Combining radioimmunotherapy and CD47 blocking agents in the treatment of cancer

Abstract

Provided are compositions and methods for treating cancer and precancerous proliferative disorders in a mammalian subject comprising the combined use of a radiotherapeutic agent, such as a radiolabeled CD33, DR5, 5T4, HER2, HER3, or TROP2 targeted agent, and a CD47 checkpoint inhibitor, such as a SIRPα-IgG Fc fusion protein or a monoclonal antibody against CD47 or SIRPα.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to each of the following patent applications: U.S. Provisional Patent Application No. 63 / 250,725, filed September 30, 2021, and U.S. Provisional Patent Application No. 63 / 226,699, filed July 28, 2021, which claims priority to International Application No. PCT / US2021 / 056259, filed October 21, 2021, and U.S. Patent Application No. 17 / 702,648, filed March 23, 2022, which claims priority to International Application No. PCT / US2021 / 056259, filed October 21, 2021. Sequence Listing This application contains an electronically submitted Sequence Listing in ASCII format, which is incorporated by reference in its entirety. The ASCII copy was created on April 20, 2022, is named ATNM-001PCT2_SL_ST25.txt, and is 262,596 bytes in size. FIELD OF THEINVENTION The present claimed invention relates to the field of radiation therapy. [Background technology]

[0002] CD47 is an integrin-associated transmembrane protein that is widely expressed on both normal and malignant tissue surfaces. Binding of CD47 to its cognate receptor partner, signaling receptor protein alpha (SIRPα), found on phagocytes such as macrophages and dendritic cells, results in inhibition of phagocytosis. Thus, CD47 provides a "don't eat me" signal to phagocytes.

[0003] CD47 is expressed on virtually all normal cells, including red blood cells, even if they do not express integrins. This pathway evolved as a natural process by which the immune system can efficiently and selectively remove old, dead, or dying cells, leaving only healthy cells. To this end, CD47 is often overexpressed on the surface of many types of tumors as a means of immune evasion to avoid phagocytosis and elimination of tumor cells. Inhibition of CD47 binding to SIRPα by therapeutic blocking antibodies allows phagocytosis.

[0004] However, suppression of don't eat me signals by CD47 is insufficient to induce macrophage phagocytosis. Under normal physiological conditions, cellular homeostasis is regulated in part by the balancing of stimulatory and anti-phagocytic signals. For a target cell to be phagocytosed upon CD47 blockade, the cell must also present a strong stimulatory phagocytic signal, a sufficient "eat me" signal, induced by surface-expressed calreticulin and phosphatidylserine. This is a step to phagocytose and remove dead or dying cells. Importantly, blocking CD47-SIRPα interactions for tumor cell phagocytosis is an emerging therapeutic strategy in the treatment of many types of cancer. However, clinical responses to monotherapy, such as treatment with anti-CD47 blocking antibody therapy, have been modest. What is needed and provided by the present invention is a novel therapeutic approach for the treatment of proliferative disorders, such as cancer and precancerous proliferative disorders, comprising the administration of one or more radiolabeled cancer targeted agents and one or more CD47 blocking agents. Summary of the Invention

[0005] The present disclosure is based on the discovery that administration of a combination comprising at least one radiotherapeutic agent, such as a radiolabeled cancer-associated antigen targeted agent, and a CD47 blocking agent, tilts the balance of pro- and anti-phagocytic signals in favor of phagocytosis of cancer cells. More specifically, the combination of a radioimmunotherapeutic agent, such as a radiolabeled targeted agent against a cancer-associated antigen, such as CD33, DR5, 5T4, HER2, HER3, TROP2, or any of those disclosed herein, and a CD47 blocking agent, such as a blocking monoclonal antibody against CD47 or SIRPα, may improve clinical outcomes in patients with cancer, including solid tumor cancers or hematopoietic malignancies.

[0006] Thus, the present invention provides compositions and methods for treating a subject with a proliferative disorder, such as a cancer or precancerous proliferative order. The compositions typically include a radiotherapeutic agent and a CD47 blocking agent. Exemplary radiotherapeutic agents include radiolabeled targeted agents to CD33, DR5, 5T4, HER2, HER3, or TROP2, such as radiolabeled antibodies, peptides, or small molecules that specifically bind to CD33, DR5, 5T4, HER2, HER3, or TROP2. Exemplary CD33 targeted agents include the monoclonal anti-CD33 antibodies lintuzumab, gemtuzumab, or vadastuximab, e.g., 225Exemplary DR5 targeted drugs include any one or more of the monoclonal anti-DR5 antibodies mapatumumab, conatumumab, lexatumumab, tigatuzumab, drozitumab, and LBY-135. Exemplary 5T4 targeted drugs include any one or more of the monoclonal anti-5T4 antibodies MED10641, ALG.APV-527, Tb535, H6-DM5, and ZV0508. Exemplary HER3 targeted drugs may bind to the epitope of HER3 recognized by patritumab, seribantumab, lumuletuzumab, elgemtumab, GSK2849330, or AV-203. Exemplary TROP2 targeting agents include the monoclonal antibodies sacituzumab and datopotamab, as well as antibodies that recognize the same epitope of TROP2 recognized by any of the above antibodies. Exemplary CD47 blocking agents include agents that can block the binding of CD47 to SIRPα, such as magrolimab, lemzoparimab, AO-176, ALX148, TTI-621, or TTI-622, as well as nucleic acid-based modulators such as MBT-001 and small molecule modulators such as RRx-001.

[0007] In certain embodiments, the radiotherapeutic agent includes actinium-labeled monoclonal antibodies against CD33, DR5, 5T4, HER2, HER3, or TROP2 administered at a radiation dose of 0.1-10 μCi / kg of subject's body weight and a protein dose of less than 10 mg / kg of subject's body weight. CD47 blockers include, for example, monoclonal antibodies that interfere with the binding of CD47 to SIRPα. For example, CD47 blockers include magrolimab, lemzoparimab, AO-176, AK117, IMC-002, IBI-188, IBI-322, BI 766063, ZL-1201, AXL148, RRx-001, azelnidipine, ES004, SRF231, SHR-1603, TJC4, TTI-621, or TTI-622. Exemplary effective doses of CD47 blocking agents include 0.05-50 mg / kg, such as 0.05-5 mg / kg of patient body weight, or doses approved for clinical trials of the drug or agent. Exemplary doses of RRx-001 include 5-80 mg / m2 or any subrange between integer values ​​therein, for example, 10 to 50 mg / m 2 , 10-30mg / m 2 , or 10 to 20 mg / m 2 or any whole integer value within the range ±5%.

[0008] In certain embodiments, the cancer may be a solid tumor or a hematological cancer, such as a myeloid malignancy. Exemplary myeloid malignancies include multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasms. In certain embodiments, the cancer may be associated with CD33-positive cells, such as myeloblast cells or malignant plasma cells. Further features, advantages, and aspects of the present invention will be set forth or will become apparent from consideration of the following detailed description, the drawings, if any, and the claims. It is also to be understood that 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]

[0009] [Figure 1] FIG. 1 is a graph showing a comparison of the effect of vehicle (control), magrolimab alone, 225Ac-trastuzumab alone, and the combination of magrolimab and 225Ac-trastuzumab on tumor growth in an NGS mouse xenograft model using the SK-OV3 human ovarian cancer cell line. [Diagram 2] FIG. 1 is a graph showing a comparison of the effect of vehicle (control), magrolimab alone, 177Lu-trastuzumab alone, and the combination of magrolimab and 177Lu-trastuzumab on tumor growth in an NGS mouse xenograft model using the SK-OV3 human ovarian cancer cell line. [Diagram 3]FIG. 1 is a graph showing the comparative effects of non-radiolabeled anti-human HER3 IgG monoclonal antibody AT-02 alone ("HER3 mAb"), anti-human CD47 antibody alone (10 μg / mL; clone B6.H12; BioXCell catalog number BE0019-1; "CD47 mAb"), 225Ac-labeled AT-02 anti-HER3 mAb alone (100 nCi / mL; 225AC-HER3 mAb), and the combination of anti-CD47 mAb (10 μg / mL) and 225Ac-labeled AT-02 anti-HER3 mAb (100 nCi / mL) on phagocytosis of BxPC3 human pancreatic cancer cell line (adenocarcinoma) cells by human macrophages. As shown in the figure, the combination significantly enhanced phagocytosis of BxPC3 cells compared to either individual agent. [Figure 4A] FIG. 1 is a graph showing that 225Ac-labeled lintuzumab induces an increase in cell surface calreticulin in human leukemia cell lines. [Figure 4B] FIG. 1 is a graph showing that 225Ac-labeled lintuzumab induces an increase in cell surface calreticulin in human leukemia cell lines. [Diagram 5] FIG. 1 is a graph showing that combination treatment of 225Ac-labeled lintuzumab and an anti-CD47 antibody enhances phagocytosis of three human leukemia cell lines compared to either agent alone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In one aspect, the present disclosure provides a method of treating a proliferative disease or disorder, such as a hematological malignancy or solid tumor, by administering an effective amount of a radiotherapeutic agent and an effective amount of a CD47 blocking agent. In certain embodiments, the radiotherapeutic agent is selected from, but is not limited to, mammalian, e.g., human, forms of CD33, DR5, 5T4, HER2 (ErbB2; HER2 / neu), HER3, TROP2, mesothelin, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL-1, GD2, GD3, B-cell maturation antigen (BCMA), TnAg, prostate-specific membrane antigen (PSMA), ROR1, FLT3, fibroblast activation protein (FAP), somatostatin receptor, somatostatin receptor 2 (SSTR2), somatostatin receptor 5 (SSTR5), gastrin releasing peptide receptor (GRPR), NKG2D ligands (e.g., MICA, MICB, RAET1E / ULBP4, RAET1G / ULBP5, RAET1H / ULBP2, RAET1 / ULBP1, RAET1L / ULBP6, and RAET1N / ULBP3), LYPD3 (C4. 4A), nectin-4, urokinase plasminogen activator receptor (uPAR), folate receptor alpha (FOLR1), CUB-domain-containing protein 1 (CDCP1), glypican-3 (GPC3), tenascin, tenascin-C, CEACAM5, cadherin-3, CCK2R, neurotensin receptor type 1 (NTSR1), human kallikrein 2 (hK2), norepinephrine transporter, integrin alpha-V-beta-6, CD37, CD66, CXCR4, fibronectin extradomain EBD, LAT-1, carbonic anhydrase IX (CAIX), B7-H3 (also known as CD276), disialoganglioside GD2 antigen (GD2), calreticulin, phosphatidylserine, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, interleukin-11 receptor a (IL-11Ra), PSCA, PRSS21, VEGFR2, LewisY, CD24, platelet-derived growth factor receptor-beta (PDGFRβ), SSEA-4, CD20, folate receptor alpha (FRa), MUCl, epidermal growth factor receptor (EGFR), EGFRvIII, NCAM, prostase, PAP, ELF2M, ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, F-fucosyl GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1 / CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE A1, MAGEA3, MAGEA3 / A6, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, prostein, survivin and telomerase, PCTA-1 / galectin 8, KRAS, MelanA / MART1, Ras mutants, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG(TMPRSS2 The antibody may be a radiolabeled targeted agent, such as a radiolabeled monoclonal antibody, a radiolabeled antigen-binding fragment of a monoclonal antibody, a radiolabeled antibody mimetic, a radiolabeled peptide, or a radiolabeled small molecule, that specifically binds to one or more cancer associated antigens, such as, for example, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-50, IL-51, IL-52, IL-53, IL-54, IL-55, IL-55, IL-56, IL-57, IL-58, IL-59 ... In certain embodiments, the CD47 blocking agent may comprise a CD47 blocking moiety, such as an antibody against CD47. Each therapeutic regimen may be administered according to a specific dosing schedule, and the methods allow for administration of each radiotherapeutic agent and CD47 blocking agent sequentially or simultaneously.

[0011] Definitions and Abbreviations Throughout this description and the appended claims, the use of the singular includes the plural and the use of the plural includes the singular, unless otherwise indicated. For example, reference is made herein to "an" antibody, "a" radionuclide, and "the" targeting agent, but one or more of any of these components and / or any other components described herein may also be used.

[0012] As used in the present description and claims, the terms "comprising" and "comprising" and "including" are not limited to including elements beyond those recited. Additionally, throughout this disclosure, various aspects or elements thereof are described with the terms "including" or "comprising", but corresponding aspects or elements described with the terms "consisting essentially of" or "consisting of" are similarly disclosed. For example, although certain aspects of the present invention have been described with the terms "including" or "comprising" methods of administering a radiolabeled targeting agent, corresponding methods described instead as "consisting essentially of" or "consisting of" administering a radiolabeled targeting agent are also within the scope of said aspects and disclosed by this disclosure.

[0013] When used in connection with a numerical indication or value, e.g., in describing temperature, time, amounts, and concentrations, the term "about" indicates a variation of ±5% or ±1% of the numerical indication or value, including range descriptions, within a variation of ±10%, and greater variations therein.

[0014] As used herein, "administering" refers to delivery of a targeted agent, such as an antibody, antibody fragment, Fab fragment, aptamer, peptide, or small molecule, to the subject's body via any known method suitable for antibody delivery. Specific modes of administration include, but are not limited to, intravenous, transdermal, subcutaneous, intraperitoneal, intrathecal, and intratumoral administration. Exemplary methods of administration of antibodies are as fully described in International Publication No. WO2016 / 187514, which is incorporated herein by reference. For example, in certain embodiments, the targeted agent can be administered as a patient-specific therapeutic composition, which can be contained in a single-dose container, the total amount of which can be administered to the patient in one treatment session. The composition includes a monoclonal antibody or antibody fragment and a pharma- ceutically acceptable carrier, and the dose of the effector molecule (e.g., a radionuclide) of the monoclonal antibody and the total protein amount of the monoclonal antibody can depend on at least one patient-specific parameter. Patient-specific parameters include, but are not limited to, the patient's weight, the patient's age, the patient's height, the patient's sex, the patient's medical condition, the patient's medical history, and the like.

[0015] Additionally, compositions containing radiolabeled targeting agents, such as radiolabeled antibodies or radiolabeled antigen-binding antibody fragments, may include one or more pharma- ceutically acceptable carriers or pharma-ceutically acceptable excipients. Such carriers are well known to those skilled in the art. For example, injectable drug delivery systems include solutions, suspensions, gels, microspheres, and polymeric injections, and may include excipients such as solubility modifiers (e.g., ethanol, propylene glycol, and sucrose) and polymers (e.g., polycaprylactone and PLGA). Exemplary formulations are fully described in International Publication No. WO2017 / 155937, which is incorporated herein by reference. For example, in certain aspects, the formulation may include 0.5%-5.0% (weight / volume) 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. A particular formulation may include 0.5-5% ascorbic acid; 0.5-4% polyvinylpyrrolidone (PVP); and monoclonal antibody in 50 mM PBS buffer, pH 7.

