Methods for treating cancer using BCL-2 inhibitors with alpha-emitting radioimmunotherapeutics

Abstract

To provide a method for treating cancer using a BCL-2 inhibitor together with an α - ray radioimmunotherapeutic agent.SOLUTION: The present invention provides a method for treating a subject afflicted with cancer, the method comprising administering to the subject (i) a BCL-2 inhibitor together with (ii) an alpha-emitting isotope-labeled agent that targets cancer cells in the subject, wherein the amounts of the BCL-2 inhibitor and the labeled agent are therapeutically effective when administered together with each other. The present invention also provides a method for inducing the death of a cancer cell, said method comprising contacting said cell with (i) a BCL-2 inhibitor and (ii) an alpha-emitting isotope-labeled agent targeted to said cancer cell, wherein the amount of said BCL-2 inhibitor and said labeled agent, when contacted with said cell simultaneously, is effective to induce the death of said cell.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 491,803, filed April 28, 2017, the contents of which are incorporated herein by reference.

[0002] Throughout this application, various publications are cited. The disclosures of these publications are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0003] FIELD OF THE INVENTION The present invention relates to treating a subject afflicted with cancer with a therapeutically effective regimen of a BCL-2 inhibitor in association with an alpha-emitting isotope-labeled agent that targets cancer cells in the subject. [Background technology]

[0004] Background of the Invention BCL-2 inhibitors BCL-2 inhibitors have the potential to treat malignant diseases. One such BCL-2 inhibitor is venetoclax, a drug approved for treating chronic lymphocytic leukemia ("CLL") (1). Venetoclax displaces pro-apoptotic proteins such as BIM and binds to the BH3-binding groove of BCL-2, initiating mitochondrial outer membrane permeabilization ("MOMP"), cytochrome c release, and caspase activation, ultimately resulting in programmed cancer cell death (i.e., apoptosis) (2).

[0005] Apoptosis, in addition to necrosis and autophagy, is a mechanism of cell death in cancer cells. (3) Ideally, by altering the balance between pro- and anti-apoptotic stimuli, venetoclax promotes programmed cell death in cancer cells, thus improving outcomes for cancer patients.

[0006] However, apoptosis is a complex pathway. Cancer cells can deploy various mechanisms to evade and / or prevent certain treatment strategies intended to induce apoptotic death (4) (as shown in Figure 1 of that reference). For example, X-linked XIAP can prevent blockade of BCL-2. XIAP is a well-characterized inhibitor of apoptosis protein (IAP) (5). Indeed, the majority of human cancers have high levels of IAPs (e.g., XIAP) (6).

[0007] Other possible mechanisms for circumventing the effects of BCL-2 inhibitors can be seen in Figure 7. These include blocking caspase-8 activation, preventing the downstream activity of venetoclax on the BAX / BCL-2 axis. Also, not stimulating or blocking part of the apoptotic pathway may not be sufficient to cause apoptosis, as pro-apoptotic stimuli are still required to trigger the apoptotic pathway (7), (8).

[0008] In conclusion, not all cancer cells respond to BCL-2 inhibitors. In one venetoclax trial, for example, the complete response rate (including complete responses with incomplete bone marrow recovery) was 7.5%, even though the majority of patients (79.4%) had some level of response to venetoclax (2). Furthermore, venetoclax has a significant myelosuppressive effect on neutrophils, with 40% of patients experiencing grade 3 and / or 4 neutropenia (2).

[0009] radiation Radiation is a recognized method for treating cancer. The cellular effects of radiation are known to include cell cycle arrest, mutation, apoptosis, necrosis, and autophagy (9). Radiation-associated mediators of cellular damage include: (i) direct LED (linear energy deposition); (ii) ROS (reactive oxygen species); and (iii) RNS (reactive nitrogen species) (9).

[0010] These mediators cause cell damage / kill / arrest through the following mechanisms: (i) DNA damage (9) (e.g., double-strand DNA breaks (most efficient), single-strand DNA breaks (less efficient, repairable), DNA base damage (less efficient, repairable), and DNA crosslinks); (ii) direct effects on the apoptotic cascade (e.g., direct activation of caspases and damage to IAPs) (10); and (iii) bystander effects (i.e., damage or killing of cells not directly damaged by radiation, which occurs through gap junction communication and / or cytokine mediation from target cells) (11).

[0011] Unpredictability of combination therapy In a mouse xenograft model of synergy between venetoclax and radiation (12), venetoclax and 90 Mice treated with the Y-based radioimmunotherapy combination had better survival rates compared to mice treated with either venetoclax or radioimmunotherapy alone. Survival outcomes in the xenografted mouse cohort are shown in Figure 8.

[0012] Importantly, however, these mouse results may not be applicable to humans. Indeed, there are various factors that may make it impractical to use radiation in conjunction with venetoclax to treat cancer in humans.

[0013] One such factor is oxygenation. Xenografted mice had small tumor masses in the Fred Hutchinson Cancer Research Center experiments. Diffuse large B-cell lymphoma ("DLBCL") tumor xenografts were grown in a volume of 50 mm. 3 Treatment in patients with DLBCL suggested tumor diameters of less than 0.5 cm. In the MD Anderson study, approximately 25% of patients had tumor diameters greater than 7 cm (13). Large xenografted tumors in rats were 3.5 cm.3 In larger tumors, baseline hypoxia was greater than 80%, while in tumors 2.5 cm 3 Smaller tumors have been found to have approximately 20% baseline hypoxia. (14) Hypoxia confers resistance to radiation by reducing ROS production. (15) (16) (17) High tumor burden, accompanied by hypoxic regions in human disease, significantly suppresses β-ray-induced ROS and RNS.

[0014] Another such factor is the range of achievable dose levels. In mouse experiments with candidate therapeutic agents, the mice typically receive drug weight / body weight doses that cannot be applied to humans. For example, 90 In the Y / venetoclax combination study, mice were treated with doses of 800 μCi and 1,200 μCi / mouse (whereby 800 μCi was combined with venetoclax). 800 μCi in mice is equivalent to 3,000 mCi in an average human. By comparison, Zevalin® ( 90 Y-RIT, ibritumomab tiuxetan) can be administered to patients at a dose not exceeding 32 mCi ( 18 ). BCL-2 inhibitors (e.g., venetoclax) and radiation therapy (e.g., 90 There remains a need for cancer treatments that address the challenges identified with HIV-1-based therapies. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] L. Harrison et al., The Oncologist (2004) 9 (Suppl. 5) 31-40 [Non-patent document 2] M. Hockel et al., Journal of the National Cancer Institute (February 21, 2001), Vol. 93, No. 4 Summary of the Invention [Means for solving the problem]

[0016] Summary of the Invention The present invention provides a method for treating a subject afflicted with cancer, comprising administering to the subject (i) a BCL-2 inhibitor and (ii) an alpha-emitting isotope-labeled agent that targets cancer cells in the subject, wherein the amounts of the BCL-2 inhibitor and the labeled agent are therapeutically effective when administered together.

