Combination therapy for the treatment of mutated CD33-positive hematopoietic malignancies

Abstract

A method is provided for treating CD33-positive hematopoietic malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with mutations such as FLT3, IDH1, IDH2, NMP1, and / or MLL1 gene mutations using combination therapy comprising one or both of a radiolabeled CD33 targeter and a drug-conjugated CD33 targeter, and one or more targeted therapies such as FLT3, IDH, and menin inhibitors.

Description

[Technical Field] 【0001】 Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 505,649 filed on 1 June 2023, U.S. Provisional Patent Application No. 63 / 517,040 filed on 1 August 2023, and U.S. Provisional Patent Application No. 63 / 578,282 filed on 23 August 2023, the entire contents of each application being incorporated herein by reference. 【0002】 Sequence List This application includes a sequence listing submitted electronically in XML format, which is incorporated by reference in its entirety. The XML copy, created on 3 June 2024, is named ATNM-026P_SL_ST26.xml and has a size of 11,818 bytes. 【0003】 The present invention relates to the field of targeted radiotherapy for cancer treatment. [Background technology] 【0004】 CD33 overexpression is common in many hematopoietic malignancies, including AML, CML, and MDS. In AML, 85–90% of patients express CD33, which has led to the development of targeted therapies. Approximately 96% of MDS patients express CD33 in myeloblasts (Sanford et al., “CD33 is frequently expressed in cases of myelodysplastic syndrome and chronic myelomonocytic leukemia with elevated blast count”, 2016, Leukemia & Lymphoma, vol.57(8):1965-1968). Another study showed that MDS patients had approximately twice as many CD33 molecules per bone marrow cell as control samples (Jilani, et al., “Differences in CD33 intensity between various myeloid neoplasms”, 2002, Am J Clin Pathol 2002, vol.118:560-566). The CD33 antigen is expressed in virtually all CML cases. Furthermore, many CD33-expressing hematological malignancies, such as AML, have cancer driver mutations, including FLT3, IDH1, IDH2, NMP1, and / or MLL1 gene mutations. For example, FLT3 mutations are the most common gene mutations in AML, found in approximately one-third of newly diagnosed patients. FLT3 tandem duplication mutations (FLT3-ITD) have been shown to be associated with increased recurrence rates and shortened overall survival. Various aspects of the present invention require and provide novel and improved methods for treating CD33-positive hematopoietic malignancies with cancer driver mutations. [Overview of the project] 【0005】 In one embodiment, the present invention relates to a method for treating hematopoietic malignancies, such as acute myeloid leukemia and myelodysplastic syndrome, involving CD33-positive malignant cells, in mammals such as human patients, comprising the following steps: A radiolabeled anti-CD33 antibody in an amount effective to kill or inhibit the proliferation of target CD33-positive malignant cells, 131 I、 125 I、 123 I、 90 Y、 177 Lu、 186 Re、 188 Re、 89 Sr、 153 Sm、 32 P、 225 Ac、 213 Po、 211 At、 212 Bi、 213 Bi、 223 Ra、 227 Th、 149 Tb、 137 Cs、 212 Pb、 103 administering a radiolabeled anti-CD33 antibody labeled with a radionuclide comprising Y, Lu, Re, Re, Sr, Sm, P, Ac, Po, At, Bi, Bi, Ra, Th, Tb, Cs, Pb, Pd, or any combination thereof; and administering to the subject one or more of an FLT3 inhibitor, an IDH1 inhibitor, an IDH2 inhibitor, and a menin inhibitor A method comprising is provided. For example, hematopoietic tumors can be characterized by one or more mutations in the FLT3, IDH1, IDH2, NMP1, and MLL1 genes. Other features, advantages, and aspects of the present invention may be shown or become apparent by consideration of the following detailed description, the drawings if present, and the claims. Further, both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed. 【Brief Description of the Drawings】 【0006】 [Figure 1] It is a figure showing the results of the 48-hour survival rates of unlabeled rituximab, 225Ac-labeled rituximab at various radiation doses (nCi / mL), human MV411 AML model cells treated with various concentrations (nM) of the FLT3 inhibitor gilteritinib, and untreated controls. [Figure 2]Figures 2A and 2B show the 48-hour survival rates of human MV411AML model cells treated with various doses (nCi / mL) of 225Ac-labeled lintuzumab alone, various concentrations (nM) of the FLT3 inhibitor gilteritinib alone, and various combinations of 225Ac-labeled lintuzumab and gilteritinib. [Figure 3] The figure shows the 48-hour survival results from the initial experiment for human MV411AML model cells treated with unlabeled lintuzumab, 225Ac-labeled IgG (non-specific) at various radiation doses (nCi / mL), 225Ac-labeled lintuzumab at various radiation doses (nCi / mL), anti-CD33ARC gemtuzumab ozogamicin (GO) at various concentrations, the FLT3 inhibitor gilteritinib at various concentrations, and an untreated control. [Figure 4] Figures 4A and 4B show the 48-hour survival rates (from the second experiment) of human MV411AML model cells treated with 225Ac-labeled lintuzumab alone at various radiation doses (nCi / mL), the FLT3 inhibitor gilteritinib alone at various concentrations (nM), and various combinations of 225Ac-labeled lintuzumab and gilteritinib. [Figure 5A] Figures 5A and 5B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the FLT3 inhibitor gilteritinib (0 nM, 10 nM, or 20 nM). [Figure 5B] Figures 5A and 5B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the FLT3 inhibitor gilteritinib (0 nM, 10 nM, or 20 nM). [Figure 6A] This figure shows the 48-hour survival rates of human MV411AML model cells treated with various concentrations (nM) of the menin inhibitors levmenib or diftmenib, and the untreated control. [Figure 6B]This figure shows the 72-hour survival rates of human MV411AML model cells treated with unlabeled lintuzumab, 225Ac-labeled lintuzumab at various radiation doses (nCi / mL), or the menin inhibitors levmenib or diftmenib at various concentrations (nM), as well as the untreated control. [Figure 7A] Figures 7A and 7B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the menin inhibitor levmenib (0 nM, 100 nM, or 300 nM). [Figure 7B] Figures 7A and 7B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the menin inhibitor levmenib (0 nM, 100 nM, or 300 nM). [Figure 8A] Figures 8A and 8B show the 48-hour survival rates of human MV411AML model cells treated with a combination of 225Ac lintuzumab (0 nCi / mL, 1 nCi / mL, or 10 nCi / mL) and the menin inhibitor levmenib (0 nM, 100 nM, or 300 nM). [Figure 8B] Figures 8A and 8B show the 48-hour survival rates of human MV411AML model cells treated with a combination of 225Ac lintuzumab (0 nCi / mL, 1 nCi / mL, or 10 nCi / mL) and the menin inhibitor levmenib (0 nM, 100 nM, or 300 nM). [Figure 9A] Figures 9A and 9B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the menin inhibitor diftmenib (0 nM, 100 nM, or 300 nM). [Figure 9B] Figures 9A and 9B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the menin inhibitor diftmenib (0 nM, 100 nM, or 300 nM). [Figure 10A] Figures 10A and 10B show the 48-hour survival rates of human MV411AML model cells treated with a combination of 225Ac lintuzumab (0 nCi / mL, 1 nCi / mL, or 10 nCi / mL) and the menin inhibitor diftmenib (0 nM, 100 nM, or 300 nM). [Figure 10B] Figures 10A and 10B show the 48-hour survival rates of human MV411AML model cells treated with a combination of 225Ac lintuzumab (0 nCi / mL, 1 nCi / mL, or 10 nCi / mL) and the menin inhibitor diftmenib (0 nM, 100 nM, or 300 nM). [Figure 11] This figure shows the 48-hour survival results for human MV411AML model cells treated with a combination of 225Ac lintuzumab and gilteritinib, or a combination of 225Ac lintuzumab and midostaurin, compared to various controls. [Figure 12] This figure shows the 48-hour survival results for human MOLM-13AML model cells (FLT3-ITD) treated with a combination of 225Ac lintuzumab and gilteritinib, or a combination of 225Ac lintuzumab and midostaurin, and various controls. [Modes for carrying out the invention] 【0007】 In one embodiment, the present invention provides a method for treating CD33-positive hematopoietic malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that have cancer driver mutations such as FLT3, IDH1, IDH2, NMP1 (nucleophosmin gene), and / or MLL1 gene mutations, using a combination therapy comprising treatment with a radiolabeled CD33-targeting agent such as 255Ac-labeled lintuzumab (e.g., 225Ac lintuzumab satetrexetan, also known as Actimab-A®, Actinium Pharmaceuticals, Inc., New York, New York) and one or more targeted therapies such as one or more of FLT3, IDH1, IDH2, and menin inhibitors. In related embodiments, subjects with CD33-positive hematopoietic malignancies having cancer driver mutations in one or more of the FLT3, IDH1, IDH2, NMP1, and / or MLL1 genes may be treated, for example, with a radiolabeled CD33 targeting agent in combination with an inhibitor of the gene product of each cancer driver mutation gene, or an inhibitor of a gene product in the same pathway as the gene product of the mutated cancer driver gene. Accordingly, for example, menin inhibitors may be used to treat cancers having cancer driver mutations in one or both of the NMP1 and MLL1 genes. 