[0016] 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 bivalent fragments or versions thereof, such as Fab, di-Fab, scFv, diabodies, minibodies, and nanobodies (sdAbs); (d) naturally occurring and non-naturally occurring antibodies, such as fully synthetic antibodies, IgG-Fc-silent, chimeras; and (e) bispecific forms thereof. Immunoglobulin molecules may be derived from any of the well-known classes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those of skill in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. The amino terminus of each chain defines a "variable region" of about 100-110 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 and heavy chains, respectively. The antibody may be a human antibody, a humanized antibody, or a non-human antibody. When certain aspects of the present disclosure refer to or describe an "antibody," it is assumed to refer to any of the full-length antibodies disclosed herein or fragments thereof, unless expressly stated otherwise. A "humanized" antibody refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with the corresponding amino acids from a human immunoglobulin. In one embodiment of a humanized antibody, some, most or all of the amino acids outside the CDR domains are replaced with amino acids from a human immunoglobulin, while some, most or all of the amino acids in one or more CDR regions are left unchanged. Minor additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen. A "humanized" antibody retains antigen specificity similar to that of the original antibody. By "chimeric antibody" is meant an antibody whose variable region derives from one species and whose constant region derives from another species, e.g., the variable region derives from a murine antibody and the constant region derives from a human antibody.

[0017] "Complementarity determining region" or "CDR" refers to the amino acid sequences which together define the binding affinity and specificity of the variable region of a native immunoglobulin binding site. There are three CDRs in each of the light and heavy chains of an antibody. "Framework region" or "FR" refers to amino acid sequences flanked by the CDRs, which are usually conserved and act as a scaffold between the CDRs. "Constant region" refers to the portion of an antibody molecule that is consistent across antibody classes and is defined by the types of light and heavy chains. For example, the light chain constant region can be of the kappa or lambda chain type, and the heavy chain constant region can be one of the five chain isotypes: alpha, delta, epsilon, gamma, or mu. This constant region is usually capable of conferring the effector functions exhibited by the antibody. The various subclasses of heavy chains (e.g., the IgG subclass of heavy chains) are primarily responsible for different effector functions.

[0018] As used herein, "immunoreactivity" refers to a measure of the ability of an immunoglobulin to recognize and bind to a specific antigen. "Specific binding" or "specifically binds" or "binds" refers to an antibody binding to an antigen or epitope within an antigen with greater affinity than to other antigens. Typically, an antibody binds to an antigen or epitope within an antigen with approximately 1x10 -8 M or less, for example, about 1x10 -9 M or less, about 1x10 -10 M or less, about 1x10 -11 M or less, or about 1x10 -12 The equilibrium dissociation constant (K D ), typically K D is the K for binding to non-specific antigens (e.g., BSA, casein) D Dissociation constants are at least 100-fold smaller than the qPCR constant. Dissociation constants may be measured using standard methods. However, antibodies that specifically bind to an antigen or an epitope within an antigen may have cross-reactivity to other related antigens, such as the same antigen in other species (homologs) such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkey, cyno), Pan troglodytes (chimpanzee, chimp), or Calithrix jackass (common marmoset, marmoset).

[0019] As used herein, the term "CD33 targeting agent" includes, for example, an antibody, antibody fragment, antibody mimetic, peptide, Fab fragment, aptamer, or small molecule that binds to any available epitope of CD33. In certain embodiments, the anti-CD33 targeting agent is a humanized antibody against CD33, such as lintuzumab (HuM195), gemtuzumab, or vadastuximab. In certain embodiments, the anti-CD33 targeting agent binds to the epitope recognized by the monoclonal antibody "lintuzumab" or "HuM195." HuM195 is known, as are methods for its production.

[0020] As used herein, the term "DR5 targeting agent" includes, for example, an antibody, antibody fragment, antibody mimetic, peptide, Fab fragment, aptamer, or small molecule that binds to any available epitope of DR5. In certain embodiments, the anti-DR5 antibody is a human or humanized antibody against DR5. In certain embodiments, the anti-DR5 antibody binds to an epitope of DR5 recognized by any of mapatumumab, conatumumab, lexatumumab, tigatuzumab, drozitumab, and LBY-135. In certain embodiments, the anti-DR5 antibody is selected from mapatumumab, conatumumab, lexatumumab, tigatuzumab, drozitumab, and / or LBY-135. [Table 1]

[0021] As used herein, the term "5T4 targeting agent" includes, for example, an antibody, antibody fragment, antibody mimetic, peptide, Fab fragment, aptamer, or small molecule that binds to any available epitope of 5T4. For example, the 5T4 targeting agent can be a monoclonal antibody. The original description of anti-5T4 antibody sequences was provided by Hole & Stern (Hole & Stern (1988) Br. J. Cancer 57, 239-246). Antibodies for use as 5T4 targeting agents according to the present disclosure, such as in preclinical trials, can be produced using the sequences provided by Hole & Stern. In certain embodiments, the 5T4 targeting agent is a humanized antibody against 5T4, such as those described in U.S. Pat. Nos. 7,074,909 and 8,044,178. Exemplary antibodies against 5T4 include at least MED10641, reported in Harper (Harper, J. et al. (2017) Mol. Cancer Ther. 16, 1576-1587) and developed by Mediimmune / AstraZeneca; ALG.APV-527, developed by Aptevo Therapeutics / Alligator Bioscience; Tb535, developed by Biotecnol / Chiome Bioscience; H6-DM5, developed by Guangdong Zhongsheng Pharmaceuticals; and ZV0508, developed by Zova Biotherapeutics. See also Table 1, which discloses additional antibodies and antibody-drug conjugates in which the anti-5T4 moiety may be used as a 5T4 targeting agent in various embodiments of the present disclosure.

[0022] As used herein, an "anti-HER2 antibody" is an antibody, such as, but not limited to, a monoclonal antibody (mAb), that binds to any available epitope of HER2 (ErbB2). In certain embodiments, the anti-HER2 antibody used may be trastuzumab or another antibody that binds to an epitope of HER2 recognized by trastuzumab, and / or the antibody used may be pertuzumab or another antibody that binds to an epitope of HER2 recognized by pertuzumab. In certain embodiments, the anti-HER2 antibody may also be a bispecific antibody against any available epitope of HER3 / HER2, such as multispecific antibodies, such as MM-111 and MM-141 / Istiratumab by Merrimack Pharmaceuticals, MCLA-128 by Merus NV, and MEHD7945A / Durigotumab by Genentech. The amino acid sequences of the light and heavy chains of Trastuzumab according to DrugBank Online are: light chain (SEQ ID NO: 102) and heavy chain (SEQ ID NO: 103). Applicants have successfully conjugated trastuzumab with p-SCN-DOTA, 225 Ac or 177 The composition was radiolabeled with Lu. The amino acid sequences of the light and heavy chains of Pertuzumab as reported by DrugBank Online are: light chain (SEQ ID NO: 104) and heavy chain (SEQ ID NO: 105). Still other radiolabeled HER2 targeted agents that may be used or implemented in various aspects of the invention to treat HER2 expressing cancers, such as breast cancer, advanced / metastatic HER2 positive breast cancer, gastric cancer, gastroesophageal junction (GEJ) cancer, and any of the cancers disclosed herein include: 212 Pb-TCMC-trastuzumab (Orano Med) and 131 I-CAM-H2( 131 and iodine-conjugated anti-HER2 sdAb 2Rs15d; Precirix NV).

[0023] As used herein, an "anti-HER3 antibody" is an antibody, such as, but not limited to, a monoclonal antibody (mAb), that binds to any available epitope of HER3. In certain embodiments, the anti-HER3 antibody may be one of the following antibodies, or may bind to an epitope of HER3 recognized by one of the following antibodies: patritumab, serivantumab, lumuletuzumab, elgemtumab, AV-203 (also known as CAN017; Aveo Oncology), or GSK2849330. In certain embodiments, the anti-HER3 antibody is selected from one or more of patritumab, serivantumab, lumuletuzumab, elgemtumab, US-1402, AV-203, CDX-3379, or GSK2849330. In certain embodiments, the anti-HER3 antibody may be a bispecific antibody directed against any available epitope of HER3 / HER2, e.g., a multispecific antibody such as MM-111 and MM-141 / Istiratumab by Merrimack Pharmaceuticals, MCLA-128 by Merus NV, and MEHD7945A / Durigotumab by Genentech. For example, the antibody may be any of the following: CAN017 (heavy chain SEQ ID NO: 119 and light chain SEQ ID NO: 120), 04D01 (heavy chain SEQ ID NO: 121 and light chain SEQ ID NO: 122), 09D03 (heavy chain SEQ ID NO: 123 and light chain SEQ ID NO: 124), 11G01 (heavy chain SEQ ID NO: 125 and light chain SEQ ID NO: 126), 12A07 (heavy chain SEQ ID NO: 127 and light chain SEQ ID NO: 128), 18H02 (heavy chain SEQ ID NO: 129 and light chain SEQ ID NO: 130), and 22A02 (heavy chain SEQ ID NO: 131 and light chain SEQ ID NO: 132). The antibody may be a HER3-binding antibody, such as one of the anti-HER3 antibodies disclosed in U.S. Patent Publication No. 20210025006, such as one of the anti-HER3 antibodies disclosed in U.S. Patent Application Publication No. 20210025006, such as the antibody disclosed in U.S. Patent Application Publication No. 20210025006 (e.g., col. no. 132), an IgG having a heavy chain of SEQ ID NO: 133 and a light chain of SEQ ID NO: 134, an IgG having a heavy chain that includes one, two or three heavy chain CDRs of any of the aforementioned antibodies and / or a light chain that has one, two or three light chain CDRs of any of the aforementioned antibodies, or an antibody that binds to an epitope of HER3 recognized by any of the aforementioned antibodies.

[0024] "Epitope" refers to a site on a target molecule (e.g., at least a portion of an antigen) that can be recognized and bound by a targeting agent, such as an antibody, antibody fragment, Fab fragment, aptamer, or small molecule. In the case of a protein antigen, it refers to the region of the protein (i.e., the amino acids, and in particular their side chains) that are bound by the targeting agent. Overlapping epitopes contain at least 1-5 common amino acid residues. Methods for identifying epitopes of antibodies are known to those of skill in the art and include, for example, those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988).

[0025] As used herein, the terms "proliferative disorder" and "cancer" are used interchangeably and may include, but are not limited to, solid cancers (e.g., tumors). "Solid cancers" include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, prostate cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood tumors, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphomas, tumor angiogenesis, spinal axis tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, and environmentally induced cancers, including those induced by asbestos. In certain aspects, the solid cancer can be breast cancer, such as tamoxifen-sensitive breast cancer, tamoxifen-resistant breast cancer or triple negative breast cancer (TNBC), gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer, such as melanoma, gastric cancer, testicular cancer, esophageal cancer, prostate cancer, such as bronchioloalveolar carcinoma, castration-resistant prostate cancer (CRPC), colorectal cancer, ovarian cancer, cervical epidermoid carcinoma, liver cancer, such as hepatocellular carcinoma (HCC) or cholangiocarcinoma, pancreatic cancer, lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), renal cancer, head and neck cancer, such as head and neck squamous cell carcinoma, carcinoma, sarcoma, or a combination thereof. As used herein, "cancer" also includes, but is not limited to, hematological malignancies. A "hematologic disease" or "hematological disorder" may be considered to mean at least a blood cancer. Such cancers originate in blood-forming tissues, such as the bone marrow or other cells of the immune system. Hematological diseases or disorders include, but are not limited to, leukemias (e.g., acute myeloid leukemia (AML), acute promyelocytic leukemia, acute lymphoblastic leukemia (ALL), acute mixed lineage leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, and large granular lymphocytic leukemia), myelodysplastic syndromes (MDS), myeloproliferative disorders (polycythemia vera, essential thrombocytosis, myelodysplastic syndromes), myeloproliferative disorders (polycythemia vera, essential thrombocytosis, myelodysplastic syndromes), myeloproliferative disorders (polycythemia vera, essential thrombocytosis, myelodysplastic syndromes), myeloproliferative disorders (polycythemia vera, essential thrombocytosis, myelodysplastic syndromes), myeloproliferative disorders (polycythemia vera, essential thrombocytosis, myelodysplastic syndromes), myelodysplastic syndromes (MDS ... These include: myelofibrosis and chronic myelogenous leukemia), lymphoma, multiple myeloma, MGUS and similar disorders, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, transformed follicular lymphoma, splenic marginal zone lymphoma, lymphocytic lymphoma, T-cell lymphoma, and other B-cell malignancies.

[0026] In certain embodiments, radiotherapeutic agents may include targeted agents labeled with radioisotopes. As used herein, "radioisotope" and "radionuclide" are used interchangeably and may be alpha-, beta-, and / or gamma-emitting isotopes. Examples of radioisotopes include the following: 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Bi, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb and103 Pd. Methods for attaching proteins such as antibodies or antibody fragments (i.e., "labeling" antibodies with radioisotopes) are well known. Specific methods of labeling are described, for example, in U.S. Pat. No. 9,603,954, International Publication No. WO2017 / 155937, and U.S. Provisional Patent Application No. 63 / 119,093, entitled "Compositions and methods for preparation of site-specific radioconjugates," filed on November 30, 2020. Both of these documents are incorporated herein by reference. For example, in certain embodiments, a radiotherapy targeted agent can be prepared by (a) conjugating a targeted agent, such as an antibody or peptide, to a chelator, such as p-SCN-Bn-DOTA, in a buffer solution; and (b) conjugating the chelator-conjugated targeted agent to 225-actinium or 225 The radiolabeled chelator-conjugated targeting agent may be labeled in a buffer solution with a radionuclide such as "Ac", (c) quenching the reaction by addition of a quenching chelate (e.g., diethylenetriaminepentaacetic acid (DTPA)), and (d) purifying the radiolabeled chelator-conjugated targeting agent, for example, by filtration. Exemplary chelators include compounds that have the dual function of sequestering metal ions, such as radionuclides, as well as the ability to covalently bind to biological carriers / targeting agents, such as antibodies.

[0027] Exemplary chelating agents that may be used include, but are not limited to, S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (p-SCN-Bn-DOTA), diethylenetriaminepentaacetic acid (DTPA); ethylenediaminetetraacetic acid (EDTA); 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA); p-isothiocyanatobenzyl-1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetra- 1,4,7,10-tetra-azacyclododecane-N,N',N"-triacetic acid (DO3A); 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrakis(2-propionic acid) (DOTMA); 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoic acid ("B-19036"); 1,4,7-triazacyclononane-N,N',N"-triacetic acid (N OTA; 1,4,8,11-Tetraazacyclotetradecane-N,N',N"-tetraacetic acid (TETA); Triethylenetetraaminehexaacetic acid (TTHA); Trans-1,2-Diaminohexanetetraacetic acid (CYDTA); 1,4,7,10-Tetra-azacyclododecane-1-(2-hydroxypropyl)-4,7,10-triacetic acid (HP-DO3A); Trans-Cyclohexanediaminetetraacetic acid (CDTA); Trans(1,2)-Cyclohexanediethylenetriaminepentaacetic acid (CDTP A); 1-oxa-4,7,10-triazacyclododecane-N,N',N"-triacetic acid (OTTA); 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrakis{3-(4-carboxyl)-butanoic acid}; 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrakis(acetic acid-methylamide); 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid); and derivatives thereof.