[0017] The present invention also provides a method for treating a human subject afflicted with acute myeloid leukemia, the method comprising administering to the subject: (i) venetoclax; (ii) 225 and administering Ac-labeled HuM195 together with the venetoclax and 225 The amounts of Ac-labeled HuM195 are therapeutically effective when administered together.

[0018] The present invention further provides a method for inducing death of cancer cells, the method comprising contacting the cells with (i) a BCL-2 inhibitor and (ii) an alpha-emitting isotope-labeled drug that targets the cancer cells, wherein the amounts of the BCL-2 inhibitor and labeled drug when simultaneously contacted with the cells are effective to induce death of the cells.

[0019] Finally, the present invention also provides a method for inducing death of acute myeloid leukemia cells, the method comprising treating the cells with (i) venetoclax and (ii) 225 and Ac-labeled HuM195, wherein the venetoclax and 225 The amount of Ac-labeled HuM195 is effective to induce death of the cells when contacted simultaneously with the cells. [Brief explanation of the drawings]

[0020] [Figure 1]This figure shows a schematic diagram of the expression plasmid for HuM195. The humanized VL and VH exons of HuM195 are flanked by XbaI sites. The VL exon was inserted into the mammalian expression vector pVk, and the VH exon was inserted into pVg1 (Co et al., J. Immunol. 148:1149-1154, 1992).

[0021] [Figure 2] This figure shows the complete sequence of the HuM195 light chain gene cloned between the XbaI and BamHI sites in pVk. Nucleotide numbers indicate their positions in the plasmid pVk-HuM195. The VL and CK exons are translated in single-letter code; a dot indicates a translation stop codon. The mature light chain begins with the double-underlined aspartic acid (D). Intron sequences are italicized. The polyA signal is underlined.

[0022] [Figure 3-1] This figure shows the complete sequence of the HuM195 heavy chain gene cloned between the XbaI and BamHI sites in pVg1. Nucleotide numbers indicate their positions in the plasmid pVg1-HuM195. The VH, CH1, H, CH2, and CH3 exons are translated in single-letter code; a dot indicates a translation stop codon. The mature heavy chain begins with the double-underlined glutamine (Q). Intron sequences are italicized. The polyA signal is underlined. [Figure 3-2] Same as above

[0023] [Figure 4] This figure shows the structure of 225Ac-lintuzumab (225Ac-HuM195).

[0024] [Figure 5] This figure shows the flow chart for the generation of 225Ac-HuM195.

[0025] [Figure 6]This figure shows the administration protocol for 225Ac-lintuzumab (225Ac-HuM195) treatment of AML.

[0026] [Figure 7] This figure shows a schematic of apoptotic cell death and mechanisms of cancer cell resistance to apoptosis (modified from (4)).

[0027] [Figure 8] This figure shows a diagram of survival in xenografted mice treated with venetoclax alone, targeted beta-radioimmunotherapy alone, and the combination of venetoclax and targeted beta-radioimmunotherapy. In Rec-1-bearing mice, venetoclax alone was ineffective (p = .12), and 800 μCi PRIT extended survival time by 111% over controls (p = .0001), while the combination extended survival by 483% over controls and cured 40% (p = .001, combination group > PRIT alone). In the U2932 xenograft model, venetoclax alone doubled survival time compared to controls (p < .0001), and 800 μCi PRIT alone doubled survival and cured 30%. The combination treatment cured 100% (12).

[0028] [Figure 9] This figure shows a comparison between the mechanisms of apoptotic cell killing by beta and alpha rays. As the figure shows, alpha rays are significantly more potent (approximately 700 times) than beta rays; they cause more dsDNA breaks than beta rays; they are independent of tissue oxygenation and cell division phase; and they can overcome cellular resistance to beta and gamma rays, as well as cytotoxic chemotherapy. These findings are collectively supported by (9)-(11) and (22)-(24). DETAILED DESCRIPTION OF THE INVENTION

[0029] Detailed Description of the Invention The present invention provides methods for treating a subject with cancer. These methods involve administering to the subject two types of drugs, one after the other. The first type of drug is a BCL-2 inhibitor (e.g., venetoclax). The second type is an alpha-emitting isotope-labeled drug (e.g., cerebrospinal fluid (CFL)) that targets cancer cells in the subject. 225 Ac-labeled HuM195).

[0030] definition In this application, certain terms are used which shall have the meanings set forth below.

[0031] As used herein, "administer," in reference to an agent, means delivering the agent to the body of a subject via any known method. Specific modes of administration include, but are not limited to, intravenous, oral, sublingual, transdermal, subcutaneous, intraperitoneal, intrathecal, and intratumoral administration.

[0032] Furthermore, in the present invention, various antibodies and other antigen targeting agents can be formulated with one or more commonly used pharmaceutically acceptable carriers.Such carriers are well known to those skilled in the art.For example, injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymer injections, and can include excipients (for example, solubility modifiers (for example, ethanol, propylene glycol and sucrose)) and polymers (for example, polycaprolactone and PLGA).

[0033] As used herein, the term "agent," whether referring to a BCL-2 inhibitor or an alpha-emitting isotope-labeled agent, can be any type of compound or composition useful for such purposes. Types of agents include, but are not limited to, antibodies, other protein-based drugs, peptides, nucleic acids, carbohydrates, and small molecule drugs.

[0034] As used herein, the term "alpha-emitting isotope" includes: 225 Ac, 213 Bi and 213 Examples include, but are not limited to, Po. Methods for attaching alpha-emitting isotopes to antibodies (ie, "labeling" antibodies with alpha-emitting isotopes) are well known.