【0008】 CD33-positive hematopoietic malignancies treated by the method of the present invention may include, for example, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasms. Hematopoietic malignancies may include, for example, relapsed and / or refractory (R / R) forms or occurrences of multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasms. Hematopoietic malignancies may be refractory and / or resistant to treatment with Bcl-2 inhibitors, such as venetoclax. Subjects may have a history of treatment with Bcl-2 inhibitors, such as venetoclax. CD33-positive hematopoietic malignancies may have, for example, TP53 (p53) mutations; that is, CD33-positive hematopoietic malignancies may include, for example, TP53-mutated CD33-positive hematopoietic malignancies such as TP53-mutated AML. As used herein, the term “subject” includes, but is not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cattle, rabbits, pigs, rats, and mice. If the subject is human, the subject may be of any age. For example, a subject may be 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, or 90 years or older. Alternatively, a subject may be 50 years or younger, 45 years or younger, 40 years or younger, 35 years or younger, 30 years or younger, 25 years or younger, or 20 years or younger. For human subjects with cancer, the subject may be newly diagnosed, relapsed and / or refractory, or in remission. A subject may be a high-risk CD33-positive hematopoietic malignancy patient, such as a high-risk AML patient, such as a high-risk R / R AML patient. 【0009】 Generally, radiolabeled CD33 targeting agents, such as monoclonal antibodies or antigen-binding fragments thereof, used in various embodiments of the present invention may be labeled with one or more of the following radionuclides: 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, and 103 Radioactive isotopes of Pd. iodine can be chemically bonded to, for example, a targeting agent. 225 American and 177 For other radionuclides such as Lu, it is convenient to chemically bind a chelating agent (chelate portion) such as DOTA or its derivatives to the targeting agent, and then radiolabel the targeting agent by chelating the radionuclide with the bound chelating agent. The chelating agents in various embodiments of the present invention may include, for example, the following: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) or its derivatives; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) or its derivatives; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ( DOTA) or its derivatives; 1,4,7-Triazacyclononane, 1-Glutaric acid-4,7-diacetic acid (NODAGA) or its derivatives; 1,4,7,10-Tetraazacyclodecane, 1-Glutaric acid-4,7,10-triacetic acid (DOTAGA) or its derivatives; 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-Tetraacetic acid (TETA) or its derivatives; 1,4,8,11-Tetraazabicyclo[6.6.2] Hexadecane-4,11-diacetic acid (CB-TE2A) or its derivatives; diethylenetriaminepentaacetic acid (DTPA), its diester, or its derivatives; 2-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA) or its derivatives; deferoxamine (DFO) or its derivatives; 1,2-[[6-carboxypyridine-2-yl]methylamino]ethane (H2dedpa) or its derivatives; DADA or its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphate) (DOTP) or its derivatives; 4-amino-6-[[16-[(6-carboxypyridine-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl]pyridine-2-carboxylic acid (MACROPA-NH2) or its derivatives; MACROPA or its derivatives; 1,4,7,10-tetrakis(carbamoylmethyl)-l,4,7,10-tetraazacyclododecane (TCMC) or its derivatives; {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxy Methyl-[1,4,7]triazonan-1-yl}-acetic acid (NETA) or its derivatives; Diamsar or its derivatives; 1,4,7-triazacyclononan-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid (TRAP, PRP9, TRAP-Pr) or its derivatives; N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H4octapa) or its derivatives; N,N'-[1-benzyl-1,2,3-triazole-4-yl]methyl-N,N'-[6-(carboxy)pyridyl] Lysine-2-yl]-1,2-diaminoethane (H2azapa) or its derivatives; N,N''-[[6-(carboxy)pyridine-2-yl]methyl]diethylenetriamine-N,N',N''-triacetic acid (H5decapa) or its derivatives; N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED) or its derivatives; N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) or its derivatives; 3,6,9,15-tetraazabicyclo[9.3.1] Pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) or its derivatives; desferrioxamine B (DFO) or its derivatives; N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridine-2-yl]methyl-1,2-diaminoethane (H6phospa) or its derivatives; 1,4,7,10,13,16-hexazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA) or its derivatives; 1,4,7,10,13-pentazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA) or its derivatives; or 3,4,3-LI(1,2-HOPO) or their derivatives. 