[0028] In certain embodiments, the radiotherapy targeted agent is 225When labeled with Ac, the effective amount is less than 50 μCi / kg, 40 μCi / kg, 30 μCi / kg, 20 μCi / kg, 10 μCi / kg, 5 μCi / kg, 4 μCi / kg, 3 μCi / kg, 2 μCi / kg, 1 μCi / kg, or 0.5 μCi / kg. In certain embodiments, the effective amount is at least 0.05 μCi / kg, or 0.1 μCi / kg, 0.2 μCi / kg, 0.3 μCi / kg, 0.4 μCi / kg, 0.5 μCi / kg, 1 μCi / kg, 2 μCi / kg, 3 μCi / kg, 4 μCi / kg, 5 μCi / kg, 6 μCi / kg, 7 μCi / kg, 8 μCi / kg, 9 μCi / kg, 10 μCi / kg, 12 μCi / kg, 14 μCi / kg, 15 μCi / kg, 16 μCi / kg, 18 μCi / kg, 20 μCi / kg, 30 μCi / kg, or 40 μCi / kg. 225 The Ac-labeled targeted drug may be administered at a dose including any combination of the upper and lower limits described herein, such as at least 0.1 μCi / kg to 5 μCi / kg or less, or at least 5 μCi / kg to 20 μCi / kg or less.

[0029] In certain embodiments, the radiotherapy targeted agent is 225 Ac-labeled, the effective amount may be less than 2 mCi (i.e. 225 Ac is administered to the subject in a non-weight-based dose.) In certain embodiments, the effective amount can be less than 1 mCi, e.g., 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 μCi, 80 μCi, 70 μCi, 60 μCi, 50 μCi, 40 μCi, 30 μCi, 20 μCi, 10 μCi, or 5 μCi. An effective amount can be at least 2 μCi, e.g., at least 5 μCi, 10 μCi, 20 μCi, 30 μCi, 40 μCi, 50 μCi, 60 μCi, 70 μCi, 80 μCi, 90 μCi, 100 μCi, 200 μCi, 300 μCi, 400 μCi, 500 μCi, 600 μCi, 700 μCi, 800 μCi, 900 μCi, 1 mCi, 1.1 mCi, 1.2 mCi, 1.3 mCi, 1.4 mCi, or 1.5 mCi. 225The Ac-labeled CD33 targeted drug may be administered at a dose including any combination of the upper and lower limits described herein, such as at least 2 μCi to 1 mCi or less, or at least 2 μCi to 250 μCi or less, or 75 μCi to 400 μCi or less. In certain embodiments, 225 Ac-labeled radiotherapy targeted agents include single doses that deliver a dose of less than 12 Gy, or less than 8 Gy, or less than 6 Gy, or less than 4 Gy, or less than 2 Gy, e.g., 2 Gy to 8 Gy, primarily to targeted solid tumors.

[0030] In certain embodiments, the radiotherapy targeted agent is 177 Radiolabeled with Lu (" 177 Lu-labeled), and an effective amount can be, for example, less than 1 mCi / kg (i.e., 177 The amount of Lu-labeled targeted agent delivers a radiation dose of less than 1000 mCi per kilogram of subject body weight.) In certain embodiments, the effective amount is at least less than 900 μCi / kg, 800 μCi / kg, 700 μCi / kg, 600 μCi / kg, 500 μCi / kg, 400 μCi / kg, 300 μCi / kg, 200 μCi / kg, 150 μCi / kg, 100 μCi / kg, 80 μCi / kg, 60 μCi / kg, 50 μCi / kg, 40 μCi / kg, 30 μCi / kg, 20 μCi / kg, 10 μCi / kg, 5 μCi / kg, or 1 μCi / kg. In certain embodiments, the effective amount is at least 1 μCi / kg, 2.5 μCi / kg, 5 μCi / kg, 10 μCi / kg, 20 μCi / kg, 30 μCi / kg, 40 μCi / kg, 50 μCi / kg, 60 μCi / kg, 70 μCi / kg, 80 μCi / kg, 90 μCi / kg, 100 μCi / kg, 150 μCi / kg, 200 μCi / kg, 250 μCi / kg, 300 μCi / kg, 350 μCi / kg, 400 μCi / kg, or 450 μCi / kg. 177 The Lu-labeled targeted drug may be administered at a dose including any combination of the upper and lower limits described herein, such as at least 5 mCi / kg to no more than 50 μCi / kg, or at least 50 mCi / kg to no more than 500 μCi / kg.

[0031] In certain embodiments, the radiotherapy targeted agent is 177 When labeled with Lu, an effective amount is less than 45 mCi, e.g., 40 mCi, 30 mCi, 20 mCi, 10 mCi, 5 mCi, 3.0 mCi, 2.0 mCi, 1.0 mCi, 800 μCi, 600 μCi, 400 μCi, 200 μCi, 100 μCi, or 50 μCi. In certain embodiments, an effective amount can be at least 10 μCi, e.g., at least 25 μCi, 50 μCi, 100 μCi, 200 μCi, 300 μCi, 400 μCi, 500 μCi, 600 μCi, 700 μCi, 800 μCi, 900 μCi, 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 10 mCi, 15 mCi, 20 mCi, 25 mCi, 30 mCi. 177 The Lu-labeled targeted drug may be administered at a dose including any combination of the upper and lower limits described herein, such as at least 10 mCi to no more than 30 mCi, or at least 100 μCi to no more than 3 mCi, or at least 3 mCi to no more than 30 mCi.

[0032] In certain embodiments, the radiotherapy targeted agent is 131 Radiolabeled with I (" 131 I-labeled), and an effective amount can be, for example, less than 1200 mCi (i.e., less than 1000 mCi administered to a subject). 131(The dose of I is not weight-based dosing and delivers a total body radiation dose of less than 1200 mCi.) In certain embodiments, the effective amount can be less than 1100 mCi, less than 1000 mCi, less than 900 mCi, less than 800 mCi, less than 700 mCi, less than 600 mCi, less than 500 mCi, less than 400 mCi, less than 300 mCi, less than 200 mCi, less than 150 mCi, or less than 100 mCi. In certain aspects, an effective amount can be less than 200 mCi, e.g., less than 190 mCi, 180 mCi, 170 mCi, 160 mCi, 150 mCi, 140 mCi, 130 mCi, 120 mCi, 110 mCi, 100 mCi, 90 mCi, 80 mCi, 70 mCi, 60 mCi, or 50 mCi. In certain embodiments, an effective amount can be at least 1 mCi, e.g., at least 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, 20 mCi, 30 mCi, 40 mCi, 50 mCi, 60 mCi, 70 mCi, 80 mCi, 90 mCi, 100 mCi, 110 mCi, 120 mCi, 130 mCi, 140 mCi, 150 mCi, 160 mCi, 170 mCi, 180 mCi, 190 mCi, 200 mCi, 250 mCi, 300 mCi, 350 mCi, 400 mCi, 450 mCi, 500 mCi. 131 The I-labeled targeted drug may be administered at a dose including any combination of the upper and lower limits described herein, such as at least 1 mCi to no more than 100 mCi, or at least 10 mCi to no more than 200 mCi. Selected radionuclides have been disclosed in detail herein, and any of these disclosures herein are contemplated for labeling targeted agents (i.e., radiotherapy or radioimmunotherapy) that are part of the disclosed invention.

[0033] In certain aspects of the present disclosure, the majority of the radiotherapy targeting agents (antibodies, antibody fragments, peptides, small molecules, etc.) administered to the subject typically consist of unlabeled targeting agents, with a minority being labeled targeting agents. The ratio of labeled / unlabeled targeting agents can be adjusted using known methods. In certain aspects, the radiotherapy (e.g., radioimmunotherapy) comprises a labeled fraction and an unlabeled fraction, and the ratio of labeled:unlabeled can be about 0.01:10 to 1:1, e.g., 0.1:10 to 1:1 labeled:unlabeled. Furthermore, the radiotherapy agent can be provided as a single dose composition tailored to a particular patient, and the amount of labeled and unlabeled targeting agents in the composition can depend on at least the patient's weight, age, sex, diagnosis, and / or medical condition or health status, as described in detail in WO2016 / 187514.

[0034] The combination of the labeled and unlabeled fractions of the targeted agent of the radiotherapy agent of the present invention allows the composition to be tailored to a particular patient. For example, if the radiotherapy is radioimmunotherapy (i.e., the targeted agent is an antibody), the radiation dose and the protein dose of the antibody can each be individualized to the patient based on at least one specific parameter. Thus, each vial of composition can be made for a particular patient, and the entire contents of the vial are delivered to the patient in a single dose. If the treatment regimen requires multiple doses, each dose can be formulated as a patient-specific dose in a vial that is administered to the patient as a "single dose" (i.e., the entire contents of the vial administered at one time). Subsequent doses can be formulated in a similar manner, whereby each dose in the regimen provides a patient-specific dose in a single dose container. One advantage of the disclosed compositions is that there is no leftover radiation that would require disposal or disposal by medical personnel, e.g., no need for dilution or other manipulation to obtain a dose for the patient. When prepared in single-dose containers, the containers need only be placed side-by-side in the infusion tubing set for infusion into the patient. Furthermore, volumes can be standardized, greatly reducing the likelihood of medical error (i.e., reducing delivery of an inaccurate dose; since the entire volume of the composition is to be administered in one injection).

[0035] In certain aspects, where the radiotherapy targeted agent is an antibody, it may be provided in an amount of 5 mg to 45 mg of total protein, such as up to 100 mg, e.g., up to 60 mg, or in an amount of 0.01 mg / kg patient weight to 16.0 mg / kg patient weight, e.g., 0.01 mg / kg patient weight to 10.0 mg / kg, or 0.05 mg / kg patient weight to 5.0 mg / kg, or 0.01 mg / kg patient weight to 1.0 mg / kg, or 0.01 mg / kg patient weight to 0.6 mg / kg patient weight, or 0.01 mg / kg patient weight, 0.015 mg / kg patient weight, 0.02 mg / kg patient weight, or 0.04 mg / kg patient weight, or 0.06 mg / kg patient weight of total protein. In a particular embodiment, an effective amount of antibody in radioimmunotherapy is 10 mg / m 2 Less than about 6 mg / m 2 , or 3 mg / m 2 , or 2 mg / m 2 The amount of total protein may be

[0036] As used herein, the term "subject" includes mammals, such as, but not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, rats, and mice. When the subject is a human, the subject may be of any age. For example, the subject may be 60 years or older, or 65 years or older, or 70 years or older, or 75 years or older, or 80 years or older, or 85 years or older, or 90 years or older. Alternatively, the subject may be 50 years or younger, or 45 years or younger, or 40 years or younger, or 35 years or younger, or 30 years or younger, or 25 years or younger, or 20 years or younger. When the subject is suffering from cancer, the subject may, for example, be newly diagnosed, or recurrent, and / or refractory, or in remission.

[0037] As used herein, "treating" a subject with cancer is intended to include, but is not limited to, (i) slowing, halting, or reversing the progression of cancer, (ii) slowing, halting, or reversing the progression of symptoms of cancer, (iii) reducing the likelihood of cancer recurrence, and / or (iv) reducing the likelihood of symptoms of cancer recurrence. In certain preferred aspects, treating a subject with cancer means (i) reversing the progression of cancer, ideally to the point where cancer is eliminated, and / or (ii) reversing the progression of symptoms of cancer, ideally to the point where symptoms are eliminated, and / or (iii) reducing or eliminating the likelihood of recurrence (i.e., resulting in consolidation, ideally the destruction of remaining cancer cells). It is to be understood that where a target antigen associated with cancer is disclosed in the present disclosure, the invention also provides a method for treating a cancer, whether hematological or solid, that expresses or overexpresses said target antigen, comprising administering to a mammalian subject, such as a human patient in need of cancer treatment, a radiolabeled targeting agent that binds to said target antigen in combination or conjunction with administration to the subject of one or more CD47 blocking agents.

[0038] A "therapeutically effective amount" or "effective amount" refers to an amount effective at the required dosage and for the required period of time to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the therapeutic agent or combination of therapeutic agents to induce a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improvement of the patient's satisfactory condition, reduction in tumor burden, prevention or slowing of tumor growth, and / or absence of metastasis of cancer cells to other sites in the body. In certain embodiments, a "therapeutically effective amount" or "effective amount" refers to an amount of therapeutic agent, i.e., a radiotherapeutic agent or a CD47 blocking agent, which, when used together or separately, can deplete or reduce the overall number of cancer cells, such as reduction of specific blood cells (e.g., CD33 expressing cells), or DR5 expressing cells, or 5T4 expressing cells, HER2 or HER3 expressing cells, or TROP2 expressing cells, or inhibit tumor growth.

[0039] "Inhibiting proliferation" means a measurable reduction or delay in proliferation of malignant cells or tissues (e.g., tumors) in vitro or in vivo when contacted with a therapeutic agent or combination of therapeutic agents, compared to a reduction or delay in proliferation of the same cells or tissues in the absence of the therapeutic agent or combination of therapeutic agents. Inhibition of proliferation of malignant cells or tissues in vitro or in vivo can be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0040] Throughout this application, various patents, patent applications, and other publications are cited, the disclosures of which are incorporated by reference in their entireties into this application. Unless otherwise defined or clear from the presented context, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention described herein, suitable methods and materials are described below.

[0041] Aspects of the invention The present disclosure relates to methods for treating a mammalian subject, such as a human patient, with cancer by administration of a radiotherapeutic agent and a CD47 blocking agent. The radiotherapeutic agent may include a radiolabeled cancer targeting agent, such as a radiolabeled antibody that recognizes a cancer associated antigen, and the CD47 blocking agent may include an agent that prevents binding of CD47 to SIRPα, such as an anti-CD47 blocking antibody or affinity agent or an anti-SIRPα blocking antibody, or an agent that otherwise downregulates CD47-SIRPα axis activity. CD47 (originally named integrin-associated protein (IAP)) is a cell surface protein of the immunoglobulin (Ig) superfamily that is abundantly glycosylated and expressed by virtually all cells in the body. Normally, it binds to the integrin avb3 on most cell types except RBCs (which lack integrins) to provide a self-indicating "don't eat me signal" to macrophages / phagocytes. That is, cell surface CD47 interacts with its receptor on macrophages, SIRPα, and inhibits phagocytosis of normal, healthy cells. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. CD47 is also highly expressed on several human cancers, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), non-Hodgkin's lymphoma, and bladder cancer, as a means of avoiding phagocytosis by the innate immune system (Eladl, et al. (2020) Hematology & Oncology, 13:96).