[0035] As used herein, the term "antibody" includes, but is not limited to, (a) immunoglobulin molecules that contain two heavy chains and two light chains and recognize an antigen; (b) polyclonal and monoclonal immunoglobulin molecules; (c) monovalent and divalent fragments thereof; and (d) bispecific forms thereof. Immunoglobulin molecules can be derived from any of the commonly known classes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are similarly well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. Antibodies can be both naturally occurring and non-naturally occurring. Furthermore, antibodies include chimeric antibodies, fully synthetic antibodies, single-chain antibodies, and fragments thereof. Antibodies can be human, humanized, or non-human.

[0036] As used herein, an "anti-CD33 antibody" is an antibody that binds to any available epitope of CD33. In one embodiment, the anti-CD33 antibody binds to the epitope recognized by the antibody HuM195.

[0037] As used herein, the term "burden," when used in reference to cancerous cells, refers to an amount. Thus, cancerous cell "burden" refers to the amount of cancerous cells. Cancerous cells have a burden in relation to their tissue of origin (i.e., the primary site of disease) (e.g., in the case of AML, "bone marrow blast burden"). Cancerous cells also have a burden in relation to one or more tissues other than the tissue of origin (e.g., blast burden in the blood, liver, and spleen in the case of AML). The term "peripheral burden" refers to such cells. The peripheral burden of cancerous cells (e.g., blasts in the case of AML) can be measured in different ways with different results. For example, in the case of AML, "peripheral blast burden" can be measured as the total blast population outside the bone marrow, or the total blast population in the blood, spleen, and liver combined, or simply the blast population of the blood when measured in cells / unit volume. As used herein with respect to AML and other cancers originating in the bone marrow, and unless otherwise stated, the term "peripheral cancerous cell burden" (e.g., peripheral blast burden) refers to the cancerous cell population of the blood as measured in cells / unit volume (e.g., cells / μl). This blood-based measure is a useful surrogate for the more cumbersome measures of, for example, spleen and liver burden.

[0038] As used herein, the peripheral cancerous cell burden in a subject is "high" when the subject is administered with a drug (e.g., an antibody) that targets a hematological malignancy-related antigen at the maximum safe dose, and the drug does not reach the primary site of disease in an amount sufficient to bind to more than 90% of its target antigens at the site. Conversely, the peripheral cancerous cell burden in a subject is "low" when the subject is administered with a drug (e.g., an antibody) that targets a hematological malignancy-related antigen at the maximum safe dose, and the drug reaches the primary site of disease in an amount sufficient to bind to more than 90% of its target antigens at the site. In the case of AML, examples of low peripheral blast burden are those that produce a blood blast burden of 1,000 blasts / μL or less, 500 blasts / μL or less, 400 blasts / μL or less, 300 blasts / μL or less, 200 blasts / μL or less, 100 blasts / μL or less, and 50 blasts / μL or less.

[0039] "Hematologic malignancies" (also known as blood cancers) are cancers originating in blood-forming tissues (e.g., bone marrow) or other cells of the immune system. Hematologic malignancies include, but are not limited to, leukemias (e.g., AML, acute promyelocytic leukemia, acute lymphoblastic leukemia, acute mixed lineage leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and large granular lymphocytic leukemia), myelodysplastic syndromes (MDS), myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myelogenous leukemia), lymphomas, multiple myeloma, and MGUS and similar disorders.

[0040] As used herein, a "hematologic malignancy-associated antigen" can be, for example, a protein and / or carbohydrate marker found exclusively or predominantly on the surface of cancer cells associated with that particular malignancy. Examples of hematologic malignancy-associated antigens include, but are not limited to, CD20, CD33, CD38, CD45, CD52, CD123, and CD319.

[0041] The antibody "HuM195" (also known as lintuzumab) is known, as are methods for producing it. 225 Methods for labeling with Ac are known. These methods are exemplified, for example, in Scheinberg et al., U.S. Patent No. 6,683,162. This information is also exemplified in the following examples and figures.

[0042] As used herein, administering to a subject a BCL-2 inhibitor "in conjunction with" an alpha-emitting isotope-labeled agent that targets cancer cells in the subject means administering the BCL-2 inhibitor before, during, or after administration of the labeled agent. This administration includes, but is not limited to, the following scenarios: (i) the BCL-2 inhibitor is administered first (e.g., orally once daily for 21, 28, 35, 42, 49 days, or longer, during which the cancer does not progress during the treatment and during which the BCL-2 inhibitor does not cause unacceptable toxicity), and the labeled agent is administered second (e.g., intravenously, in a single dose or multiple doses over a period of several weeks); (ii) the BCL-2 inhibitor is administered simultaneously with the labeled agent (e.g., the BCL-2 inhibitor is administered orally once daily for n days, and the labeled agent is administered intravenously in a single dose on day 2 through day n-1 of the BCL-2 inhibitor regimen); (iii) the BCL-2 inhibitor is administered simultaneously with the labeled agent (e.g., For example, the BCL-2 inhibitor is administered orally for a duration of more than one month (e.g., administered orally once daily for 35, 42, 49 days, or longer, during which the cancer does not progress during the treatment and during which the BCL-2 inhibitor does not cause unacceptable toxicity), and the labeled agent is administered intravenously in a single dose on a day within the first month of the BCL-2 inhibitor regimen; and (iv) the labeled agent is administered first (e.g., intravenously, in a single dose or in multiple doses over a period of several weeks), and the BCL-2 inhibitor is administered second (e.g., administered orally once daily for 21, 28, 35, 42, 49 days, or longer, during which the cancer does not progress during the treatment and during which the BCL-2 inhibitor does not cause unacceptable toxicity). Further modifications are provided in the Examples section below.

[0043] As used herein, the term "subject" includes, but is not limited to, mammals (e.g., humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, rats, and mice). When the subject is a human, the subject can be of any age. For example, the subject can be 60 years of age or older, 65 years of age or older, 70 years of age or older, 75 years of age or older, 80 years of age or older, 85 years of age or older, or 90 years of age or older. Alternatively, the subject can be 50 years of age or younger, 45 years of age or younger, 40 years of age or younger, 35 years of age or younger, 30 years of age or younger, 25 years of age or younger, or 20 years of age or younger. With respect to human subjects with AML, the subject can be newly diagnosed, or can be relapsed and / or refractory, or can be in remission.