【0010】 The group of chelating agents in various embodiments of the present invention may include, for example, a group of chelating agents selected from the following: [ka] JPEG2026519137000003.jpg161150 JPEG2026519137000004.jpg16586 【0011】 As used herein, the term “antibody” includes, without limitation, (a) immunoglobulin molecules comprising two heavy chains and two light chains that recognize an antigen; (b) polyclonal and monoclonal immunoglobulin molecules; (c) monovalent and divalent fragments thereof, e.g., Fab, di-Fab, scFv, diabodies, minibodies, and nanobodies (sdAb); (d) naturally occurring and non-naturally occurring antibodies, e.g., fully synthetic antibodies, IgG-Fc silents, and chimeric antibodies; and (e) bispecific forms thereof. Immunoglobulin molecules may originate from any known class, including, but not limited to, IgA, secretory IgA, IgG, and IgM. The IgG subclass is also well known to those skilled in the art, including, but not limited to, human IgG1, IgG2, IgG3, and IgG4. The N-terminus of each chain defines a “variable region” consisting of about 100 to 110 or more amino acids, primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these regions of the light chain and heavy chain, respectively. Antibodies may be human, humanized, or non-human. When “antibody” is referred to or described in any particular aspect of the invention disclosed herein, unless expressly indicated otherwise, it is assumed to refer to either the full-length antibody or any fragment thereof disclosed herein. 【0012】 A "humanized" antibody refers to an antibody in which some, most, or all of the amino acids outside the CDR domain of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulin. In one embodiment of the humanized form of an antibody, some, most, or all of the amino acids outside the CDR domain are replaced with amino acids from human immunoglobulin at the corresponding positions, while some, most, or all of the amino acids within one or more CDR regions remain unchanged. The CDR and framework regions containing the variable domain of the antibody may be defined, for example, according to Kabat specifications. Minor additions, deletions, insertions, substitutions, or modifications of amino acids are permissible as long as they do not impair the antibody's binding ability to a particular antigen. A "humanized" antibody retains similar antigen specificity to the original antibody. A "chimeric antibody" refers to an antibody in which the variable region originates from one species and the constant region originates from another species, such as an antibody in which the variable region originates from a mouse antibody and the constant region originates from a human antibody. 【0013】 A composition comprising a radiolabeled antibody or a radiolabeled antigen-binding antibody fragment may comprise one or more pharmaceutically acceptable carriers or pharmaceutically acceptable excipients. Such carriers are well known to those skilled in the art. For example, an injectable drug delivery system may comprise a solution, suspension, gel, microsphere, and polymeric injectable preparation and may comprise excipients such as solubility modifiers (e.g., ethanol, propylene glycol, and sucrose) and polymers (e.g., polycaprolactone and PLGA). Typical preparations may be substantially similar to those described in International Publication No. 2017 / 155937, incorporated herein by reference. For example, according to a particular embodiment, a preparation may comprise 0.5–5.0% (w / v) of an excipient selected from the group consisting of ascorbic acid, polyvinylpyrrolidone (PVP), human serum albumin (HSA), water-soluble salts of HSA, and mixtures thereof. Certain formulations may contain 0.5–5% ascorbic acid, 0.5–4% polyvinylpyrrolidone (PVP), and a monoclonal antibody in 50 mM PBS buffer at pH 7. 【0014】 Throughout this disclosure, various aspects or elements are described using the terms “includes” or “incorporates,” but it should be understood that corresponding aspects or elements described using the terms “essentially consist of” or “consist of” are also disclosed and provided by this disclosure. For example, in certain aspects of the Invention, the administration of a radiolabeled antibody is described using the terms “includes” or “incorporates,” but a corresponding method of describing it instead as “essentially consisting of” or “consisting of” the administration of a radiolabeled antibody is also within the scope of the aforementioned aspects and is disclosed by this disclosure. 【0015】 225 Ac-labeled lintuzumab (HuM195), etc. 225Methods for preparing Ac-labeled radioimmune complexes and pharmaceutical compositions thereof are further disclosed, for example, in the present applicant's U.S. Patent No. 9,603,954, and these methods are for use in various embodiments of the present invention. 