[0042] There are as many as 30 CD47 blocking agents being developed for the treatment of both solid tumors and hematopoietic malignancies. Strategies to block the CD47-SIRPα axis include biologics that bind to or affect CD47 or SIRPα, many of which are currently in clinical trials. Examples include magrolimab, lemzoparimab, and AO-176. These molecules block the binding between CD47 and SIRPα, but they may be modified to include or remove Fc functions, e.g., IgG1 vs. IgG2 or IgG4, so that the mechanistic properties of these molecules may differ. For example, certain CD47 blocking antibodies also bind to CD47 expressed on red blood cells, and as a result, an associated adverse event in the clinic is anemia.

[0043] Antitumor responses have been observed in preclinical studies to anti-CD47 antibodies such as AO-176, but in human clinical trials, overall responses to single-agent anti-CD47 or anti-SIRPα have been modest. This is likely due to the need for a stimulatory phagocytic response, e.g., upregulation of eat me signals, in addition to don't eat me blockade to enable efficient tumor cell phagocytosis. Under normal physiological conditions, cellular homeostasis is regulated in part by the balancing of stimulatory and anti-phagocytic signals. For target cells to be phagocytosed upon CD47 blockade, the cells must also present strong stimulatory phagocytic signals, sufficient "eat me" signals, induced by surface-expressed calreticulin and phosphatidylserine. Thus, drugs targeting the CD47-SIRPα axis are likely to require therapeutic combinations to enable significant clinical responses. The present disclosure relates directly to compositions and methods for tipping the balance of cellular homeostasis toward pro-phagocyte signals, such as for certain cell types involved in cancer and hematopoietic malignancies. To this end, the present disclosure relates to blockers of CD47 interaction with SIRPα (on phagocytes), which disrupt or downregulate "don't eat me" signals, in combination with radiotherapeutic agents that enhance "eat me" signals. As an example, the anti-CD47 antibody magrolimab has recently shown significant clinical responses in high-risk, previously untreated patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). The requirement for upregulation of eat me signals appears essential to enable these responses. Irradiation is an ideal combination therapy for agents that block the CD47 pathway due to its ability to induce both innate and adaptive immune responses (de la Cruz-Merino, et al. (2014) Frontiers in Immunology, vol 5, article 102; Vermeer, et al. (2012) International Journal of Cancer, 133:120).

[0044] The radiobiological response results in the activation of different cell lines and generates a "switch-on" of the adaptive immune response. The radiobiological model considers that DNA damage after irradiation induces different types of biological responses, either as a result of direct damage of tumor cells or indirectly due to the induction of free radicals. After irradiation, most cells survive for a limited time, during which they produce molecular signals (damage-associated molecular patterns (DAMPs)) that induce the overexpression of specific genes that control the expression of growth factors, cytokines, chemokines, and cell surface receptors, activating the inflammatory response of both the innate and adaptive immune systems.

[0045] Radiation has been delivered to cells via IR and to human patients via targeted external beam radiation. It has been shown to enhance the release of cancer-specific peptides from damaged cancer cells, promote antigen uptake and presentation by dendritic cells, reduce CD47 and increase calreticulin, and upregulate MHC-I expression on tumor cells, enhancing cancer cell recognition by T cells. Furthermore, radiation-induced DNA damage activates the cGAS-STING pathway to activate IFN gene transcription. However, this approach is not an option for patients with hematological or blood cancers, because these diseases are disseminated and total body irradiation with external beam radiation would expose normal tissues and organs to radiation and risk significant toxicity. In contrast, targeted irradiation with antibody-radioconjugates (ARC) or other radiotherapeutic agents directed at selective tumor antigens or selectively targeted cancer cells allows for efficient delivery of radiation efficacy to tumor cells by targeted agents. Such combinations result in in vivo tumor elimination in targeted cells without significant effects on most normal cells. Exemplary radiotherapeutic agents of the present disclosure include antibody-radioconjugates (ARC) against CD33, DR5, 5T4, HER2, HER3, and / or TROP2. Exemplary ARCs include the powerful alpha particle emitting radioisotope Actinium 225 ( 225 For example, the radiotherapeutic agent may be any of anti-CD33, DR5, 5T4, HER2, HER3 and / or TROP2 antibodies labeled with Actinium-225 (Ac). 225 With Ac lintuzumab, radiation is delivered directly to CD33 positive cells and used as a therapeutic agent against heme malignancies such as AML, MDS, and multiple myeloma. By delivering radiation directly to tumor cells, ARC has the potential to provide the powerful radiobiological effects of external beam radiation therapy in a manner that is safe for administration to patients, particularly those with disseminated disease. As a result, exposure of tumor cells to the ARC of the present invention upregulates "eat me" signals such as calreticulin and downregulates CD47 on the surface of cancer cells. Thus, the combined use of ARC and a CD47-SIRPα blocking agent is an object of the present invention, enhancing the stimulatory phagocytic response to the CD47-SIRPα blocking agent as a result of the radioimmunobiological effect of the targeted radionuclide warhead.

[0046] Moreover, because targeted ARC irradiation itself can confer a direct antitumor effect as well as further stimulate an adaptive immune response, the combination of these two types of agents provides a synergistic therapeutic agent that improves both the treatment outcome and the durability of the response. 225 Aclintuzumab has shown evidence of clinical activity and tolerability in human trials in relapsed / refractory AML and has shown promising responses in early combination studies with standard therapies. Several anti-CD47 blocking agents are currently being tested in myeloid diseases, such as AML and MDS, as single agents and in combination with chemotherapy and targeted therapies. 225 The combination of Aclintuzumab with CD47 blockade offers a potent and potentially well-tolerated treatment strategy in these diseases. This approach can also be extended to other tumor types, including solid tumors and other hematological cancers.

[0047] CD33-targeted radiotherapy Overexpression of CD33 is commonly found in hematopoietic malignancies, including AML, CML, and MDS. In AML, 85-90% of patients express CD33, which has led to the development of targeted therapy drugs such as gemtuzumab-ozogamicin (Mylotarg™). Approximately 96% of MDS patients express CD33 on their bone marrow blasts (Sanford et al. (2016) Leukemia & Lymphoma, vol. 57(8): 1965-1968). In another study, MDS patients showed approximately twice as many CD33 molecules per bone marrow cell as control samples (Jilani, et al. (200) Am J Clin Pathol vol. 118: 560-566). The CD33 antigen is expressed in virtually all cases of CML. Furthermore, patients older than 60 years of age show poor prognosis, with only 10%-15% of AML patients experiencing a 4-year disease-free survival. The high relapse rate and poor prognosis of elderly AML patients are due to CD33 + This clearly highlights the urgent need for novel therapeutic agents that selectively target cells. Thus, the methods disclosed herein may include administration of a radioimmunotherapeutic agent against CD33 in combination with a CD47 blocking agent. Such methods may be used to treat proliferative disorders such as solid cancers and / or hematological diseases or disorders (e.g., hematological cancers) and / or may be used to inhibit the growth and / or proliferation of cells expressing CD33 and / or may be used to treat diseases or disorders involving cells expressing or overexpressing CD33. Additionally, the methods may be used to treat hematological diseases or disorders that are multiple myeloma, acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, chronic myelogenous leukemia (CML), or relapsed / refractory (relapsed and / or refractory) versions of any of the foregoing.

[0048] Radiolabeled CD33 targeted drugs may also be used to deplete CD33-expressing myeloid-derived suppressor cells (MDSCs) found in solid tumors or in hematological cancers such as leukemia and lymphoma, which function as immune suppressors during the treatment of such disorders. Thus, in one aspect of the invention, a radiolabeled CD33 targeted drug, such as one or more radiolabeled anti-CD33 monoclonal antibodies, or 225 Aclintuzumab etc. 225A radiolabeled CD33-binding antibody fragment, such as an Ac-labeled anti-CD33 antibody, may be administered to a mammalian subject, such as a human subject, in need of treatment for a hematological cancer or proliferative disorder or a solid tumor, such as a solid tumor infiltrated by or subject to infiltration by MDSC, in combination with or simultaneously with administration of one or more CD47 blocking agents to the subject. Suitable CD33 targeting agents for radiotargeting and use include, for example, lintuzumab, gemtuzumab, vadastuximab, antibodies having the heavy and light chain CDRs of the aforementioned monoclonal antibodies, and CD33-binding fragments of any of the aforementioned monoclonal antibodies. The solid tumor can be, for example, a sarcoma, osteosarcoma, fibrosarcoma, pancreatic cancer, breast cancer, tamoxifen-resistant breast cancer, TNBC, hepatocellular carcinoma, melanoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), Lewis lung carcinoma, solid Ehrlich carcinoma, endometrial carcinoma, glioma, glioblastoma, mesothelioma, carcinoma, colon cancer, colorectal carcinoma, oral cancer, renal cancer, ovarian cancer, or a solid tumor cancer disclosed herein. CD33 is a 67 kd type I transmembrane receptor glycoprotein that can function as a sialic acid-dependent cell adhesion molecule. CD33 has a long N-terminal extracellular domain, a helical transmembrane domain, and a short C-terminal cytoplasmic domain. CD33 is expressed on early myeloid progenitor myeloid leukemic (e.g., acute myeloid leukemia) cells, but not on stem cells. Amino acid residues 1-259 of the CD33 protein are the extracellular domain, amino acids 260-282 are the helical transmembrane domain, and amino acids 283-364 are the cytoplasmic domain (intracellular). There are at least three known single nucleotide polymorphisms ("SNPs") in the extracellular domain of CD33 (i.e., W22R, R69G, S128N).

[0049] Antibodies against CD33, such as lintuzumab (HuM195), gemtuzumab, and vadastuximab, have been and are currently being evaluated in the clinic for their efficacy in treating hematopoietic malignancies and plasma cell disorders, including acute myeloid leukemia (AML). Each antibody has been shown to bind to a different portion of the extracellular domain of CD33, and each has been shown to show different clinical responses (e.g., antitumor effects). Gemtuzumab is available from Pfizer as the ADC Mylotarg™, and vadastuximab is available from Seattle Genetics as the ADC vadastuximab butarilin. Studies with unconjugated M195 derived from mice immunized with live human leukemic myeloblasts showed a transient reduction in peripheral blast counts in human patients when administered at saturating or supersaturating doses. The humanized antibody HuM195 was constructed by grafting the complementarity determining regions of M195 onto a human IgG1 framework and backbone. HuM195 demonstrated eight-fold higher avidity than M195 and, unlike M195, also demonstrated antibody-dependent cellular cytotoxicity (ADCC). Still, limited studies have shown some indication of activity in acute promyelocytic leukemia (APL) when used in patients with minimal residual disease, but HuM195 has only very little activity as a single agent in AML, even at supersaturating doses that completely block the CD33 binding site, for example, over a four-week period, with few achievements of complete or partial remissions restricted to patients with low tumor burden. Efficacy is probably increased when supersaturating doses are given repeatedly, as suggested by a small study in which very high doses of lintuzumab were given weekly for 5 weeks, followed by biweekly dosing for patients with clinical benefit.

[0050] While these currently available anti-CD33 antibodies eliminate CD33 positive cells by antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis in their unlabeled state, the presently disclosed invention provides for the use of such antibodies (ARC) that contain a radiolabel. Thus, the concentration required to induce a radiobiological effect on the target cells is much lower, as disclosed herein. Thus, the negative side effects associated with the high concentrations of unlabeled antibodies of the prior art methods are reduced or eliminated. Furthermore, when the anti-CD33 antibody is radiolabeled with an alpha-emitting radionuclide, such as Actinium-225, the radiobiological effect is highly targeted. 225 Ac loading delivers high-energy alpha particles directly to tumor sites or CD33-expressing cells, causing lethal double-stranded DNA breaks without the need for large accumulations of loading in tumor cells, providing therapeutic benefit even to tumors with low target antigen expression. Due to its short path length, the range of high-energy alpha particle emission is only a few cell diameters thick, thereby limiting damage to nearby normal tissues. The preparation of lintuzumab tetraxetane Ac225 has been reported, for example, in U.S. Pat. No. 9,603,954.

[0051] DR5-targeted radiotherapy Humans express two functional death receptors (DR4 and DR5), also known as tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2 (TRAIL-R1 and -R2), which are upregulated on the cell surface as part of an immune surveillance mechanism to alert the immune system to the presence of virally infected or transformed cells. TRAIL, the ligand that binds to the death receptors, is expressed on immune cells such as T cells and NK cells, and upon binding to DR4 or DR5, TRAIL trimerizes the death receptors and induces an apoptotic cascade that is independent of p53 (Naoum, et el. (2017) Oncol. Rev. 11, 332). DR4 and DR5 can be found expressed at low levels in some normal tissues (Spierings, et al. (2004) J. Histochem. Cytochem., 52, 821-31), while they are upregulated on the surface of many tumor tissues, including kidney, lung, acute myeloid leukemia (AML), cervical, and breast cancer. After the death receptors were identified as promising therapeutic targets, many DR4 and DR5-targeting antibodies and recombinant TRAIL (rTRAIL) proteins were developed, including mapatumumab, conatumumab, lexatumumab, tigatuzumab, drozitumab, and LBY-135. Tigatuzumab was evaluated in a phase 2 clinical trial with patients with triple-negative breast cancer (TNBC), confirming DR5 expression in both primary and metastatic tumor samples, indicating that DR5 is a suitable target for directing therapeutic intervention in this cancer type and metastatic disease (Forero-Torres, et al. (2015) Clin. Cancer Res., 21, 2722-9). In targeted treatment regimens for solid tumors such as breast cancer, radiation is usually only used to treat the site of the primary tumor after surgical resection and only palliatively for metastases.An additional or alternative approach to achieve targeted delivery of radiation to both primary and metastatic tumors and spare normal tissues from radiation toxicity is by using the radiotherapeutic agents disclosed herein that target the tumor-associated antigen DR5. Thus, radiotherapeutic agents that may be used include at least antibodies, peptides, and / or small molecules that target DR5. Exemplary radiotherapies include DR5-targeted ARCs, such as radiolabeled monoclonal antibodies against DR5 (e.g., 225 Exemplary antibodies against DR5 include at least tigatuzumab (CD-1008) by Daiichi Sankyo, conatumumab (AMG655) by Amgen, mapatumumab by AstraZeneca, lexatumumab (also known as ETR2-ST01), LBY-135 by Creative Biolabs (Shirley, NY, USA), and doroditumab by Genentech. Testing in mice may use the surrogate mouse antibodies TRA-8 or MD5-1.