[0044] As used herein, a "sub-saturating dose" of an agent targeting an antigen (e.g., CD33) or marker (e.g., BCL-2) is a dose that introduces fewer target antigen binding sites (e.g., of the Fab) than there are target antigens, or, if applicable, fewer target marker binding sites (e.g., venetoclax molecules) than there are target markers, into the subject's body. By way of example, with respect to an anti-CD33 antibody, a sub-saturating dose is a dose that introduces fewer CD33 binding sites than there are CD33 molecules into the subject's body. In one embodiment, a sub-saturating dose of an agent targeting a hematological malignancy-associated antigen is a dose at which the ratio of target antigen binding sites to target antigen is less than or equal to 9:10. In another embodiment, the ratio of target antigen binding sites to target antigen is less than or equal to 1:2, less than or equal to 1:5, less than or equal to 1:10, less than or equal to 1:20, or less than or equal to 1:100. By way of further illustration, with respect to a BCL-2 inhibitor, a subsaturating dose is one that introduces fewer BCL-2 binding sites into the subject's body than there is BCL-2 protein present. In one embodiment, a subsaturating dose of a BCL-2 inhibitor is one in which the ratio of inhibitor to BCL-2 protein is less than or equal to 9:10. In another embodiment, the ratio of target antigen binding sites to BCL-2 protein is less than or equal to 9:10. The target antigen ratio is less than or equal to 1:2, less than or equal to 1:5, less than or equal to 1:10, less than or equal to 1:20, or less than or equal to 1:100. In a further embodiment, a "subsaturating dose" of a BCL-2 inhibitor (e.g., venetoclax) is a dose lower than the maximum approved dose of that inhibitor in humans (e.g., less than 400 mg / day, less than 300 mg / day, less than 200 mg / day, less than 100 mg / day, less than 50 mg / day, or less than 10 mg / day).

[0045] For agents such as antibodies labeled with alpha-emitting isotopes, the majority of the agent administered to a subject typically consists of unlabeled antibody, with a minority being labeled antibody. Thus, in one embodiment, a subsaturating dose of an agent targeting a hematological malignancy-associated antigen is one in which the ratio of total (i.e., labeled and unlabeled) target antigen binding sites to target antigen is less than or equal to 9:10 (and may be less than or equal to 1:2, less than or equal to 1:5, less than or equal to 1:10, less than or equal to 1:20, or less than or equal to 1:100). In another embodiment, a subsaturating dose of an agent targeting a hematological malignancy-associated antigen is one in which the ratio of labeled target antigen binding sites to target antigen is less than or equal to 9:10 (and may be less than or equal to 1:2, less than or equal to 1:5, less than or equal to 1:10, less than or equal to 1:20, or less than or equal to 1:100).

[0046] Subsaturating doses of labeled agents used in accordance with the present invention include, for example, single administrations, and two or more administrations (i.e., partial administrations). The amount administered in each dose may be expressed, for example, in terms of labeled radiation activity (e.g., μCi / kg) or antibody weight (e.g., μg / kg or μg / m 2 ) for treating AML. 225 In the case of Ac-HuM195, human dosing regimens include, but are not limited to: (i) 2 x <0.5 μCi / kg, 2 x 0.5 μCi / kg, 2 x 1.0 μCi / kg, 2 x 1.5 μCi / kg, or 2 x 2.0 μCi / kg (wherein portions are administered one week apart); (ii) <0.5 μCi / kg, or 0.5 μCi / kg to 10 μCi / kg; (iii) 2 x <7.5 μg / kg, 2 x 7.5 μg / kg, 2 x 10 μg / kg, or 2 x 12.5 μg / kg (wherein portions are administered one week apart); or (iv) <15 μg / kg, or 15 μg / kg to 50 μg / kg.

[0047] As used herein, an amount of a BCL-2 inhibitor and an amount of an alpha-emitting isotope-labeled agent that targets cancer cells in a subject are "therapeutically effective" if, when administered together, the subject is treated.

[0048] As used herein, "treating" a subject afflicted with a disorder includes, but is not limited to, (i) slowing, halting, or reversing the progression of the disorder, (ii) slowing, halting, or reversing the progression of symptoms of the disorder, (iii) reducing the likelihood of the disorder recurring, and / or (iv) reducing the likelihood of symptoms of the disorder recurring. In preferred embodiments, treating a subject afflicted with a disorder means (i) reversing the progression of the disorder, ideally to the point of eliminating the disorder, and / or (ii) reversing the progression of symptoms of the disorder, ideally to the point of eliminating the symptoms, and / or (iii) reducing or eliminating the likelihood of recurrence (i.e., consolidation, which is a common goal of post-remission therapy for AML and ideally results in the destruction of any remaining leukemia cells).

[0049] Treatment of hematological malignancies (e.g., treatment of AML) can be measured according to a number of clinical endpoints, including, but not limited to, survival (e.g., improved survival by weeks, months, or years, e.g., 1, 2, or more additional months of survival) and response status (e.g., complete remission (CR), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete peripheral blood recovery (CRi), morphologic leukemia free status (MLFS), and partial remission (PR)).

[0050] In one embodiment, treatment of hematological malignancies (e.g., treatment of AML) can be measured in terms of remission, including, but not limited to, the following: (1) Morphologic complete remission ("CR"): ANC ≥ 1,000 / mcl, platelet count ≥ 100,000 / mcl, < 5% myeloblasts, no Auer rods, and no evidence of extramedullary disease (no requirement for bone marrow cellularity or hemoglobin concentration). (2) Morphologic complete remission with incomplete blood count recovery ("CRi"): Same as CR, but ANC < 1,000 / mcl and / or platelet count < 100,000 / mcl. (3) Partial remission (PR): ANC ≥ 1,000 / mcl, platelet count > 100,000 / mcl, and at least a 50% reduction in the percentage of bone marrow aspirate blasts from 5 to 25%, or < 5% myeloblasts with persistent Auer rods. These criteria and others are known and are described, for example, in the SWOG Oncology Research Professional (ORP) Manual Volume I, Described in Chapter 11A, Leukemia (2014).

[0051] Embodiments of the invention The present invention utilizes the use of alpha particles. These particles induce apoptosis in target cells, such as leukemia cells (10, 19). Alpha and beta emitters induce apoptosis in leukemia cells with comparable activity but different efficiencies (10). Alpha particles can overcome doxorubicin resistance, CD95 resistance, and radioresistance to beta and gamma rays in leukemia cells (10). The particles induce apoptosis via: (i) double-strand DNA breaks (20, 21); (ii) caspase activation; (iii) [ 213 the fact that Bi]anti-CD45 activates caspases 2, 3, 8, and 9 through a mitochondrial pathway independent of the CD95 ligand / receptor system (10), (19); and (iv) inactivation of XIAP and Bcl-XL (19).