225 Ac-labeled anti-CD33 antibodies and their respective pharmaceutical compositions can be used to produce these. The full-length nucleotide sequence and encoded amino acid sequence of the lintuzumab light chain (including the leader sequence) are disclosed as SEQ ID NO: 1 and SEQ ID NO: 2, respectively. The full-length nucleotide sequence and encoded amino acid sequence of the lintuzumab heavy chain (including the leader sequence) are disclosed as SEQ ID NO: 3 and SEQ ID NO: 4, respectively. 【0016】 Figure 1 shows the 48-hour survival results for human MV411AML model cells treated with unlabeled lintuzumab, 225Ac-labeled lintuzumab at various radiation doses (nCi / mL), the FLT3 inhibitor gilteritinib at various concentrations (nM), and an untreated control. Figures 2A and 2B show the 48-hour survival rates of human MV411AML model cells treated with 225Ac-labeled lintuzumab alone at various radiation doses (nCi / mL), the FLT3 inhibitor gilteritinib alone at various concentrations (nM), and various combinations of 225Ac-labeled lintuzumab and gilteritinib. Figure 3 shows the 48-hour survival results for human MV411AML model cells treated with unlabeled lintuzumab, 225Ac-labeled IgG (non-specific) at various doses (nCi / mL), 225Ac-labeled lintuzumab at various doses (nCi / mL), anti-CD33ARC gemtuzumab ozogamicin (GO) at various concentrations, the FLT3 inhibitor gilteritinib at various concentrations (nM), and an untreated control. Figures 4A and 4B show the 48-hour survival rates of human MV411AML model cells treated with various doses (nCi / mL) of 225Ac-labeled lintuzumab alone, various concentrations (nM) of the FLT3 inhibitor gilteritinib alone, and various combinations of 225Ac-labeled lintuzumab and gilteritinib. These experiments demonstrate that the combination of 225Ac-labeled lintuzumab and gilteritinib specifically enhances the killing of MV411 cells compared to either drug alone. 【0017】 Figures 5A and 5B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the FLT3 inhibitor gilteritinib (0 nM, 10 nM, or 20 nM). Figure 6A shows the 48-hour survival results for human MV411AML model cells treated with various concentrations (nM) of the menin inhibitors levmenib or diftmenib, and for the untreated control. Figure 6B shows the 72-hour survival results for human MV411AML model cells treated with unlabeled lintuzumab, 225Ac-labeled lintuzumab at various radiation doses (nCi / mL), or the menin inhibitors levmenib or diftmenib at various concentrations (nM), as well as for the untreated control. Figures 7A and 7B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the menin inhibitor levmenib (0 nM, 100 nM, or 300 nM). Figures 8A and 8B are shown below. 225 The results for the 48-hour survival rate of human MV411AML model cells treated with a combination of Acrin lintuzumab (0 nCi / mL, 1 nCi / mL, or 10 nCi / mL) and the menin inhibitor levmenib (0 nM, 100 nM, or 300 nM) are shown. Figures 9A and 9B show the 48-hour survival rates of human MV411AML model cells treated with a combination of GO (0 μg / mL, 0.05 μg / mL, or 0.1 μg / mL) and the menin inhibitor diftmenib (0 nM, 100 nM, or 300 nM). Figures 10A and 10B are shown below. 225 The results for the 48-hour survival rate of human MV411AML model cells treated with a combination of Acrin lintuzumab (0 nCi / mL, 1 nCi / mL, or 10 nCi / mL) and the menin inhibitor diftmenib (0 nM, 100 nM, or 300 nM) are shown. Figures 11 and 12 show, 225 This study shows that when Ac lintuzumab (Lint-Ac225) is used in combination with the FLT3 inhibitor gilteritinib (Gilt) or midostaurin (Mido), it enhances cytotoxicity in FLT3-ITD AML cell lines MV-411 (also known as MV-4-11; Figure 11) and MOLM-13 (Figure 12) compared to monotherapy. The dosage of each drug was selected based on the data obtained from monotherapy. 225 Acetaminophen lintuzumab (or control) was incubated with growth medium for 1 hour, then replaced with fresh medium containing gilteritinib or midostaurin (or control), and viability was measured after 48 hours. Each sample was repeated three times. Statistical analysis using multiple t-tests was performed using GraphPad Prism software to compare combination therapy with each monotherapy (Legend: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns = no significant difference, error bars indicate SD). 【0018】 The 225Ac-labeled lintuzumab used in all experiments was 225Ac-labeled p-SCN-Bn-DOTA-conjugated lintuzumab. Without limitation, the present invention further provides the following aspects / embodiments. 