[0052] 5T4-targeted radiotherapy Trophoblast glycoprotein (TBPG), also known as 5T4, is a glycoprotein classified as a carcinoembryonic antigen, which is expressed on cells during fetal development but not in adult tissues, except on tumors (Southall, PJ et al. (1990) Br. J. Cancer 61, 89-95). 5T4 is widely expressed across many different tumor types, including lung, breast, head and neck, colorectal, bladder, ovarian, pancreatic, and many others (Stern, PL & Harrop, R. (2017) Cancer Immunol. Immunother. 66, 415-426). Favorable properties of 5T4 for targeting with radiolabeled targeting agents include its high internalization rate, expression on the tumor periphery, and expression on cancer stem cells. Due to 5T4 expression, several attempts have been made to develop therapeutics against tumors, including antibodies, vaccines, and cellular therapies. Although unlabeled 5T4-targeting antibodies are not effective therapeutics (Boghaert, et al. (2008) Int. J. Oncol. 32, 221-234), armed antibodies such as antibody-drug conjugates (ADCs) with toxins have been developed and tested preclinically. Only one auristatin-based ADC developed by Pfizer has been clinically tested, with no objective responses reported and toxicity associated with auristatin conjugates observed (Shapiro, GI et al. (2017) Invest. New Drugs 35, 315-323). Thus, the radiotherapeutic agents of the present disclosure include at least an antibody, peptide, and / or small molecule that targets 5T4. Exemplary radiotherapies include 5T4-targeted ARCs, such as radiolabeled monoclonal antibodies against 5T4 (e.g., 225 Exemplary antibodies against 5T4 include at least MED10641, developed by Mediimmune / AstraZeneca; ALG.APV-527, developed by Aptevo Therapeutics / Alligator Bioscience; Tb535, developed by Biotecnol / Chiome Bioscience; H6-DM5, developed by Guangdong Zhongsheng Pharmaceuticals; and ZV0508, developed by Zova Biotherapeutics.

[0053] HER3-targeted radiation therapy Human epidermal growth factor receptor 3 (ErbB3, also known as HER3) is a receptor protein tyrosine kinase that belongs to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases. The transmembrane receptor HER3 consists of an extracellular ligand-binding domain with a dimerization domain therein, an intracellular protein tyrosine kinase-like domain, and a C-terminal phosphorylation domain. Unlike other HER family members, the kinase domain of HER3 displays very low intrinsic kinase activity. The ligands Neuregulin 1 or Neuregulin 2 bind to the extracellular domain of HER3 and promote dimerization with other dimerization partners such as HER2, thereby activating the receptor-mediated signaling pathway. Heterodimerization leads to activation and transphosphorylation of the intracellular domain of HER3, and is a means not only for signal diversification but also for signal amplification. In addition, HER3 heterodimerization can occur in the absence of activating ligands, which is generally referred to as ligand-independent HER3 activation. For example, when HER2 is expressed at high levels as a result of gene amplification (e.g., in breast, lung, ovarian or gastric cancer), spontaneous HER2 / HER3 dimers can form. In this situation, HER2 / HER3 is considered the most active ErbB signaling dimer and is highly transforming. Increased HER3 has been found in several types of cancer, including breast, lung, gastrointestinal and pancreatic cancer. Interestingly, a correlation has been shown between HER2 / HER3 expression and progression from non-invasive to invasive stages (Alimandi et al. (1995) Oncogene 10:1813-1821; DeFazio et al. (2000) Cancer 87:487-498). Thus, the radiotherapeutic agents of the present disclosure include at least an antibody, peptide, and / or small molecule that targets HER3. Exemplary radiotherapies include HER3-targeted ARC, such as a radiolabeled monoclonal antibody against HER3 (e.g., 225 Exemplary antibodies against HER3 include the monoclonal antibodies patritumab, seribantumab, lumuletuzumab, elgemtumab, US-1402, AV-203, CDX-3379, and GSK2849330, the bispecific antibodies MM-111, MM-141 / istiratumab, MCLA-128, and MEHD7945A / durigotumab, and other anti-HER3 antibodies disclosed herein. Exemplary anti-HER3 antibodies (also referred to herein as "HER3 antibodies"), e.g., anti-human HER3 antibodies that may be radiolabeled and implemented and / or used in various aspects of the disclosed invention, include, but are not limited to, antibodies and antibodies, such as, for example, for example, immunoglobulins, such as, for example, for example, IgG, that (i) contain a heavy chain variable region of a HER3 antibody or heavy chain, (ii) contain one, two or three of the heavy chain CDRs (e.g., according to the Kabat definition) of a HER3 antibody or heavy chain or enumerated, (iii) contain a light chain variable region of a HER3 antibody or light chain, and / or (iv) contain one, two or three of the light chain CDRs (e.g., according to the Kabat definition) of a HER3 antibody or light chain or enumerated. It should also be understood that where a HER3 antibody heavy chain or a HER3 antibody light chain that includes an N-terminal leader sequence is disclosed, the corresponding heavy chain and the corresponding light chain lacking the leader sequence are also intended to be disclosed for implementation and use in various aspects of the invention.

[0054] Exemplary HER3 antibodies that may be radiolabeled and practiced and / or used in the disclosed invention may include, for example, a mouse monoclonal antibody against HER3 comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 or 11 and / or a light chain having the amino acid sequence set forth in SEQ ID NO: 10 or 12, or an antibody such as a humanized antibody derived from one or more of said sequences. Exemplary HER3 antibodies that may be radiolabeled and practiced and / or used in the disclosed invention may include a heavy chain having an N-terminal region having the sequence set forth in SEQ ID NO: 13 and / or a light chain having an N-terminal region having the sequence set forth in SEQ ID NO: 14. Similarly, HER3 antibodies that may be practiced or used in various aspects of the invention may include, for example, a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7, and / or a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; and / or a heavy chain comprising one or more of CDR1, CDR2 and CDR3 having the amino acid sequences set forth in SEQ ID NO: 1-3, respectively, and / or a light chain comprising one or more of CDR1, CDR2 and CDR3 having the amino acid sequences set forth in SEQ ID NO: 4-6, respectively. HER3 antibodies implemented and / or used in any aspect of the invention may include, for example, any combination of the light chain and / or heavy chain sequences described above.

[0055] An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 15, CDR-H2 comprising SEQ ID NO: 16, and CDR-H3 comprising SEQ ID NO: 17, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 18, CDR-L2 comprising SEQ ID NO: 19, and CDR-L3 comprising SEQ ID NO: 20. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO: 21 and / or an immunoglobulin light chain variable region comprising SEQ ID NO: 22. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO: 23 and / or an immunoglobulin light chain amino acid sequence of SEQ ID NO:24. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO:25, CDR-H2 comprising SEQ ID NO:26, and CDR-H3 comprising SEQ ID NO:27, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO:28, CDR-L2 comprising SEQ ID NO:29, and CDR-L3 comprising SEQ ID NO:30. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:31 and / or an immunoglobulin light chain variable region comprising SEQ ID NO:32. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:33 and / or an immunoglobulin light chain amino acid sequence of SEQ ID NO:34. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 35, CDR-H2 comprising SEQ ID NO: 36, and CDR-H3 comprising SEQ ID NO: 37, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 38, CDR-L2 comprising SEQ ID NO: 39, and CDR-L3 comprising SEQ ID NO: 40. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO: 41 and / or an immunoglobulin light chain variable region comprising SEQ ID NO: 42. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO: 43 and an immunoglobulin light chain amino acid sequence of SEQ ID NO: 44. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 45, CDR-H2 comprising SEQ ID NO: 46, and CDR-H3 comprising SEQ ID NO: 47, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 48, CDR-L2 comprising SEQ ID NO: 29, and CDR-L3 comprising SEQ ID NO: 49. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO: 50 and / or an immunoglobulin light chain variable region comprising SEQ ID NO: 51. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO: 52 and / or an immunoglobulin light chain amino acid sequence of SEQ ID NO: 53. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO:54, CDR-H2 comprising SEQ ID NO:55, and CDR-H3 comprising SEQ ID NO:56, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO:28, CDR-L2 comprising SEQ ID NO:29, and CDR-L3 comprising SEQ ID NO:30. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:57 and / or an immunoglobulin light chain variable region comprising SEQ ID NO:58. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:59 and / or an immunoglobulin light chain amino acid sequence of SEQ ID NO:60. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO:61, CDR-H2 comprising SEQ ID NO:62, and CDR-H3 comprising SEQ ID NO:63, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO:64, CDR-L2 comprising SEQ ID NO:65, and CDR-L3 comprising SEQ ID NO:66. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:67 and / or an immunoglobulin light chain variable region comprising SEQ ID NO:68. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:69 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:70. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO:71, CDR-H2 comprising SEQ ID NO:72, and CDR-H3 comprising SEQ ID NO:66, and / or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO:28, CDR-L2 comprising SEQ ID NO:29, and CDR-L3 comprising SEQ ID NO:30. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:73 and / or an immunoglobulin light chain variable region comprising SEQ ID NO:74. An exemplary HER3 antibody comprises an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:75 and / or an immunoglobulin light chain amino acid sequence of SEQ ID NO:76. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:77 and / or the immunoglobulin light chain amino acid sequence of SEQ ID NO:78. Exemplary HER3 antibodies comprise an immunoglobulin light chain variable region comprising SEQ ID NO: 86, 87, 88, 89, 90 or 91 and / or a heavy chain variable region comprising SEQ ID NO: 79, 80, 81, 82, 83, 84 or 85. Exemplary HER3 antibodies comprise an immunoglobulin heavy chain sequence comprising SEQ ID NO: 92, 94, 95, 98 or 99 and / or an immunoglobulin light chain sequence comprising SEQ ID NO: 93, 96, 97, 100 or 101. Exemplary HER3 antibodies also include Barecetamab (ISU104) by Isu Abxis Co and any of the HER3 antibodies disclosed in U.S. Pat. No. 10,413,607. Exemplary HER3 antibodies also include HMBD-001 (10D1F) by Hummingbird Bioscience Pte. and any of the HER3 antibodies disclosed in International Publication Nos. WO2019185164, and WO2019185878, U.S. Patent No. 10,662,241; and U.S. Patent Application Publication Nos. 20190300624, 20210024651, and 20200308275. Exemplary HER3 antibodies also include the HER2 / HER3 bispecific antibody MCLA-128 by Merus NV (i.e., xenoctuzumab); and any of the HER3 antibodies, whether monospecific or multispecific, disclosed in U.S. Patent Application Publication Nos. 20210206875, 20210155698, 20200102393, 20170058035, and 20170037145. Exemplary HER3 antibodies also include the HER3 antibody patritumab (U3-1287), an antibody comprising the reported heavy chain sequence SEQ ID NO:106 and / or light chain sequence SEQ ID NO:7 of patritumab, and any of the HER3 antibodies disclosed in U.S. Patritumab, U.S. Pat. Nos. 9,249,230 and 7,705,130 and WO2007077028. Exemplary HER3 antibodies also include the HER3 antibody MM-121, and any of the HER3 antibodies disclosed in U.S. Patent No. 7,846,440 and International Publication No. WO2008100624. Exemplary HER3 antibodies also include the EGFR / HER3 bispecific antibody DL1, and any of the HER3 antibodies, whether monospecific or multispecific, disclosed in U.S. Patent Nos. 9,327,035 and 8,597,652, U.S. Patent Publication No. 20140193414, and International Publication No. WO2010108127. Exemplary HER3 antibodies also include the HER2 / HER3 bispecific antibody MM-111, and any of the HER3 antibodies, whether monospecific or multispecific, disclosed in U.S. Patent Publication Nos. 20130183311 and 20090246206, and International Publication Nos. WO2006091209 and WO2005117973.

[0056] In certain embodiments, HER3 targeted agents include anti-HER3 antibodies that bind to the epitope of HER3 recognized by patritumab by Daiichi Sankyo, seribantumab (MM-121) by Merrimack Pharmaceuticals, lumletuzumab by Roche, elgemtumab by Novartis, GSK2849330 by GlaxoSmithKline, CDX-3379 by Celldex Therapeutics, EV20 and MP-RM-1 by MediPharma, varsetamab (ISU104) by Isu Abxis Co., HMBD-001 (10D1F) by Hummingbird Bioscience Pte., REGN1400 by Regeneron Pharmaceuticals, and / or AV-203 by AVEO Oncology. In certain embodiments, the anti-HER3 antibody is selected from one or more of patritumab, seribantumab or an antibody comprising the reported heavy chain sequence SEQ ID NO: 108 and / or light chain sequence SEQ ID NO: 109 for seribantumab, lumuletuzumab or an antibody comprising the reported heavy chain sequence SEQ ID NO: 110 and / or light chain sequence SEQ ID NO: 111 for lumuletuzumab, elgemtumab or an antibody comprising the reported heavy chain sequence SEQ ID NO: 112 and / or light chain sequence SEQ ID NO: 113 for elgemtumab, AV-203, CDX-3379, GSK2849330, EV20, MP-RM-1, ISU104, HMBD-001 (10D1F), and REGN1400. Exemplary antibodies along with exemplary therapeutic indications are set forth in Table 2. [Table 2]

[0057] The sequences and structures of human HER3, human HER2, and human EGFR (HER1) are all known. The sequence of human HER3 precursor protein (receptor tyrosine protein kinase erbB-3 isoform 1 precursor NCBI reference sequence: NP_001973.2) is provided herein as SEQ ID NO: 115. Those skilled in the art will readily appreciate that, given the known target protein amino acid sequence, various types of suitable antibodies and antibody mimetics specific for the extracellular domain of HER3, such as human HER3, for use in the various aspects of the present invention, can be produced using immunization and / or panning and / or antibody design techniques that are well established in the art. HER3 targeted agents that are radiolabeled for use in various embodiments of the present invention may include HER3 binding peptides, such as chelator-containing HER3 binding peptides, such as DOTA-containing HER3 binding peptides, such as any of those described in U.S. Patent Application Publication No. 20200121814.