[0052] Specifically, the present invention provides a first method of treatment for treating a subject afflicted with cancer, comprising administering to the subject (i) a BCL-2 inhibitor and (ii) an alpha-emitting isotope-labeled agent that targets cancer cells in the subject, wherein the amounts of the BCL-2 inhibitor and the labeled agent are therapeutically effective when administered together.

[0053] The present invention also provides a second method of treatment for treating a human subject with acute myeloid leukemia, the method comprising administering to the subject (i) venetoclax, (ii) 225 and administering Ac-labeled HuM195 together, wherein said venetoclax and 225 The amounts of Ac-labeled HuM195 are therapeutically effective when administered together.

[0054] Preferably, in the first and second therapeutic methods, the subject is a human. In one embodiment of the first and second therapeutic methods, the cancer is a hematological malignancy, preferably a leukemia, such as acute myeloid leukemia.

[0055] In preferred embodiments of the first and second treatment methods, the BCL-2 inhibitor is venetoclax. Also, in preferred embodiments of the first and second treatment methods, the alpha-emitting isotope-labeled agent is an alpha-emitting isotope-labeled anti-CD33 antibody, ideally 225 Ac-labeled HuM195. In these methods, the BCL-2 inhibitor, the labeled agent, or both are preferably administered (i) at a subsaturating dose and / or (ii) at a dose that is lower (and / or of shorter duration) than those currently prescribed for their respective labels. Also, in these methods, the subject's peripheral blast burden is preferably low, and the method preferably does not cause unacceptable levels of neutropenia.

[0056] The present invention provides a third method for inducing death of cancer cells, comprising contacting the cells with (i) a BCL-2 inhibitor and (ii) an α-emitting isotope-labeled agent that targets the cancer cells, wherein the amounts of the BCL-2 inhibitor and the labeled agent, when simultaneously contacted with the cells, are effective to induce cell death.

[0057] Preferably, the cancer cells are human cancer cells, hi one embodiment, the cancer cells are blood cells, preferably leukemia cells, such as acute myeloid leukemia cells.

[0058] In a preferred embodiment, the BCL-2 inhibitor is venetoclax. Also in a preferred embodiment, the alpha-emitting isotope-labeled agent is an alpha-emitting isotope-labeled anti-CD33 antibody, ideally 225 Ac-labeled HuM195.

[0059] The present invention also provides a fourth method for inducing death of acute myeloid leukemia cells, the method comprising treating the cells with (i) venetoclax and (ii) 225 and Ac-labeled HuM195, wherein the venetoclax and 225 The amount of Ac-labeled HuM195 is effective to induce death of the cells when contacted simultaneously with the cells.

[0060] Finally, the present invention provides two articles of manufacture, the first of which comprises (i) a BCL-2 inhibitor (e.g., venetoclax) and (ii) an alpha-emitting isotope-labeled agent (e.g., venetoclax) that delivers the BCL-2 inhibitor to the subject and targets cancer cells in the subject (e.g., 225The second article includes labeling instructing the user (e.g., the patient or a healthcare provider) to treat a subject afflicted with cancer (e.g., acute myeloid leukemia) by administering to a subject a BCL-2 inhibitor (e.g., an α-emitting isotope-labeled agent) that targets cancer cells (e.g., Ac-labeled HuM195), wherein the amounts of the BCL-2 inhibitor and the labeled agent are therapeutically effective when administered together. 225 Ac-labeled HuM195) and (ii) labeling instructing the user to treat a subject afflicted with cancer (e.g., acute myeloid leukemia) by administering the labeled agent to the subject in combination with a BCL-2 inhibitor (e.g., venetoclax), wherein the amounts of the BCL-2 inhibitor and the labeled agent, when administered together, are therapeutically effective.

[0061] Whenever applicable, the methods of the present invention can also be performed using pre-targeted radioimmunotherapy (PRIT). PRIT-based methods involve (i) administering a monoclonal antibody labeled with a marker (e.g., streptavidin), (ii) then administering a suitable clearing agent (e.g., biotin galactose clearing agent), and (iii) administering an alpha-emitting isotope-labeled agent (e.g., 225 Thus, the various embodiments of the present invention relating to non-PRIT-based methods for administering alpha-emitting isotope-labeled drugs apply mutatis mutandis to these PRIT-based methods.

[0062] The present invention will be better understood by reference to the following examples, although those skilled in the art will readily recognize that the detailed embodiments are merely illustrative of the invention as more fully described in the claims that follow. [Example]

[0063] Example 1 225Ac-lintuzumab ( 225 Structure of Ac-HuM195 225 Ac-lintuzumab contains three key components: the humanized monoclonal antibody HuM195 (generic name, lintuzumab), an alpha-emitting radioisotope, and 225 Ac, and the bifunctional chelating compound 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA). As shown in Figure 4, HuM195 225 It is radiolabeled using the bifunctional chelator p-SCN-Bn-DOTA, which binds to Ac and is covalently attached to IgG via lysine residues on the antibody.

[0064] Example 2 - p-SCN-Bn-DOTA DOTA, 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (Macrocyclics item code B205-GMP), is synthesized by a multi-step organic synthesis fully described in US Pat. No. 4,923,985.

[0065] Example 3 225 Ac-lintuzumab ( 225 Preparation of Ac-HuM195 225 The procedure for preparing Ac-lintuzumab is described in Michael R. McDevitt, "Design and synthesis of 225 Ac radioimmuno-pharmaceuticals, Applied Radiation and Isotope", 57 (2002), 841-847. The procedure involves the coupling of the bifunctional chelating compound p-SCN-Bn-DOTA with a radioisotope. 225 This involves radiolabeling p-SCN-Bn-DOTA with Ac, followed by binding the radiolabeled p-SCN-Bn-DOTA to an antibody (HuM195). 225Ac-p-SCN-Bn-DOTA-HuM195 was purified using 10 DG size exclusion chromatography and eluted with 1% human serum albumin (HSA). 225 - The lintuzumab is then passed through a 0.2 μm sterile filter.