【0019】 Embodiment 1. A method for treating hematopoietic tumors containing CD33-positive malignant cells in mammals such as human patients, comprising the following steps: (i) A radiolabeled anti-CD33 antibody in an amount effective to kill or inhibit the proliferation of target CD33-positive malignant cells, 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Po, 211 At, 212 Bi, 213Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, 103 Radiolabeled anti-CD33 antibodies labeled with radionuclides including Pd or any combination thereof; and (ii) A radioactive anti-CD33 antibody conjugate (anti-CD33ARC), such as gemtuzumab ozogamicin (GO), in an amount effective in killing or inhibiting the proliferation of target CD33-positive malignant cells. To administer to one or both of the following; and Administering one or more of the following to the target population: FLT3 inhibitors, IDH1 inhibitors, IDH2 inhibitors, and menin inhibitors. A method that includes this. Embodiment 2. The method according to Embodiment 1, wherein the step of administering a radiolabeled anti-CD33 antibody in an amount effective to kill or inhibit the proliferation of target CD33-positive malignant cells is performed before the step of administering one or more of the FLT3 inhibitor, IDH1 inhibitor, IDH2 inhibitor, and menin inhibitor to the target. Embodiment 3. The method according to Embodiment 1 or 2, wherein the radiolabeled anti-CD33 antibody comprises radiolabeled lintuzumab (HuM195), radiolabeled gemtuzumab, radiolabeled vadatuximab, a radiolabeled antibody containing a heavy chain complementarity determining region (CDR) and / or a light chain CDR of any of the aforementioned antibodies, a radiolabeled antibody containing a heavy chain variable region and / or a light chain variable region of any of the aforementioned antibodies, or a radiolabeled antigen-binding fragment of any of the aforementioned antibodies. Embodiment 4. Radiolabeled anti-CD33 antibody, 225 Ac or 177 The method according to any one of embodiments 1 to 3, wherein the radioactive labeling is with Lu. Embodiment 5. A radiolabeled anti-CD33 antibody is chemically conjugated to a chelating agent containing 1,4,5,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof, and the radionuclide is chelated to the conjugated chelating agent. 225 Ac or 177 The method according to embodiment 4, which involves labeling with Lu. Apparatus 6. Radiolabeled anti-CD33 antibody 225 Labeled with Ac, 225 The method according to any one of embodiments 1 to 5, wherein the effective amount of Ac-labeled antibody is a dose of 0.1 to 10 μCi / kg of target body weight. Embodiment 7. Radiolabeled anti-CD33 antibody 225 Labeled with Ac, 225 The method according to any one of embodiments 1 to 6, wherein the effective amount of Ac-labeled antibody is a dose of 0.5 to 4 μCi / kg of target body weight. Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the step of administering one or more FLT3 inhibitors, IDH1 inhibitors, IDH2 inhibitors, and menin inhibitors to a target is to administer one or more of sorafenib, restaurtinib, midostaurin, gilteritinib, quizartinib, ivosidenib, enasidenib, ortasidenib, levmenib, and diftmenib to a target. Embodiment 9. The method according to any one of Embodiments 1 to 8, wherein the step of administering a certain amount of radiolabeled anti-CD33 antibody to a target comprises administering a composition containing a radiolabeled fragment of anti-CD33 antibody and a non-radiolabeled fragment of anti-CD33 antibody in a ratio of 0.1:1 to 1:1 between the radiolabeled and non-radiolabeled fragments. Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein the step of administering a certain amount of radiolabeled anti-CD33 antibody to a target comprises administering a composition containing a radiolabeled fragment of anti-CD33 antibody and a non-radiolabeled fragment of anti-CD33 antibody in a ratio of 0.1:1 to 1:1 between radiolabeled and non-radiolabeled. Embodiment 11. The method according to Embodiment 10, wherein the amount of anti-CD33 antibody in the administered composition (i.e., the composition described in Embodiment 10) is less than 16 mg / kg of body weight. Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein the hematopoietic tumor is acute myeloid leukemia (AML), multiple myeloma, chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm. Embodiment 13. The method according to any one of Embodiments 1 to 12, wherein the hematopoietic tumor is recurrent and / or refractory. Aspect 14. The method according to any one of Aspects 1 to 13, wherein the mammalian subject is a human patient. Aspect 15. The method according to any one of Aspects 1 to 14, wherein the hematopoietic tumor comprises one or more genetic mutations in one or more of the FLT3, IDH1, IDH2, NMP1, and / or MLL1 genes. Aspect 16. The method according to any one of Aspects 1 to 15, further comprising administering a hypomethylating agent to the subject. Aspect 17. The method according to Aspect 16, wherein the hypomethylating agent comprises azacitidine or decitabine. Aspect 18. The method