[0058] TROP2-targeted radiotherapy Tumor-associated calcium signal transduction 2, also known as Trop2 and epithelial glycoprotein-1 antigen (EGP-1), is a protein encoded by the human TACSTD2 gene that is overexpressed in carcinomas. Overexpression of TROP2 is associated with poor survival in human solid tumor patients. Cancers that may be targeted with TROP2 targeting agents and treated with radiolabeled TROP2 targeting agents according to the present invention include, but are not limited to, carcinoma, squamous cell carcinoma, adenocarcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, triple negative breast cancer (TNBC), prostate cancer, hormone refractory prostate cancer, pancreatic ductal adenocarcinoma, head and neck cancer, renal cell carcinoma, bladder tumor, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and glioblastoma multiforme. Exemplary TROP2-targeting drugs that may be radiolabeled and used with one or more CD47 blocking agents in the treatment of proliferative disorders include the monoclonal antibodies sacituzumab and datopotamab, antibodies having one or both of the heavy and light chains of said antibodies, and antibodies having one or both of the heavy and light chain CDRs of said antibodies, or TROP2-binding fragments of any of the above-mentioned antibodies. Sacituzumab biosimilars are commercially available from BioVision Incorporated (an Abcam company, Waltham, MA, USA) under catalog number A2175. Datopotamab biosimilars are commercially available from ProteoGenix (Schiltigheim, France) under catalog number PX-TA1653. Exemplary TROP2 targeted agents that may be radiolabeled and used in conjunction with one or more CD47 blocking agents in the treatment of proliferative disorders include monoclonal antibodies having a heavy chain SEQ ID NO: 135 and / or a light chain SEQ ID NO: 140 (reported as the heavy and light chains of sacituzumab), or antibodies comprising either or both of the heavy chain variable region (SEQ ID NO: 136) or the light chain variable region (SEQ ID NO: 141) of said chains, or antibodies comprising one, two, or three of the heavy chain CDRs of said heavy chain (CDR H1-3: SEQ ID NOs: 137-139, respectively) and / or one, two, or three of the light chain CDRs of said light chain (CDR H1-3: SEQ ID NOs: 137-139, respectively). L1 to L3: antibodies comprising SEQ ID NOs: 142 to 144, respectively, and anti-human TROP antibodies disclosed in U.S. Pat. Nos. 7,238,785 (hRS7), 9,492,566, 10,195,517, or 11,116,846, or antibodies comprising one or both of the heavy and light chain variable regions of the above antibodies, or antibodies comprising a heavy chain comprising one, two, or three of the heavy chain CDRs of any of the above antibodies and / or a light chain comprising one, two, or three of the light chain CDRs of any of the above antibodies. Further exemplary TROP2 targeted agents that may be radiolabeled and used in conjunction with one or more CD47 blocking agents in the treatment of a proliferative disorder include monoclonal antibodies comprising the heavy chain SEQ ID NO: 145 and / or the light chain SEQ ID NO: 150 (reported to be the heavy and light chains of datopotamab), or an antibody comprising one or both of the variable regions of said heavy chain (SEQ ID NO: 146) and said light chain (SEQ ID NO: 151), or one, two or three of the heavy chain CDRs of said heavy chain (CDRs 1-3: SEQ ID NOs: 147-149, respectively) and / or one, two or three of the light chain CDRs of said light chain (CDRs H1 to H3: antibodies comprising SEQ ID NOs: 152 to 154, respectively, and the anti-human TROP antibodies disclosed in International Publication No. WO2015098099 or U.S. Patent Application Publication No. 20210238303, or antibodies comprising one or both of the heavy and light chain variable regions of the above antibodies, or antibodies comprising a heavy chain comprising one, two, or three of the heavy chain CDRs of any of the above antibodies and / or a light chain comprising one, two, or three of the light chain CDRs of any of the above antibodies.

[0059] MUC1-targeted radiotherapy Exemplary MUC1-targeting agents that may be radiolabeled and used in combination or with one or more CD47 blocking agents, such as any of those disclosed herein, for the treatment of proliferative disorders, such as MUC1-expressing cancers, include hTAB004 (OncoTAb, Inc.) and any of the anti-MUC1 antibodies disclosed in U.S. Patent Application Publication No. 20200061216 and any of U.S. Patent Nos. 8,518,405; 9,090,698; 9,217,038; 9,546,217; 10,017,580; 10,507,251; 10,517,966; 10,919,973; 11,136,410; and 11,161,911. Exemplary radiolabeled MUC1 targeted agents that may be combined or used in conjunction with one or more CD47 blocking agents according to the present invention include: 90 Y IMMU-107 (hPAM4-Cide; Immunomedics, Inc.; Gilead Sciences, Inc.), or 177Lu or 225 The radiolabeled MUC1 targeted drugs may be used to treat MUC1-overexpressing cancers, such as pancreatic cancer, locally advanced or metastatic pancreatic cancer and MUC1-overexpressing solid tumors, such as metastatic breast cancer, tamoxifen-resistant breast cancer, HER2-negative breast cancer, and breast cancer, such as triple-negative breast cancer (TNBC).

[0060] LYPD3 (C4.4A) targeted radiotherapy Exemplary LYPD3 (C4.4A) targeted agents that may be radiolabeled for use in combination or with one or more CD47 blocking agents according to the invention include, for example, the auristatin-based anti-C4.4A (LYPD3) ADC BAY1129980 (also known as Lupartumab amadotin; Bayer AG, Germany) or its antibody component Rupatumab, IgG1 mAb GT-002 (Glycotope GmbH, Germany), and those disclosed in U.S. Patent Publication 2005 / 0236366. GmbH, Germany), and any of those disclosed in U.S. Patent Application Publication Nos. 20210309711, 20210238292, 20210164985, 20180031566, 20170158775, or 20150030618, 20120321619, Canadian Patent Application Publication No. CA3124332A1, Taiwanese Patent Application Publication No. TW202202521A, or International Publication No. WO2021260208, WO2007044756, WO2022042690, or WO2020138489. Such use may be, for example, for the treatment of a mammalian LYPD3-expressing hematological or solid tumor cancer, such as carcinoma, primary and metastatic transitional cell carcinoma (TCC), adenocarcinoma, lung cancer, lung adenocarcinoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), breast cancer, endocrine therapy resistant breast cancer (e.g., tamoxifen resistant breast cancer), HER2 positive breast cancer, triple negative breast cancer (TNBC), esophageal cancer, renal cell carcinoma, colorectal cancer, cervical cancer, head and neck cancer, urothelial carcinoma, skin cancer, melanoma, and acute myeloid leukemia (AML).

[0061] In the present disclosure, whenever a specific antibody, specific antibody heavy chain and specific antibody light chain against CD33, 5T4, DR5, HER2, HER3, TROP2 or against any target is disclosed, what is intended to be disclosed for embodiments of the present invention or for use in various aspects is an antibody, e.g., as a non-limiting example, an immunoglobulin, e.g., as a non-limiting example, an IgG, that (i) comprises a heavy chain variable region of a disclosed antibody or heavy chain, (ii) comprises one, two or three heavy chain CDRs (e.g., according to the Kabat definition) of a disclosed antibody or heavy chain, (iii) comprises a light chain variable region of a disclosed antibody or light chain, and / or (iv) comprises one, two or three light chain CDRs (e.g., according to the Kabat definition) of a disclosed antibody or light chain. In the present disclosure, whenever an antibody heavy chain or antibody light chain that comprises an N-terminal leader sequence is disclosed, what is also intended to be disclosed for embodiments and for use in various aspects of the present invention is the corresponding heavy chain and the corresponding light chain that lacks the leader sequence.

[0062] PSMA-targeted radiation therapy In one aspect of the invention, a radiolabeled targeted agent for use in combination or with one or more CD47 blocking agents is, for example: 177 Lu or 225 A radiolabeled anti-PSMA monoclonal antibody, such as J591 labeled with Ac, or e.g. 177 Lu or 225 Radiolabeled PSMA-targeted drugs, such as Ac-labeled Rosopatamab, or, for example, 177 Lu or 225 Ac-labeled PSMA-617, e.g. 177 Lu or 225 Ac-labeled PSMA I&T, e.g. 177 Lu-labeled FrhPSMA-7, 64 / 67Cu-SAR-bisPSMA (Clarity Pharmaceuticals), e.g. 225 CONV 01-α (Convergent Therapeutics, Inc.) labeled with Ac; 177 Lu-PSMA I&T-β+ 225Ac-CONV01-α combination (Convergent Therapeutics, Inc.), 131 I-1095 (Lantheus Holdings / Progenics Pharmaceuticals, Inc.), 131 I PSMA-PK-Rx (Noria Therapeutics, Inc.; Bayer), or, for example, 177 Lu-labeled PSMA-R2, e.g. 177 Lu-labeled CTT1403 (Cancer Targeted Technology LLC), PNT2002 / Lu-177-PSMA-I&T (Point Biopharma Global Inc.), PNT2002 / Lu-177-PSMA-I&T+ 225 Ac-J591, TLX591 ( 177 Lu-losopatamab; Telix Pharmaceuticals Ltd.), TLX-591-CHO (Telix Pharmaceuticals Ltd.), and 177 The agent may be a radiolabeled PSMA-binding small molecule, such as Lu-EB-PSMA-617 (Sinotau Radiopharmaceutical). Such agents may be used in combination or with one or more CD47 agents according to the present invention to treat prostate cancer, such as, for example, metastatic prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and / or hormone therapy-resistant prostate cancer (antiandrogen therapy-resistant prostate cancer). Any agent that includes DOTA or a DOTA derivative as a chelator may alternatively be chelated by DOTA. 225 Ac, 177 Lu and 90 It may be labeled with any therapeutically active radionuclide, such as Y.

[0063] Other radiolabeled cancer-targeting drugs The radiolabeled cancer targeting agent used in combination or with one or more CD47 blocking agents can also be, for example, any of the following radiolabeled targeting agents: Radiolabeled FAP targeted drugs, such as those disclosed herein for treating solid tumors or any cancer.177 Lu-FAP-2286 (Clovis Oncology, Inc.); A radiolabeled CCK2R targeted drug, e.g., DEBIO 1124 / for treating advanced unresectable extrapulmonary small cell carcinoma, thyroid cancer, such as metastatic thyroid cancer, or any cancer disclosed herein. 177 Lu-DOTA-PP-F11N (Debiopharm International SA); Radiolabeled CDH3 (cadherin-3, P-cadherin) targeted agents, e.g., for treating solid tumors such as epithelial ovarian peritoneal or fallopian tube cancer, TNBC, head and neck squamous cell carcinoma (HNSCC), cholangiocarcinoma, pancreatic, colorectal cancer, or any of the cancers disclosed herein. 90 Y-labeled FF-21101 (FujiFilm Holdings Corporation / FujiFilm Toyama Chemical); Radiolabeled IGF-R1 targeted drugs, e.g., for treating solid tumors expressing IGF-R1, or any of the cancers disclosed herein. 225 Ac FPI-1434 (Fusion Pharmaceuticals, Inc.); Radiolabeled CEACAM5 targeted agents, for example, for treating solid tumors such as colon cancer, colorectal cancer, pancreatic cancer, breast cancer, such as HER-negative breast cancer, and thyroid cancer, such as medullary thyroid cancer, or any of the cancers disclosed herein. 90 Y-hMN14 and 90 Y TF2 (Immunomedics, Inc.; Gilead Sciences Inc.); Radiolabeled CD22 targeted drugs, such as IMMU-102 ( 90 Y-epratuzumab) (Immunomedics, Inc.; Gilead Sciences Inc.); Radiolabeled SSTR2 targeted agents, e.g., Lutathera™ (lutetium Lu177 dotatate; 177Lu-DOTA0-Tyr3-octreotate; Novartis), Lutathera™ (lutetium Lu177 dotatate)+ for the treatment of SSTR2-expressing cancers, such as neuroendocrine tumors, prostate cancer, such as small cell lung cancer, breast cancer, metastatic prostate cancer, such as metastatic castration-resistant prostate cancer, neuroendocrine tumors, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and locally advanced or metastatic forms thereof, or solid tumors, such as any of the cancers disclosed herein. 90 Y-Dotatate combination (Novartis), 177 Lu-OPS201 (Ipsen Pharmaceuticals) combination 177 LU-OPS201 / 177 Lu-IPN01072 (Ipsen Pharmaceuticals), EBTATE ( 177 Lu-DOTA-EB-TATE; Molecular Targeting Technologies, Inc.), ORM2110 (AlphaMedix™; Orano Med), and, for example, 177 PNT2003 labeled with Lu (Point Biopharma Global Inc.); Radiolabeled SSTR2 and SSTR5 targeted drugs, such as Solucin™ ( 177 Lu-Edotreotide;Isotopen Technologien Munchen AG (ITM)); Radiolabeled neurotensin receptor type 1 (NTSR1) targeted agents for use in treating NTSR1-expressing solid tumors, such as pancreatic ductal adenocarcinoma, colorectal cancer, gastric cancer, squamous cell carcinoma of the head and neck, bone cancer, advanced cancer, recurrent disease, metastatic tumors, or any of the cancers disclosed herein. 177 Lu-IPN01087 / 177 Lu-3BP-227 (Ipsen Pharmaceuticals); Radiolabeled human kallikrein 2 (hK2) targeted agents, e.g., for treating prostate cancer, such as locally advanced or metastatic prostate cancer, or any cancer disclosed herein, e.g., 225 JNJ-69086420 labeled with Ac (Janssen / Janssen Pharmaceutica NV); Radiolabeled NET (via norepinephrine transporter) targeted agents, e.g., for treating neuroblastoma, such as relapsed / refractory neuroblastoma, or any cancer disclosed herein. 131 I-MIBG (Jubilant Radiopharma); Radiolabeled neuroepinephrine transporter targeted drugs, such as Azedra™ (iobenguane), for treating glioma, paraglioma, malignant pheochromocytoma / paraganglioma, and malignant relapsed / refractory pheochromocytoma / paraganglioma, or any cancer disclosed herein. 131 I;Lantheus Holdings / Progenics Pharmaceuticals, Inc.); A radiolabeled integrin αVβ6 targeted drug, for example for treating a solid tumor, such as pancreatic cancer, or any cancer disclosed herein. 177 Lu, 225 Ac or 90 DOTA-ABM-5G, labeled with Y, αVβ6-binding peptide (ABP; Luminance Biosciences, Inc.); Radiolabeled CD37 targeted drugs, such as Betartin™ ( 177 Lu-Rirotomab satetraxetane;Nordic Nanovector ASA); Radiolabeled GRPR targeted drugs, e.g., for treating GRPR-expressing cancers, e.g., prostate cancer, such as advanced prostate cancer, locally advanced prostate cancer, metastatic prostate cancer, and castration-resistant prostate cancer, or any cancer disclosed herein. 177 Lu-NeoB (Novartis) and 212Pb-DOTAM-GRPR1 (Orano Med); Radiolabeled CXCR4 targeted drugs, e.g., for treating lymphoproliferative or myeloid malignancies, including relapsed and / or refractory forms, or any of the cancers disclosed herein. 177 Lu, 90 Y or 225 PentixaTher™ (PentixaPharm GmbH) labeled with Ac; Radiolabeled tenascin-C targeted drugs, e.g., for treating solid tumors or hematopoietic malignancies, such as any of those disclosed herein. 131 I-F16SIP (Philogen SpA); Radiolabeled fibronectin extra domain B (EBD) targeted agents, e.g., for treating solid tumors, such as solid tumor brain metastases and non-small cell lung cancer (NSCLC), or any cancer disclosed herein. 131 I-L19SIP (Philogen SpA)); Radiolabeled LAT-1 targeted agents, such as 4- 131 Iodo-L-phenylalanine (Telix Pharmaceuticals Ltd.); Radiolabeled carbonic anhydrase IX (CAIX) targeted agents, e.g., for treating renal cell carcinoma, such as ccRCC, or any cancer disclosed herein, e.g., 177 Lu (TLX250, etc.; Telix Pharmaceuticals Ltd.), 225 Ac or 90 Radiolabeled Direntuximab (cG250), such as DOTA-conjugated Girentuximab (cG250) labeled with Y; Radiolabeled CD66 targeted drugs, for example for treating leukemia, myeloma and lymphoma, such as any of those disclosed herein, including pediatric and adult forms, or any of the cancers disclosed herein. 90 Y-besilesomab ( 90 Y-anti-CD66-MTR;Telix Pharmaceuticals Ltd.); Radiolabeled B7-H3 targeted agents, for example, for treating gliomas, such as non-progressive diffuse pontine gliomas, such as non-progressive diffuse pontine gliomas pretreated with external beam radiation therapy, brain tumors, central nervous system tumors, neuroblastomas, sarcomas, leptomeningeal metastases from solid tumors, and medulloblastoma, including pediatric and adult forms, or any cancer disclosed herein. 131 I-8H9 (131I-omburtamab; Y-mAbs Therapeutics, Inc.) and 177 radiolabeled ombartamab, such as Lu-ombartamab (Y-mAbs Therapeutics, Inc.); Radiolabeled NKG2D ligand targeted agents, e.g., for treating solid tumors or hematopoietic malignancies expressing one or more NKG2D ligands, or any of the cancers disclosed herein - radiolabeled recombinant human NKG2D Fc chimeric protein, e.g., catalogue number 1299-NK by Biotechne (R&D Systems, Inc., Minneapolis, MN, USA), which is a radiolabeled recombinant human NKG2D comprising an amino-terminal histidine tag, such as Phe78-Val216 (accession number #P26718) or SEQ ID NO: 155 ± (His)6 of human NKG2D. Fc chimeric proteins or radiolabeled antibodies or antigen-binding fragments thereof against NKG2D ligands such as MICA, MICB, RAET1E / ULBP4, RAET1G / ULBP5, RAET1H / ULBP2, RAET1 / ULBP1, RAET1L / ULBP6, or RAET1N / ULBP3; Radiolabeled GD2 targeted drugs, e.g., GD2-SADA, for treating SCLC, melanoma, sarcoma, or any cancer disclosed herein: 177 Lu-DOTA (Y-mAbs Therapeutics, Inc.); radiolabeled folate receptor alpha (FOLR1) targeted agents, e.g., radiolabeled anti-FOLR1 antibodies, such as radiolabeled mirvetuximab or farletuzumab, for treating solid cancers, such as ovarian cancer, lung cancer, NSCLC, breast cancer, TNBC, brain cancer, glioblastoma, colorectal cancer, or any cancer disclosed herein; A radiolabeled Nectin-4 targeted agent, e.g., a radiolabeled anti-Nectin-4 antibody, such as radiolabeled enfortumab or any anti-Nectin-4 antibody in radiolabeled form, for treating solid tumors, such as urothelial carcinoma, bladder cancer, breast cancer, TNBC, lung cancer, NSCLC, colorectal cancer, pancreatic cancer, endometrial cancer, ovarian cancer, or any cancer disclosed herein, or a targeted agent disclosed in US Patent Publication Nos. 20210130459, 20200231670, U.S. Pat. No. 10,675,357, or WO2022051591; radiolabeled CUB domain-containing protein 1 (CDCP1) targeted agents, e.g., radiolabeled monoclonal antibodies, such as any of the radiolabeled CDCP1 targeted agents, for treating solid cancers, such as breast cancer, TNBC, lung cancer, colorectal cancer, ovarian cancer, renal cancer, liver cancer, HCC, pancreatic cancer, skin cancer, melanoma, or hematological malignancies, such as acute myeloid leukemia, or any of the cancers disclosed herein, and antibodies disclosed in US Patent Publication Nos. 20210179729, 20200181281, 20090196873, U.S. Patent Nos. 8,883,159, 9,346,886, or WO2021087575; Radiolabeled glypican-3 (GPC3) targeted agents, such as radiolabeled humanized IgG1 mAb GC33 (also known as codrituzumab; commercially available from Creative Biolabs under catalog number TAB-H14), for treating GPC3-expressing cancers, such as hepatocellular carcinoma, ovarian clear cell carcinoma, melanoma, NSCLC, squamous cell carcinoma of the lung, hepatoblastoma, nephroblastoma (Wilms tumor), yolk sac tumor, gastric cancer, colorectal carcinoma, head and neck cancer, and breast cancer, such as 225Ac-Macropa-GC33 (Bell et al., Glypican-3-Targeted Alpha Particle Therapy for Hepatocellular Carcinoma. Molecules. 2020 Dec 22;26(1):4.) or a radiolabeled anti-GPC3 antibody or other targeted agent disclosed in U.S. Pat. Nos. 10,118,959, 10,093,746, 10,752,697, 9,932,406, 9,217,033, 8,263,077, 7,871,613, 7,867,734, U.S. Patent Application Publication Nos. 20190046659, 20180243451, 20170369561, or 20150315278; A radiolabeled urokinase plasminogen activator receptor (uPAR) targeted agent, for example, a radiolabeled MNPR-101, such as MNPR-101-PTCA-Ac225 (Monopar Therapeutics, Inc., Wilmette, IL, USA), for treating a solid cancer or hematopoietic malignancy, such as any of those disclosed herein (either a radiolabeled monoclonal antibody such as huATN-658 or a radiolabeled form of an anti-uPAR antibody, or a targeted agent disclosed in U.S. Pat. No. 9,029,509, U.S. Patent Publication No. 20080199476, U.S. Patent Publication No. 20040204348, or International Publication No. WO2021257552; and / or Radiolabeled Lewis Y antigen (LeY) targeted drugs, for example, radiolabeled anti-LeY monoclonal antibodies, such as radiolabeled 3S1931 and / or humanized versions thereof, such as radiolabeled Hu3S1933, or radiolabeled versions of any of the monoclonal antibodies B34, BR55-2, BR55 / BR96, and IGN 133, or antigen-binding fragments of any of the aforementioned antibodies, for treating solid tumors, such as lung squamous cell carcinoma, lung adenocarcinoma, ovarian cancer, or colorectal adenocarcinoma, or any of the cancers disclosed herein.