[0066] Example 4 225 Ac-lintuzumab ( 225 Process flow for the preparation of Ac-HuM195 The procedure (shown in Figure 5) begins with verifying the identity of every component and its subsequent QC release to production. 225 The actinium is assayed to confirm the level of radioactivity and reconstituted with hydrochloric acid to the desired radioactivity concentration. A vial of lyophilized p-SCN-Bn-DOTA is reconstituted with metal-free water to a concentration of 10 mg / mL. To the actinium reaction vial, 0.02 ml of ascorbic acid solution (150 mg / mL) and 0.05 ml of reconstituted p-SCN-Bn-DOTA are added, and the pH is adjusted to between 5 and 5.5 with 2 M tetramethylammonium acetate (TMAA). The mixture is then heated at 55 ± 4°C for 30 minutes.

[0067] the 225 To determine the labeling efficiency of Ac-p-SCN-Bn-DOTA, an aliquot of the reaction mixture is removed and applied to a 1 ml column of Sephadex C25 cation exchange resin. The product is eluted in 2-4 ml fractions with 0.9% saline solution. 225 The fraction of Ac radioactivity is 225 The fraction retained on the column is Ac-p-SCN-Bn-DOTA, which is unchelated and non-reactive. 225 Ac. Typically, the labeling efficiency is greater than 95%.

[0068] To the reaction mixture, 0.22 ml of previously prepared HuM195 in DTPA (1 mg HuM195) and 0.02 ml of ascorbic acid are added. The DTPA is added to bind any trace metals that may compete with the antibody label. Ascorbic acid is added as a radioprotectant. The pH is adjusted to pH 8.5-9 with carbonate buffer. The mixture is heated at 37±3°C for 30 minutes.

[0069] The final product is purified by size exclusion chromatography using 10DG resin and eluted with 2 ml of 1% HSA. Typical reaction yields are 10%.

[0070] Example 5 – Venetoclax and its usual dosing regimen Venetoclax is marketed by Genentech (San Francisco, CA) under the trade name Venclexta TM It is sold under the FDA's Venclexta TM According to the label, the drug is "a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a 17p deletion... and who have received at least one prior therapy." TMVenetoclax is available in 10 mg, 50 mg, and 100 mg tablet forms. Treatment should be initiated with 20 mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. The ramp-up dosing schedule is as follows: Week 1, 20 mg / day; Week 2, 50 mg / day; Week 3, 100 mg / day; Week 4, 200 mg / day; and Week 5 and beyond, 400 mg / day. This dosing regimen is referred to herein as the "normal" human dosing regimen for venetoclax, regardless of the disorder being treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving fewer doses of venetoclax (e.g., 20 mg / day for a total of 21 days) is referred to herein as a "reduced" human dosing regimen. The terms "normal" human dosing regimen and "reduced" human dosing regimen also apply mutatis mutandis to any other BCL-2 inhibitor, with respect to its approved or otherwise customary dosing regimen.

[0071] "Normal" and "reduced" mouse dosing regimens are also contemplated, each proportional to mouse weight and tumor xenograft size. Furthermore, a "normal" mouse dosing regimen has a duration of at least 21 days.

[0072] Example 6 225 Ac-HuM195 and its usual dosing regimen 225 In the case of Ac-HuM195, its "typical" human dosing regimen (regardless of the disorder being treated), as that term is used herein, includes either of the following: (i) 2 x 2.0 μCi / kg (wherein portions are administered one week apart); and (ii) 4.0 μCi / kg, if delivered in a single dose. 225Any dosing regimen involving administration of Ac-HuM195 (e.g., 2.0 μCi / kg if delivered in a single dose) is referred to herein as a "reduced" human dosing regimen (which may also be considered a subsaturating dose). The terms "conventional" and "reduced" human dosing regimen also apply mutatis mutandis to any other α-emitting isotope-labeled drug with respect to its approved or otherwise customary dosing regimen.

[0073] "Normal" and "reduced" mouse dosing regimens are also envisioned, each proportional to mouse body weight and tumor xenograft size.

[0074] Example 7 225 Ac-HuM195 and venetoclax dosing scenario I Human AML patients are treated according to the following regimen: Venetoclax is administered orally according to its usual dosing regimen (i.e., for at least 5 weeks), followed by: 225 Ac-HuM195 is administered intravenously according to its usual dosing regimen (either a single dose or divided doses). In one embodiment, the first (and, if applicable, only) dose of Ac-HuM195 is 225 Ac-HuM195 will be administered on the same day as the last dose of venetoclax or one day after that last dose.

[0075] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0076] Example 8 225 Ac-HuM195 and venetoclax dosing scenario II Human AML patients are treated according to the following regimen: Venetoclax is administered orally according to its usual dosing regimen (i.e., for at least 5 weeks), followed by: 225The reduced dosing regimen of Ac-HuM195 is administered intravenously (either as a single dose or in divided doses). In one embodiment, the first (and, if applicable, only) dose 225 Ac-HuM195 is administered on the same day as the last dose of venetoclax or one day after the last dose. 225 The reduced dosing regimens for Ac-HuM195 are (i) 2 x 0.5 μCi / kg, 2 x 1.0 μCi / kg, or 2 x 1.5 μCi / kg (wherein portions are administered one week apart); or (ii) 1 x 0.5 μCi / kg, 1 x 1.0 μCi / kg, 1 x 2.0 μCi / kg, or 1 x 3.0 μCi / kg (for single administration).

[0077] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0078] Example 9 225 Ac-HuM195 and venetoclax dosing scenario III Human AML patients are treated according to the following regimen: Venetoclax is administered orally according to a reduced dosing regimen, followed by 225 The usual dosing regimen of Ac-HuM195 (either a single dose or divided doses) is administered intravenously. In one embodiment, the first (and, if applicable, only) dose 225Ac-HuM195 is administered on the same day as the last dose of venetoclax or one day after the last dose. In another embodiment, the reduced dosing regimen of venetoclax is one of the following: (i) 20 mg once daily for 7 days; (ii) 20 mg once daily for 14 days; (iii) 20 mg once daily for 21 days; (iv) 50 mg once daily for 7 days; (v) 50 mg once daily for 14 days; (vi) 50 mg once daily for 21 days; (vii) 100 mg once daily for 7 days; (xii) 200 mg once daily for 21 days; (xiii) 400 mg once daily for 7 days; and (xiv) 20 mg / day for the first week, 50 mg / day for the second week, and 100 mg / day for the third week.