according to any one of Aspects 1 to 17, further comprising administering an antimetabolite to the subject. Aspect 19. The method according to Aspect 18, wherein the antimetabolite comprises cytarabine. Aspect 20. The method according to any one of Aspects 1 to 19, wherein the hematopoietic tumor is refractory or resistant to treatment with a BCL-2 inhibitor, such as being refractory or resistant to treatment with venetoclax. Aspect 21. A radiolabeled anti-CD33 antibody effective to kill or inhibit the growth of CD33-positive malignant cells of a subject, 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, 103 Pd, or a combination of any of these radiolabeled with a radionuclide, comprising the step of administering to the subject, the method according to any one of Aspects 1 to 20. Embodiment 22. The method according to Embodiment 21, wherein the subject has a history of treatment with gemtuzumab ozogamicin (GO) for hematopoietic tumors. Embodiment 23. The method according to Embodiment 20 or 21, wherein the hematopoietic malignancy treated by administration of a radiolabeled anti-CD33 antibody is refractory and / or resistant to treatment with gemtuzumab ozogamicin (GO). Embodiment 24. The method according to any one of Embodiments 21 to 23, wherein the subject has relapsed after prior treatment of a hematopoietic malignancy with gemtuzumab ozogamicin (GO). 【0020】 Without limitation, human doses of various targeted therapies disclosed herein, such as 225Ac lintuzumab, gemtuzumab ozogamicin, and FLT3 inhibitors, menin inhibitors, and IDH inhibitors, may be the same as, for example, the approved dose of the drug or the dose studied in human clinical trials of the drug. Gemtuzumab ozogamicin may be administered, for example, at a dose of 2-6 mg / m² on days 1, 4, and 7 of treatment. 2 / day, for example, 3mg / m² 2 It can be administered intravenously at a daily dose. Gilteritinib can be administered orally to adult patients at a daily dose of, for example, 50-200 mg, for example, 100-150 mg, for example, 120 mg. Midostaurin can be administered orally to adult patients at a dose of, for example, 10-100 mg once or twice daily, for example, 25-75 mg once or twice daily, for example, 50 mg once or twice daily. Ivosidenib can be administered orally at a dose of, for example, 100-500 mg daily, for example, 250 mg or 500 mg daily. Ortasidenib can be administered orally at a dose of, for example, 150 mg once daily, 150 mg twice daily, or 300 mg once daily. Enacidenib can be administered orally at a dose of, for example, 50-100 mg daily, for example, 100 mg daily. Targeted therapies such as FLT3, IDH, or menin inhibitors may be administered to the subject for, for example, at least one week, at least two consecutive weeks, or at least three consecutive weeks. 【0021】 Throughout this application, various patents, patent applications, and other publications are referenced, all of which are incorporated herein by reference in their entirety. While various specific embodiments have been illustrated and described herein, it will be understood that various modifications are possible without departing from the spirit and scope of the invention. Furthermore, features described in relation to one aspect of the invention may be used in combination with other aspects of the invention, even if not explicitly shown as combination examples.

Claims

[Claim 1] A method for treating hematopoietic malignancies containing CD33-positive malignant cells in mammals such as human patients, comprising the following steps: (i) A radiolabeled anti-CD33 antibody in an amount effective to kill or inhibit the proliferation of the target CD33-positive malignant cells, 131 I、 125 I、 123 I、 90 Y、 177 Lu、 186 Re、 188 Re、 89 Sr、 153 Sm、 32 P、 225 Ac、 213 Po、 211 At、 212 Bi、 213 Bi、 223 Ra、 227 Th、 149 Tb、 137 Cs、 212 Pb、 103 A radioactively labeled anti-CD33 antibody labeled with a radionuclide comprising Pd or any combination thereof; and (ii) an amount effective in killing or inhibiting the proliferation of the target CD33-positive malignant cells, such as gemtuzumab ozogamicin (GO), an anti-CD33 antibody radioconjugate (anti-CD33 ARC). Administering one or both of the above to the subject; and Administering one or more of the following to the subject: FLT3 inhibitor, IDH1 inhibitor, IDH2 inhibitor, and menin inhibitor. A method that includes this. [Claim 2] The method according to claim 1, wherein the step of administering to the subject an amount of radiolabeled anti-CD33 antibody effective in killing or inhibiting the proliferation of the target CD33-positive malignant cells is performed before the step of administering to the subject one or more of a FLT3 inhibitor, an IDH1 inhibitor, an IDH2 inhibitor, and a menin inhibitor. [Claim 3] The method