[0064] In further embodiments of the invention, the radiolabeled targeted agent used in combination or with one or more CD47 blocking agents for the treatment of cancer or a proliferative disorder, such as any of those disclosed herein, in a mammal, such as a human, comprises a phospholipid-based cancer targeting agent. In certain embodiments, the phospholipid-based cancer targeting agent includes, for example and without limitation, 225 Ac, 177 Lu, or 90 Chelated with radionuclides such as Y [ka] (also known as NM600) or a pharma- ceutically acceptable salt thereof, or any of the radioactive phospholipid metal chelates disclosed in U.S. Patent Publication No. 20200291049, herein incorporated by reference.

[0065] In certain embodiments, lipid-based radiolabeled targeted agents used in conjunction with one or more CD47 blocking agents include, but are not limited to, [ka] That is, 18-(p-iodophenyl)octadecylphosphocholine (wherein iodine is 131No. 6,417,384, such as CD47 blocking agent or a pharma- ceutical acceptable salt thereof. In certain embodiments, the phospholipid-based radiolabeled targeting agent used in conjunction with one or more CD47 blocking agents includes any of the phospholipid drug conjugate compounds disclosed in U.S. Pat. Appl. Pub. No. 20140030187 or U.S. Pat. No. 6,417,384.

[0066] Multispecific targeting aspects Whereas exemplary radiotherapeutic agents disclosed herein include antibody-radioconjugates (ARC) directed against a single antigen, such as CD33, DR5, 5T4, HER2, HER3, or TROP2, multispecific antibodies are also within the scope of the invention. Thus, in certain aspects, the radiotherapeutic agent may include a multispecific targeted agent, such as a multispecific antibody that recognizes a first epitope of an antigen (CD33, DR5, 5T4, HER2, HER3, TROP2, or any of the cancer associated antigen targets disclosed herein) and a second epitope of the same antigen, or that recognizes an epitope of a first antigen and an epitope of one or more different antigens, e.g., selected from any of the cancer associated antigens disclosed herein. Thus, in one aspect, the ARC can comprise a multispecific antibody, such as a bispecific antibody, that comprises at least a first target recognition component that specifically binds to an epitope of a first antigen (e.g., CD33, DR5, 5T4, HER2, HER3, TROP2, or any of the cancer associated antigen targets disclosed herein) and a second target recognition component that specifically binds to an epitope of an antigen other than the first antigen, such as any of the cancer associated antigens disclosed herein.

[0067] The present invention also provides compositions and methods for the treatment of a proliferative disorder, such as any of those disclosed herein, that comprise or utilize at least two separate radiolabeled targeting agents, the two targeting agents having specificity for different cancer-associated antigens and / or different cancer / tumor targeting mechanisms, which targeting agents may, for example, be any of those disclosed herein and / or may be directed to any of the targets disclosed herein.

[0068] In various aspects of the invention, the cancer-associated antigens for which a radiolabeled targeted agent (such as ARC) has specificity can include, for example, one or more of the following: CD33, DR5, 5T4, HER2 (ErbB2; HER2 / neu), HER3, TROP2, mesothelin, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL-1, GD2, GD3, B-cell maturation antigen (BCMA), TnAg, prostate-specific membrane antigen (PSMA), ROR1, FLT3, fibroblast activation protein (FAP), somatostatin receptor, somatostatin receptor 2 (SSTR2), somatostatin receptor 5 (SSTR5), gastrin releasing peptide receptor (GRPR), NKG2D ligands (e.g., MICA, MICB, RAET1E / ULBP4, RAET1G / ULBP5, RAET1H / ULBP2, RAET1 / ULBP1, RAET1L / ULBP6, and RAET1N / ULBP3), LYPD3 (C4. 4A), nectin-4, urokinase plasminogen activator receptor (uPAR), folate receptor alpha (FOLR1), CUB-domain-containing protein 1 (CDCP1), glypican-3 (GPC3), tenascin, tenascin-C, CEACAM5, cadherin-3, CCK2R, neurotensin receptor type 1 (NTSR1), human kallikrein 2 (hK2), norepinephrine transporter, integrin alpha-V-beta-6, CD37, CD66, CXCR4, fibronectin extradomain EBD, LAT-1, carbonic anhydrase IX (CAIX), B7-H3 (also known as CD276), disialoganglioside GD2 antigen (GD2), calreticulin, phosphatidylserine, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, interleukin-11 receptor a (IL-11Ra), PSCA, PRSS21, VEGFR2, LewisY, CD24, platelet-derived growth factor receptor-beta (PDGFRβ), SSEA-4, CD20, folate receptor alpha (FRa), MUCl, epidermal growth factor receptor (EGFR), EGFRvIII, NCAM, prostase, PAP, ELF2M, ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, F-fucosyl GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1 / CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE A1, MAGEA3, MAGEA3 / A6, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, prostein, survivin and telomerase, PCTA-1 / galectin 8, KRAS, MelanA / MART1, Ras mutants, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG(TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin Bl, MYCN, RhoC, TRP-2, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxylesterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, GPA7, and IGLL1.

[0069] The first target recognition component may, for example, comprise one of a first full-length heavy chain and a first full-length light chain, a first Fab fragment, or a first single-chain variable fragment (scFv). The first target recognition component may, for example, be derived from any of the monoclonal antibodies listed herein against CD33, DR5, 5T4, HER2, or HER3. The second target recognition component may, for example, comprise one of a second full-length heavy chain and a second full-length light chain, a second Fab fragment, or a second single-chain variable fragment (scFv). Additionally, the second target recognition component may be derived from any of the additional different antigens listed above. Alternatively, the present disclosure contemplates a method comprising administration of a first ARC directed against at least one first antigen (i.e., CD33, DR5, 5T4, HER2 or HER3) and administration of a second ARC, wherein the second ARC is directed against a different epitope of the first antigen, or against an epitope of a different antigen, such as an antigen selected from the list provided above, or against another antigen against CD33, DR5, 5T4, HER2 or HER3 that is not targeted by the first ARC. In certain embodiments, an effective amount of a radiotherapeutic agent, such as any of the ARCs disclosed herein, includes the maximum tolerated dose (MTD).

[0070] In certain embodiments, when more than one ARC or other cancer-targeted radiotherapy agent is administered, the agents can be administered simultaneously. Thus, in certain embodiments of the present invention, the agents can be provided, for example, as a single composition. Alternatively, the two radiotherapy agents can be administered sequentially. Thus, the first ARC or other cancer-targeted radiotherapy agent can be administered before the second ARC or other cancer-targeted radiotherapy agent, after the second ARC or other cancer-targeted radiotherapy agent, or both before and after the second ARC or other cancer-targeted radiotherapy agent. Furthermore, the second ARC or other cancer-targeted radiotherapy agent can be administered before the first ARC or other cancer-targeted radiotherapy agent, after the first ARC or other cancer-targeted radiotherapy agent, or both before and after the first ARC or other cancer-targeted radiotherapy agent. In certain aspects, the ARC or other cancer targeted radiation therapeutic agent can be administered according to a dosing schedule selected from the group consisting of once every 7, 10, 12, 14, 20, 24, 28, 35, and 42 days throughout the treatment period, which treatment period includes at least two administrations. In certain embodiments, the ARC or other cancer targeted radiotherapeutic agent may be administered according to a dosing schedule that includes two administrations, such as on days 1 and 5, 6, 7, 8, 9, or 10 of the treatment period, or on days 1 and 8 of the treatment period.

[0071] Administration of the ARC of the present invention can be provided in several ways, depending on whether local or systemic treatment is desired in addition to other therapeutic agents, and on the area to be treated. Administration can be intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. In some embodiments, sustained release formulations containing targeted agents and / or other therapeutic agents can be administered. The various agents can be administered as a single treatment or as a series of treatments continued over a duration that reduces or ameliorates one or more symptoms of cancer, or achieves another desired effect, as needed. Dosages may vary, for example, depending on the identity, size, and condition of the subject, as well as the route by which the composition is administered and the desired effect. Appropriate dosages of therapeutic agents depend on their potency on the expression or activity to be modulated. Therapeutic agents are initially administered to animals (e.g., humans) at relatively low dosages, and dosages are then increased until an appropriate response is obtained. The radiation therapeutic agents disclosed herein, such as any of the ARCs, may be administered simultaneously or sequentially with one or more additional therapeutic agents. Further, when more than one additional therapeutic agent is included, the additional therapeutic agents may be administered with each other and / or with the radiation therapeutic agents.

[0072] Radiotargeting of cancer-targeting drugs The radiotherapeutic agents are capable of binding to an alpha-emitting source (e.g., 225 In certain embodiments, the radiotherapeutic agent may be an antibody that is deglycosylated in the constant region, such as at asparagine-297 (Asn-297, N297; Kabat numbering) in the heavy chain CH2 domain, to reveal a unique conjugation site, glutamine (i.e., Gln-295, Q295), available for conjugation with a bifunctional chelating molecule.

