compound (I), (3) A BCL-2 inhibitor for use according to embodiment 24, which is TIFF0007927043000007.tif73170 or a pharmaceutically acceptable salt thereof. (Aspect 26) In the aforementioned subjects, azacitidine or decitabine is administered in addition, as in embodiment 24 or embodiment A BCL-2 inhibitor for use as described in item 25. (Aspect 27) A method for treating malignant tumors in humans, preferably myeloid malignancies, wherein the subject is given the treatment method, and the method is described in Embodiment 1. The method comprising administering an effective amount of any one of the combinations described in item ~18. (Aspect 28) A method for treating malignant tumors in humans, preferably myeloid malignancies, (i) The step of administering to the subject an antibody that binds to CD70 or an antigen-binding fragment thereof; and (ii) To the subject, a BCL-2 inhibitor, preferably compound (I) or a pharmaceutically acceptable substance thereof Steps to administer salt, The method, including the method described above. (Aspect 29) The aforementioned myeloid malignancies are selected from newly diagnosed or recurrent / refractory myeloid malignancies. The method described in embodiment 27 or embodiment 28. (Aspect 30) The aforementioned myeloid malignancies include acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); and myeloproliferative tumors. A condition selected from MPN (Myeloid Neoplasm); Chronic Myeloid Leukemia (CML); and Chronic Myelomonocytic Leukemia (CMML), The method described in any one of the items 27-29. (Aspect 31) The method according to embodiment 30, wherein the myeloid malignant tumor is acute myeloid leukemia (AML). (Aspect 32) The aforementioned subjects are newly diagnosed AML patients who are ineligible for standard intensive chemotherapy. The method described in item 31. (Aspect 33) The aforementioned subjects are newly diagnosed AML patients aged 75 years or older, or newly diagnosed and standard The method according to embodiment 32, wherein the AML patient has a comorbidity that prevents the use of intensive chemotherapy. (Aspect 34) The CD70 antibody or its antigen-binding fragment is in the range of 0.1 to 25 mg / kg, preferably 10 mg / kg. The method described in any one of the embodiments 27 to 33, wherein the dose is administered. (Aspect 35) The BCL-2 inhibitor is administered in a dose ranging from 100 mg to 600 mg, as in any of embodiments 27 to 34. The method described in item 1. (Aspect 36) The combination further includes azacitidine, or the method adds azacitidine to the target. The method according to any one of embodiments 27 to 35, further comprising the additional step of administering. (Aspect 37) The azacitidine mentioned above is 70-80 mg / m² 2 Preferably 75 mg / m² 2 Administered in the following dose, aspect 36 Method of description. (Aspect 38) The combination further includes decitabine, or the method involves administering decitabine to the subject. The method according to any one of embodiments 27 to 35, including the additional step of providing. (Aspect 39) The aforementioned decitabine is 15-25 mg / m² 2 Preferably 20 mg / m² 2 Administered in the dose described in Embodiment 38 Method of loading. (Pattern 40) The dose to which the CD70 antibody or its antigen-binding fragment is administered and the dose to which the BCL-2 inhibitor is administered The amounts are selected such that the combination provides a synergistic treatment, according to embodiments 27-39. Either the method described in item 1. (Aspect 41) Any one of embodiments 31 to 40 further includes monitoring the blast count of the patient. The method described in the section. (Aspect 42) The method according to embodiment 41, wherein the bone marrow blast count of the patient is reduced to less than 5%. (Aspect 43) Compared to before treatment, the myeloblast count of the aforementioned patients decreased by 5% to 25%, and before treatment The method according to embodiment 41, wherein the percentage of myeloblasts decreases by more than 50% compared to the previous method. (Aspect 44) A method according to any one of embodiments 27 to 43 for inducing a partial response or a complete response. (Aspect 45) The method according to embodiment 44, which induces a complete response accompanied by platelet recovery. (Aspect 46) The method according to embodiment 44 or 45, which induces a complete response accompanied by neutrophil recovery. (Aspect 47) Aspects 27-4, which induce transfusion withdrawal of red blood cells, platelets, or both for 8 weeks or more. The method described in any one of item 6. (Aspect 48) A method for extending the survival period, as described in any one of the descriptions in paragraphs 27 to 47. (Aspect 49) Aspect 27: Extending the survival time compared to the standard for therapeutic agents used in the treatment of myeloid malignancies. The method described in any one of the items ~48. (Appearance 50) A method according to any one of embodiments 27 to 49 for inducing a negative minimal residual disease state. (Aspect 51) The method according to any one of embodiments 27 to 50, further comprising providing a bone marrow transplant to the subject. (Appearance 52) The administration of one or more additional anticancer agents is suitable for the treatment of malignant tumors, preferably myeloid malignancies. The method according to any one of embodiments 27 to 51, further comprising doing the following. (Aspect 53) The one or more additional anticancer agents are selected from drugs suitable for the treatment of AML, as described in Embodiment 52. The method. (Aspect 54) The one or more additional anticancer agents mentioned above include selectin inhibitors (e.g., GMI-1271); FMS-like tyrosine FLT3 receptor 3 (FLT3) inhibitors (e.g., midostaurine or gilteritinib); cyclase Phosphate-dependent kinase inhibitors; aminopeptidase inhibitors; JAK / STAT inhibitors; cytarabine; Fludarabine; anthracycline compounds (e.g., daunorubicin, idarubicin); Xorubicin; Hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors, Idohif Idhifa (or enasidenib) or Tibsovo (or ivosidenib), etc.; S Mothened inhibitors, such as Grass-Degib; BET bromodomain inhibitors; CD123 or CD33 targeting agents; HDAC inhibitors; LSC targeting agents; AML bone marrow niche targeting agents; NEDD8 activating enzyme inhibitors, pevonidonexase Stats, etc.; G-CSF, as well as topoisomerase inhibitors, mitoxantrone, selinexo The method according to embodiment 52 or 53, selected from ru and etoposide, etc.