according to claim 1 or 2, wherein the radiolabeled anti-CD33 antibody comprises radiolabeled lintuzumab (HuM195), radiolabeled gemtuzumab, radiolabeled vadatuximab, a radiolabeled antibody containing a heavy chain complementarity determining region (CDR) and / or a light chain CDR of any of the aforementioned antibodies, a radiolabeled antibody containing a heavy chain variable region and / or a light chain variable region of any of the aforementioned antibodies, or a radiolabeled antigen-binding fragment of any of the aforementioned antibodies. [Claim 4] The aforementioned radiolabeled anti-CD33 antibody 225 Ac or 177 The method according to any one of claims 1 to 3, wherein the material is radiolabeled with Lu. [Claim 5] The radiolabeled anti-CD33 antibody is chemically conjugated to a chelating agent containing 1,4,5,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof, and the radionuclide is chelated to the conjugated chelating agent. 225 Ac or 177 The method according to claim 4, wherein the label is made with Lu. [Claim 6] The radiolabeled anti-CD33 antibody 225 Labeled with Ac, and the above 225 The method according to any one of claims 1 to 5, wherein the effective amount of Ac-labeled antibody is a dose of 0.1 to 10 μCi / kg of target body weight. [Claim 7] The radiolabeled anti-CD33 antibody 225 Labeled with Ac, and the above 225 The method according to any one of claims 1 to 6, wherein the effective amount of Ac-labeled antibody is a dose of 0.5 to 4 μCi / kg of target body weight. [Claim 8] The method according to any one of claims 1 to 7, wherein the step of administering one or more FLT3 inhibitors, IDH1 inhibitors, IDH2 inhibitors, and menin inhibitors to the subject comprises administering one or more sorafenib, resaturtinib, midostaurin, gilteritinib, quizartinib, ivosidenib, enasidenib, levmenib, and diftmenib to the subject. [Claim 9] The method according to any one of claims 1 to 8, wherein the step of administering a certain amount of radiolabeled anti-CD33 antibody to the subject comprises administering to the subject a composition comprising a radiolabeled fragment of anti-CD33 antibody and a non-radiolabeled fragment of anti-CD33 antibody in a ratio of 0.1:1 to 1:1 in which the radiolabeled and non-radiolabeled fragments are present. [Claim 10] The method according to any one of claims 1 to 9, wherein the step of administering a certain amount of radiolabeled anti-CD33 antibody to the subject comprises administering to the subject a composition comprising a radiolabeled fragment of anti-CD33 antibody and a non-radiolabeled fragment of anti-CD33 antibody in a ratio of 0.1:1 to 1:1 in which the radiolabeled and non-radiolabeled fragments are combined. [Claim 11] The method according to claim 10, wherein the amount of anti-CD33 antibody in the composition to be administered is less than 16 mg / kg of body weight. [Claim 12] The method according to any one of claims 1 to 11, wherein the hematopoietic tumor is acute myeloid leukemia (AML), multiple myeloma, chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm. [Claim 13] The method according to any one of claims 1 to 12, wherein the hematopoietic tumor is recurrent and / or refractory. [Claim 14] The method according to any one of claims 1 to 13, wherein the mammalian subject is a human patient. [Claim 15] The method according to any one of claims 1 to 14, wherein the hematopoietic tumor comprises one or more gene mutations in one or more of the FLT3, IDH1, IDH2, NMP1, and / or MLL1 genes. [Claim 16] A radiolabeled anti-CD33 antibody in an amount effective for killing or inhibiting the proliferation of the aforementioned target CD33-positive malignant cells, 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, 103 Radiolabeled anti-CD33 antibody labeled with radionuclides containing Pd or any combination thereof. The method according to any one of claims 1 to 15, comprising the step of administering to the subject. [Claim 17] The method according to claim 16, wherein the subject has a history of treatment with gemtuzumab ozogamicin (GO) for the hematopoietic tumor. [Claim 18] The method according to claim 16 or 17, wherein the hematopoietic tumor of the target treated by administration of the radiolabeled anti-CD33 antibody is refractory and / or resistant to treatment with gemtuzumab ozogamicin (GO). [Claim 19] The method according to any one of claims 16 to 18, wherein the subject has recurred after prior treatment of the hematopoietic malignancy with gemtuzumab ozogamicin (GO). [Claim 20] The method according to any one of claims 1 to 19, wherein the hematopoietic tumor is AML. [Claim 21] The method according to claim 20, wherein the AML is recurrent and / or refractory AML.

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