[0079] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0080] Example 10 225 Ac-HuM195 and venetoclax dosing scenario IV Human AML patients are treated according to the following regimen: Venetoclax is administered orally according to a reduced dosing regimen, followed by 225 The reduced dosing regimen of Ac-HuM195 (either a single dose or divided doses) is administered intravenously. In one embodiment, the first (and, if applicable, only) dose 225Ac-HuM195 is administered on the same day as the last dose of venetoclax or one day after the last dose. In another embodiment, (a) the reduced dosing regimen of venetoclax is one of the following: (i) 20 mg once daily for 7 days; (ii) 20 mg once daily for 14 days; (iii) 20 mg once daily for 21 days; (iv) 50 mg once daily for 7 days; (v) 50 mg once daily for 14 days; (vi) 50 mg once daily for 21 days; (vii) 100 mg once daily for 7 days. mg; (viii) 100 mg once daily for 14 days; (ix) 100 mg once daily for 21 days; (x) 200 mg once daily for 7 days; (xi) 200 mg once daily for 14 days; (xii) 200 mg once daily for 21 days; (xiii) 400 mg once daily for 7 days; and (xiv) 20 mg / day for week 1, 50 mg / day for week 2, and 100 mg / day for week 3; and (b) 225 The reduced dosing regimen for Ac-HuM195 is one of the following: (i) 2 x 0.5 μCi / kg, 2 x 1.0 μCi / kg, or 2 x 1.5 μCi / kg (wherein portions are administered one week apart); or (ii) 1 x 0.5 μCi / kg, 1 x 1.0 μCi / kg, 1 x 2.0 μCi / kg, or 1 x 3.0 μCi / kg (for single administration).

[0081] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0082] Example 11 225 Ac-HuM195 and venetoclax dosing scenario V Human AML patients are treated according to the following regimen: venetoclax is administered orally according to its usual dosing regimen (i.e., for at least 5 weeks); 225Ac-HuM195 is administered intravenously according to its usual single dose regimen during the course of a venetoclax administration regimen. In one embodiment, the single dose 225 Ac-HuM195 is administered (a) on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of the venetoclax dosing regimen; or (b) on the last day, the day before the last day, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days before the last day of the venetoclax dosing regimen.

[0083] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0084] Example 12 225 Ac-HuM195 and venetoclax dosing scenario VI Human AML patients are treated according to the following regimen: venetoclax is administered orally according to its usual dosing regimen (i.e., for at least 5 weeks); 225 Ac-HuM195 is administered intravenously according to a reduced single dose regimen during the course of the venetoclax dosing regimen. In one embodiment, the single dose 225Ac-HuM195 is administered (a) on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of a venetoclax dosing regimen, or (b) on the last day, the day before, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days before the last day of the venetoclax dosing regimen. 225 The reduced dosing regimens for Ac-HuM195 are (i) 2 x 0.5 μCi / kg, 2 x 1.0 μCi / kg, or 2 x 1.5 μCi / kg (wherein portions are administered one week apart); or (ii) 1 x 0.5 μCi / kg, 1 x 1.0 μCi / kg, 1 x 2.0 μCi / kg, or 1 x 3.0 μCi / kg (for single administration).

[0085] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0086] Example 13 225 Ac-HuM195 and venetoclax dosing scenario VII Human AML patients are treated according to the following regimen: venetoclax is administered orally according to a reduced dosing regimen; 225 Ac-HuM195 is administered intravenously according to its usual single dose regimen during the course of the venetoclax dosing regimen. In one embodiment, a single dose 225Ac-HuM195 is administered (a) on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of the venetoclax dosing regimen; or (b) on the last day, the day before the last day, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days before the last day of the venetoclax dosing regimen. In another embodiment, the reduced dosing regimen of venetoclax is one of the following: (i) 20 mg once daily for 7 days; (ii) 20 mg once daily for 14 days; (iii) 20 mg once daily for 21 days; (iv) 50 mg once daily for 7 days; (v) 50 mg once daily for 14 days; (vi) 50 mg once daily for 21 days; (vii) 100 mg once daily for 7 days; (xii) 200 mg once daily for 21 days; (xiii) 400 mg once daily for 7 days; and (xiv) 20 mg / day for week 1, 50 mg / day for week 2, and 100 mg / day for week 3.

[0087] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0088] Example 14 225 Ac-HuM195 and venetoclax dosing scenario VIII Human AML patients are treated according to the following regimen: venetoclax is administered orally according to a reduced dosing regimen; 225Ac-HuM195 is administered intravenously according to a reduced single dose regimen during the course of the venetoclax administration regimen. In one embodiment, the single dose 225 Ac-HuM195 is administered (a) on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of the venetoclax dosing regimen; or (b) on the last day, the day before the last day, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days before the last day of the venetoclax dosing regimen. In another embodiment, (a) the reduced dosing regimen of venetoclax is one of the following: (i) 20 mg once daily for 7 days; (ii) 20 mg once daily for 14 days; (iii) 20 mg once daily for 21 days; (iv) 50 mg once daily for 7 days; (v) 50 mg once daily for 14 days; (vi) 50 mg once daily for 21 days; (vii) 100 mg once daily for 7 days mg; (viii) 100 mg once daily for 14 days; (ix) 100 mg once daily for 21 days; (x) 200 mg once daily for 7 days; (xi) 200 mg once daily for 14 days; (xii) 200 mg once daily for 21 days; (xiii) 400 mg once daily for 7 days; and (xiv) 20 mg / day in week 1, 50 mg / day in week 2, and 100 mg / day in week 3; and (b) 225 The reduced dosing regimen for Ac-HuM195 is one of the following: (i) 2 x 0.5 μCi / kg, 2 x 1.0 μCi / kg, or 2 x 1.5 μCi / kg (wherein portions are administered one week apart); or (ii) 1 x 0.5 μCi / kg, 1 x 1.0 μCi / kg, 1 x 2.0 μCi / kg, or 1 x 3.0 μCi / kg (for single administration).

[0089] This scenario also contemplates treatment of experimental mouse models according to the treatment regimen, where the appropriate dosing regimen is proportional to mouse body weight and tumor xenograft size.