Claims

1. A pharmaceutical composition for use in the treatment of myeloid malignancies in humans, comprising an antibody or antigen-binding fragment thereof that binds to CD70, The pharmaceutical composition is for administering the antibody or its antigen-binding fragment in combination with a BCL-2 inhibitor and a nucleoside metabolism inhibitor. The BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. The subject is treated in a 28-day treatment cycle. The nucleoside metabolism inhibitor is intended to be administered daily during the first 5 to 10 days of a 28-day cycle, according to the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the nucleoside metabolism inhibitor is to be administered daily during the first seven days of the 28-day cycle.

3. The pharmaceutical composition according to claim 1 or 2, wherein the dose of the nucleoside metabolism inhibitor is intended to be administered on the same day as the dose of the antibody or its antigen-binding fragment.

4. The pharmaceutical composition according to claim 3, wherein each of the nucleoside metabolism inhibitor and the antibody or its antigen-binding fragment is intended to be administered on day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

5. The pharmaceutical composition according to claim 4, wherein the initial dose of the antibody or its antigen-binding fragment is to be administered on any one of the 1st to 3rd days of the treatment cycle.

6. The pharmaceutical composition according to claim 5, wherein the second dose of the antibody or its antigen-binding fragment is to be administered 14 to 17 days after the first dose.

7. The pharmaceutical composition according to claim 6, wherein the first dose of the antibody or its antigen-binding fragment is for administration on the third day, and the second dose is for administration on the 17th day of the 28-day cycle.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the antibody or its antigen-binding fragment is to be administered on the 1st and 15th days of the 28-day cycle.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition contains the antibody or its antigen-binding fragment in an amount ranging from 0.1 to 25 mg / kg.

10. The pharmaceutical composition according to claim 9, wherein the amount of the antibody or its antigen-binding fragment in the pharmaceutical composition is 10 mg / kg.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the BCL-2 inhibitor is intended to be administered in an amount ranging from 100 mg to 600 mg.

12. The antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain, wherein the VH domain and VL domain are represented by the following CDR sequence: HCDR3 containing or derived from sequence number 3; HCDR2 containing or derived from sequence number 2; HCDR1 containing or derived from sequence number 1; LCDR3 containing or consisting of sequence number 7; LCDR2 containing or derived from sequence number 6; and LCDR1 containing or containing sequence number 5: A pharmaceutical composition according to any one of claims 1 to 11, comprising:

13. The pharmaceutical composition according to claim 12, wherein the VH domain comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 4, and the VL domain comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO:

8.

14. The pharmaceutical composition according to claim 13, wherein the antibody or antigen-binding fragment thereof comprises a VH domain containing the amino acid sequence represented by SEQ ID NO: 4 and a VL domain containing the amino acid sequence represented by SEQ ID NO:

8.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the antibody or its antigen-binding fragment, a BCL-2 inhibitor, and a nucleoside metabolism inhibitor are individually formulated as separate compositions.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the antibody is IgG.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, or antibody-dependent cell phagocytosis (ADCP) activity.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the antibody comprises a defucosylated antibody domain.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the antibody is ARGX-110 (xatuzumab).

20. The pharmaceutical composition according to any one of claims 1 to 15, wherein the antigen-binding fragment is selected from the group consisting of a single-chain antibody (scFv); F(ab')2 fragment; Fab fragment; Fd fragment; Fv fragment; a one-armed (monovalent) antibody; a diabody, triabody, tetrabody, and any antigen-binding fragment formed by a combination, assembly, or conjugation of such antigen-binding fragments.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the pharmaceutical composition is intended for use in combination with one or more additional anticancer agents suitable for the treatment of malignant tumors.

22. The pharmaceutical composition according to claim 21, wherein the malignant tumor is a myeloid malignant tumor.

23. The pharmaceutical composition according to claim 21 or 22, wherein the one or more additional anticancer agents are selected from agents suitable for the treatment of AML.

24. The one or more additional anticancer agents mentioned above include: selectin inhibitors; FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors; cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK / STAT inhibitors; cytarabine; fludarabine; anthracycline compounds; doxorubicin; hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors, such as Idhifa (or enasidenib) or Tibsovo (or ivosidenib); smoothed inhibitors, such as glassebib; BET bromodomain inhibitors; CD123 or CD33 targeters; HDAC inhibitors; LSC targeters; AML bone marrow niche targeters; NEDD8 activating enzyme inhibitors, such as pevonedistat; The pharmaceutical composition according to claim 23, comprising G-CSF and selected from topoisomerase inhibitors, mitoxantrone, selinexol, and etoposide, etc.

25. The pharmaceutical composition according to claim 24, wherein the selectin inhibitor is GMI-1271.

26. The pharmaceutical composition according to claim 24, wherein the FLT3 inhibitor is midostaurin or gilteritinib.

27. The pharmaceutical composition according to claim 24, wherein the anthracycline compound is daunorubicin or idarubicin.

28. The pharmaceutical composition according to claim 24, wherein the one or more additional anticancer agents are CD123 targeting agents.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the nucleoside metabolism inhibitor is a hypomethylating agent.

30. The pharmaceutical composition according to claim 29, wherein the low-methylating agent is azacitidine or decitabine.

31. The pharmaceutical composition according to claim 30, wherein the low-methylating agent is azacitidine.

32. The azacitidine mentioned above is 70-80 mg / m² 2 The pharmaceutical composition according to claim 31, for administration in a dose of azacitidine.

33. The dose of azacitidine is 75 mg / m². 2 The pharmaceutical composition according to claim 32.

34. The pharmaceutical composition according to claim 30, wherein the low-methylating agent is decitabine.

35. The aforementioned decitabine is 15-25 mg / m² 2 The pharmaceutical composition according to claim 34, for administration in a dose of decitabine.

36. The dose of decitabine is 20 mg / m². 2 The pharmaceutical composition according to claim 35.

37. The pharmaceutical composition according to any one of claims 1 to 36, wherein the myeloid malignant tumor is a newly diagnosed or recurrent / refractory myeloid malignant tumor.

38. The pharmaceutical composition according to any one of claims 1 to 37, wherein the myeloid malignant tumor is selected from AML; myelodysplastic syndrome (MDS); myeloproliferative neoplasm (MPN); chronic myeloid leukemia (CML); and chronic myelomonocytic leukemia (CMML).

39. The pharmaceutical composition according to claim 38, wherein the myeloid malignant tumor is AML.

40. The subject is a newly diagnosed AML patient who is ineligible for standard intensive chemotherapy, according to any one of claims 1 to 39, the pharmaceutical composition.

41. The pharmaceutical composition according to claim 40, wherein the subject is a newly diagnosed AML patient aged 75 years or older, or a newly diagnosed AML patient with a comorbidity that prevents the use of standard intensive chemotherapy.

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