[0090] References 1. FDA News Release, FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality, April 11, 2016. 2. Venclexta TM Product Monograph Including Patient Medication Information (2016). 3. G. Kroemer, et al., Classification of Cell Death: Recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death and Differentiation (2009) 16, 3-11. 4. S. Fulda, Tumor resistance to apoptosis, Int. J. Cancer: 124, 511-515 (2009). 5. E. Shiozaki, et al., Mechanism of XIAP-Mediated Inhibition of Caspase-9. Molecular Cell, Vol. 11, 519-527, February 2003. 6. I. Tamm, et al., Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000; 6(5):1796-1803. 7. D. Potter and A. Letai, To Prime, or Not to Prime: That Is the Question, Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXXI, November 3, 2016. 8. Venetoclax Advisory Committee Briefing Document, June 28, 2016. 9. J. Kiang, et al., Radiation Combined Injury: DNA Damage, Apoptosis, and Autophagy. Adaptive Medicine 2(1): 1-10, 2010. 10. C. Friesen, et al., Breaking Chemoresistance and Radioresistance with [ 213 Bi]anti-CD45 Antibodies in Leukemia Cells, Cancer Res 2007, 67(5):1950-8. 11. S. Sofou, Radionuclide carriers for targeting of cancer, International Journal of Nanomedicine 2008:3(2), 181-199. 12. S. O’Steen, et al., Venetoclax Synergizes with Radiation Therapy for Treatment of B-Cell Lymphomas, ASH Annual Meeting 2016, Abstract 467. 13. R. Wilder, et al., International Prognostic Index-Based Outcomes for Diffuse Large B-Cell Lymphomas. CANCER June 15, 2002 / Volume 94 / Number 12. 14. V. Bourke, et al., Correlation of Radiation Response with Tumor Oxygenation in the Dunning Prostate R3327-AT1 Tumor. Int. J. Radiat. Oncol. Biol. Phys. 2007 March 15; 67(4):1179-1186. 15. P. Vaupel, Tumor microenvironmental physiology and its implications for radiation oncology. Seminars in Radiation Oncology, Vol. 14, Issue 3, July 2004. 16. L. Harrison, et al., Hypoxia and Anemia: Factors in Decreased Sensitivity to Radiation Therapy and Chemotherapy? The Oncologist 2004, 9 (Suppl. 5), 31-40. 17. M. Hockel, et al., Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects, Journal of the National Cancer Institute, Vol. 93, No. 4, February 21, 18. Zevalin(Polymer) USA Package Insert (2001). 19. M. Roscher, et al., Targeted alpha-therapy using [Bi-213]anti-CD20 as a novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells, Oncotarget, February 2013, Vol. 4, No. 20. A. Konishi, et al., Involvement of Histone H1.2 in Apoptosis Induced by DNA Double-Strand Breaks. Cell, Vol. 114, 673–688, September 19, 2003. 21. J. Stap, et al., Induction of linear tracks of double-stranded DNA breaks by alpha-particle irradiation of cells. Nat. Methods, 2008 March, 5(3):261-6. doi: 10.1038 / nmeth.f.206. 22. Pogozelski, et al., Quantitative assessment of the contribution of clustered damage to DNA double-strand breaks induced by 60Co gamma rays and fission neutrons. Radiat. Res. 1999 April, 151(4):442-8. 23. F. Graf, et al., (2014), DNA Double Strand Breaks as Predictor of Efficacy of the Alpha-Particle Emitter Ac-225 and the Electron Emitter Lu-177 for Somatostatin Receptor Targeted Radiotherapy. PLoS ONE 9(2): e88239. doi:10.1371 / journal.pone.0088239. 24. PA Jeggo and M. Lobrich, DNA double-strand breaks: their cellular and clinical impact? Oncogene (2007) 26, 7717-7719. The present invention provides, for example, the following items. (Item 1) 1. A method for treating a subject suffering from cancer, comprising administering to the subject (i) a BCL-2 inhibitor together with (ii) an alpha-emitting isotope-labeled agent that targets cancer cells in the subject, wherein the amounts of the BCL-2 inhibitor and the labeled agent, when administered together, are therapeutically effective. (Item 2) Item 10. The method of item 1, wherein the subject is a human. (Item 3) 2. The method of item 1, wherein the cancer is a hematological malignancy. (Item 4) 4. The method of claim 3, wherein the hematological malignancy is leukemia. (Item 5) 5. The method of claim 4, wherein the leukemia is acute myeloid leukemia. (Item 6) 2. The method of item 1, wherein the BCL-2 inhibitor is venetoclax. (Item 7) 2. The method of claim 1, wherein the α-emitting isotope-labeled agent is an anti-CD33 antibody labeled with an α-emitting isotope. (Item 8) The α-emitting isotope-labeled anti-CD33 antibody is 225 The method according to item 7, wherein the antibody is Ac-labeled HuM195. (Item 9) 1. A method for treating a human subject afflicted with acute myeloid leukemia, the method comprising administering to the subject: (i) venetoclax; (ii) 225 Ac-labeled HuM195, wherein said venetoclax and said 225 The amounts of Ac-labeled HuM195 are therapeutically effective when administered together with each other. (Item 10) 1. A method for inducing death of cancer cells, the method comprising contacting the cells with (i) a BCL-2 inhibitor and (ii) an alpha-emitting isotope-labeled drug that targets the cancer cells, wherein the amounts of the BCL-2 inhibitor and the labeled drug are effective to induce death of the cells when contacted simultaneously with the cells. (Item 11) 11. The method of claim 10, wherein the cancer cells are human cancer cells. (Item 12) 11. The method of claim 10, wherein the cancer cells are blood cells. (Item 13) Item 13. The method of item 12, wherein the cancer cells are leukemia cells. (Item 14) Item 14. The method of item 13, wherein the leukemia cells are acute myeloid leukemia cells. (Item 15) 11. The method of item 10, wherein the BCL-2 inhibitor is venetoclax. (Item 16) 11. The method of claim 10, wherein the α-emitting isotope-labeled agent is an anti-CD33 antibody labeled with an α-emitting isotope. (Item 17) The α-emitting isotope-labeled anti-CD33 antibody is 225 Item 17. The method according to item 16, wherein the antibody is Ac-labeled HuM195. (Item 18) 1. A method for inducing death of acute myeloid leukemia cells, the method comprising treating the cells with (i) venetoclax and (ii) 225 Ac-labeled HuM195, wherein said venetoclax and said 225 The method, wherein the amount of Ac-labeled HuM195 is effective to induce death of said cells when contacted simultaneously with said cells.

Claims

[Claim 1] A method or composition as described in the specification.

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