[0073] In certain aspects, the radiotherapeutic agent may be an antibody that may have disulfide bonds reduced, such as by use of a reducing agent, which may then be converted to dehydroalanine for chelation with a bifunctional chelating molecule. In certain embodiments, the radiotherapeutic agent is an antibody whose disulfide bonds have been reduced with a reducing agent, which is then conjugated via an aryl bridge with a bifunctional chelating molecule. For example, in certain embodiments, a linker molecule such as 3,5-bis(bromomethyl)benzene can be used to crosslink free sulfhydryl groups to the antibody. In certain aspects, the radiotherapeutic agent may be an antibody that may have certain existing amino acids replaced with cysteines that can then be used for site-specific labeling. In certain embodiments, the radiotherapeutic agent may be radiolabeled by site-specific conjugation of a suitable bifunctional chelator. Exemplary chelator molecules that may be used include p-SCN-Bn-DOTA, NH2-DOTA, NH2-(CH2) 1-20 -DOTA, NH2-(PEG) 1-20 -DOTA, HS-DOTA, HS-(CH2) 1-20 -DOTA, HS-(PEG) 1-20 -DOTA, dibromo-S-(CH2) 1-20 -DOTA, dibromo-S-(PEG) 1-20 -DOTA, p-SCN-Bn-DOTP, NH2-DOTP, NH2-(CH2) 1-20 -DOTP, NH2-(PEG) 1-20 -DOTP, HS-DOTP, HS-(CH2) 1-20 -DOTP, HS-(PEG) 1-20 -DOTP, dibromo-S-(CH2) 1-20 -DOTP, and dibromo-S-(PEG) 1-20 -DOTP is one example. The chelating molecule can be attached to the targeting agent, for example, via a linker molecule. Exemplary linker molecules include: -CH2(C6H4)NH2 or -CH2(C6H4)NH-XY, and X is -R2-CH2CH2O(CH2CH2O) n CH2CH2-, -R2-CH2CH2NHC(O)CH2CH2O(CH2CH2O) n CH2CH2-, -R2-(CH2) n CH2-, -R2-CH2CH2NHC(O)(CH2) n CH2-, -R2-CH(C(O)R3)CH2- (R3 is -OH or a short peptide (1-20 amino acids)), -R2-CH2CH2O(CH2CH2O) n CH2C(O)O-, or -R2-CH2CH2NHC(O)CH2CH2O(CH2CH2O) n CH2CC(O)O-, where n is 1 to 20, and R2 is -C(O)- or -C(S)NH-, and Y is -NH2 or -SR4-, where R4 is -H or -CH2-3,5-bis(bromomethyl)benzene.

[0074] Targeting agents, such as protein targeting agents, such as antibodies and antigen-binding antibody fragments, and peptide targeting agents, can be conjugated, for example, with chelating agents for radiotargeting of the targeting agent via chelation of a radionuclide. Such lysine-containing protein or peptide targeting agents can be conveniently conjugated to a DOTA chelating moiety, for example, using the bifunctional agent S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid, also known as "p-SCN-Bn-DOTA" (catalog number B205; Macrocyclics, Inc., Plano, TX, USA). p-SCN-Bn-DOTA can be synthesized by a multi-step organic synthesis fully described in U.S. Pat. No. 4,923,985. Chelation of a radionuclide with a DOTA moiety can be performed prior to and / or after chemical conjugation of the antibody with p-SCN-Bn-DOTA. Exemplary radionuclide labeling methods for chelator-conjugated targeting agents are described in Example 1.

[0075] CD47 blockers As used herein, the term "CD47 blocking agent" refers to any agent that reduces binding of CD47 (e.g., on a target cell) to SIRPα (e.g., on a phagocyte). Non-limiting examples of suitable anti-CD47 reagents include, but are not limited to, SIRPα polypeptides, anti-SIRPα antibodies, soluble CD47 polypeptides, and SIRPα reagents including anti-CD47 antibodies or antibody fragments. In certain aspects, suitable anti-CD47 agents (e.g., anti-CD47 antibodies, SIRPα reagents, etc.) specifically bind to CD47 and reduce binding of CD47 to SIRPα. Agents for use in the methods of the invention upregulate phagocytosis by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 120%, at least 140%, at least 160%, at least 180%, or at least 200%) compared to phagocytosis in the absence of the agent. Similarly, in vitro assays of tyrosine phosphorylation levels of SIRPα show a decrease in phosphorylation of at least 5% (e.g., at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%) compared to phosphorylation observed in the absence of the candidate agent.

[0076] In certain embodiments, a SIRPα reagent may include a portion of SIRPα sufficient to bind CD47 with appreciable affinity, usually between the signal sequence and the transmembrane domain, or between fragments thereof. A suitable SIRPα reagent reduces (e.g., blocks, prevents, etc.) the interaction between the native protein SIRPα and CD47. For example, the CD47 blocker may be any of those disclosed in U.S. Pat. No. 9,969,789, including, but not limited to, the SIRPα-IgG Fc fusion proteins disclosed therein, such as TTI-621 and TTI-622. In certain aspects, anti-CD47 agents include antibodies that specifically bind to CD47 (i.e., anti-CD47 antibodies) and reduce the interaction between CD47 on one cell (e.g., an infected or malignant cell) and SIRPα on another cell (e.g., a phagocyte). Non-limiting examples of suitable antibodies include clones B6H12, 5F9, 8B6, and C3 (e.g., those described in WO 2011 / 143624). Suitable anti-CD47 antibodies include fully human, humanized, or chimeric versions of such antibodies. Exemplary human or humanized antibodies that are particularly useful for in vivo applications in humans due to their low antigenicity include monoclonal antibodies against at least CD47, such as Hu5F9-G4, a humanized monoclonal antibody available as magrolimab from Gilead (Sikic, et al. (2019) Journal of Clinical Oncology 37:946); lemzoparimab and TJC4 available from I-Mab Biopharma; AO-176 from Arch Oncology, Inc; AK117 from Akesobio Australia Pty; IMC-002 from Innovent Biologics; ZL-1201 from Zia Lab; SHR-1603 from Jiangsu HengRui Medincine Co.; and SRF231 from Surface Oncology. Bispecific monoclonal antibodies are also available, such as IBI-322, which targets both CD47 and PD-L1 from Innovent Biologics. By blocking the CD47-SIRPα interaction, in addition to inducing tumor phagocytosis, AO-176 was found to selectively bind to tumor cells, unlike normal cells (where binding was negligible, especially RBCs), and directly kill tumors, unlike normal cells.

[0077] Antibodies against SIRPα can also be used as CD47 blockers. Non-limiting anti-SIRPα antibodies (also referred to herein as SIRPα antibodies) that may be used or practiced in any of the aspects of the invention include, but are not limited to, the following anti-SIRPα antibodies, antibodies comprising one or both of the heavy and light chain variable regions of the following anti-SIRPα antibodies, antibodies comprising one or both of the heavy and light chain CDRs of any of the following anti-SIRPα antibodies, and antigen-binding fragments of any of the foregoing anti-SIRPα antibodies: (1) ADU-1805 (Sairopa BV; Aduro) and any of the SIRPα antibodies disclosed in International Publication No. WO2018190719 or U.S. Pat. No. 10,851,164; (2) AL008 (Alector LLC) and any of the SIRPα antibodies disclosed in International Publication No. WO2018107058, U.S. Patent Application Publication No. 20190275150, or U.S. Patent Application Publication No. 20210179728; (3) AL008 (Apexigen, Inc.) and any of the SIRPα antibodies disclosed in International Publication No. WO2021174127 and U.S. Provisional Patent Application No. 63 / 108,547; (4) SIRP-1 and SIRP-2 (Arch Oncology, Inc.) and any of the SIRPα antibodies disclosed in International Publication No. WO2021222746, U.S. Provisional Patent Application No. 63 / 107,200, or U.S. Patent Application Publication No. 20200297842; (5) OSE-172 (also known as BI 765063; Boehringer Ingelheim) and any of the SIRPα antibodies disclosed in International Publication No. WO2017178653 or U.S. Patent Application Publication No. 20190127477; (6) CC-95251 (Bristol Myers Squibb; Celgene) and any of the SIRPα antibodies disclosed in International Publication No. WO2020068752 or U.S. Patent Publication No. 20200102387; (7) ES004 (Elpiscience Biopharma) and any of the SIRPα antibodies disclosed in International Publication No. WO2021032078 or U.S. Patent Application Publication No. 20210347908; (8) FSI-189 (Gilead Sciences, Inc.; Forty Seven) and any of the SIRPα antibodies disclosed in International Publication No. WO2019023347, U.S. Patent No. 10,961,318, or U.S. Patent Application Publication No. 20210171654; (9) BYON4228 (Byondis BV; Synthon) and any of the SIRPα antibodies disclosed in International Publication No. WO2018210793 or WO2018210795, or U.S. Patent Application Publication No. 20210070874; (10) any of the SIRPα antibodies disclosed in International Publication No. WO2018057669, U.S. Pat. No. 11,242,404, or U.S. Patent Application Publication No. 20220002434 (Alexo Therapeutics Inc., now ALX Oncology Inc.); (11) any of the SIRPα antibodies disclosed in International Publication No. WO2015138600, U.S. Pat. No. 10,781,256, or U.S. Pat. No. 10,081,680 (Leland Stanford Junior University); (12) BR105 (Bioray Pharma); or (13)BSI-050 (Biosion, Inc.).

[0078] Other CD47 blocking agents that may be employed include any of those disclosed in U.S. Pat. No. 9,969,789, including, but not limited to, SIRPα-IgG Fc fusion proteins TTI-621 and TTI-622 (Trillium Therapeutics, Inc.), both of which selectively bind to CD47 on tumor cells while simultaneously binding to activating Fc receptors. For example, SIRPα-IgG Fc fusion proteins comprising amino acid sequences SEQ ID NO: 116, SEQ ID NO: 117, or SEQ ID NO: 118 may be used. Still other SIRPα Fc domain fusion proteins that may be used include ALX148 from Alx Oncology or any of those disclosed in International Publication No. WO2017027422 or U.S. Pat. No. 10,696,730. CD47 blocking agents alternatively or additionally include phosphorodiamidate morpholino oligomers that block translation of CD47, such as MBT-001 (PMO, morpholino, sequence: 5'-CGTCACAGGCAGGACCCACTGCCCA-3') [SEQ ID NO: 114], or agents that modulate CD47 and / or SIRPα expression, such as any of the PMO oligomeric CD47 inhibitors disclosed in U.S. Pat. Nos. 8,557,788, 8,236,313, 10,370,439 and International Publication No. WO2008060785.

[0079] Small molecule inhibitors of the CD47-SIRPα axis may also be used, such as RRx-001 (1-bromoacetyl-3,3 dinitroazetidine) and azelnidipine (CAS number 123524-52-7) from EpicentRx, or a pharma- ceutically acceptable salt thereof. Various CD47 blocking agents that can be used can be found in Table 1 of Zhang, et al., (2020), Frontiers in Immunology vol 11, article 18, and Table 3 below. [Table 3]

[0080] A therapeutically effective amount of an anti-CD47 antibody or other protein CD47 inhibitor can be a dosage that leads to a sustained serum level of protein of about 40 μg / ml or more (about 50 ug / ml or more, about 60 ug / ml or more, about 75 ug / ml or more, about 100 ug / ml or more, about 125 ug / ml or more, or about 150 ug / ml or more). A therapeutically effective amount or dosage of a CD47 blocking agent, such as an anti-CD47 antibody or a SIRPα fusion protein or a small molecule, is, for example, 0.05 to 10 mg / kg (drug mass / subject body weight), for example, at least 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, or an amount equal to or less than 10 mg / kg, 9.5 mg / kg, 9.0 mg / kg, 8.5 mg / kg, 8.0 mg / kg, 7.5 mg / kg, 7.0 mg / kg, 6.5 mg / kg, 6.0 mg / kg, 5.5 mg / kg, 5.0 mg / kg, 4.5 mg / kg, 4.0 mg / kg, 3.5 mg / kg, 3.0 mg / kg, 2.5 mg / kg, 2.0 mg / kg, 1.5 mg / kg, 1.0 mg / kg, or any combination of these upper and lower limits. Small molecule CD47 blocking agents such as those disclosed herein also include, for example, 0.01 mg / kg to 1,000 mg / kg and any subrange or mg / kg value therein, for example, 0.01 mg / kg to 500 mg / kg, or 0.05 mg / kg to 500 mg / kg, or 0.5 mg / kg to 200 mg / kg, or 0.5 mg / kg to 150 mg / kg, or 1.0 mg / kg to 100 mg / kg, or 10 mg / kg to 50 mg / kg.

[0081] In certain embodiments, the anti-CD47 drug is a soluble CD47 polypeptide that specifically binds to SIRPα, reducing the interaction between CD47 on one cell (e.g., an infected cell) and SIRPα on another cell (e.g., a phagocyte). A suitable soluble CD47 polypeptide can bind to SIRPα without activating or stimulating signaling through SIRPα, because activation of SIRPα should inhibit phagocytosis. Instead, a suitable soluble polypeptide promotes selective phagocytosis of infected cells compared to non-infected cells. Those cells (e.g., infected cells) that express higher levels of CD47 compared to normal non-target cells (normal cells) are selectively phagocytosed. Thus, a suitable soluble CD47 polypeptide specifically binds to SIRPα in the absence of sufficient activation / stimulation of a signaling response that inhibits phagocytosis. In some cases, a suitable soluble CD47 polypeptide can be a fusion protein (e.g., as described in US Patent Publication No. 20100239579).

[0082] Additional drugs The method of the present invention, which includes the administration of a radiotherapeutic agent and a CD47 blocking agent, further includes the administration of one or more additional therapeutic agents. In certain embodiments, the additional agent may be related to the disease or condition being treated. Such administration may be simultaneous, separate or sequential administration of the radiotherapeutic agent and the CD47 blocking agent. In the case of simultaneous administration, the agents may be administered as one composition or as separate compositions, as appropriate. Exemplary additional therapeutic agents include at least a chemotherapeutic agent, an anti-inflammatory agent, an immunosuppressant, an immunomodulatory agent, or a combination thereof. Additionally, the one or more additional therapeutic agents include anti-myeloma drugs such as dexamethasone, doxorubicin, bortezomib, lenalidomide, prednisone, carmustine, etoposide, cisplatin, vincristine, cyclophosphamide, and thalidomide. In certain aspects of the invention, the methods may further comprise administration of a cytokine, such as granulocyte colony stimulating factor (GCSF), following administration of the radiotherapeutic agent and / or CD47 blocking agent. GCSF may be administered, for example, 7, 8, 9, 10, or 11 days following administration of the radiolabeled CD33 targeted agent.

[0083] Chemotherapeutic agents include, but are not limited to, antineoplastic agents, including nitrogen mustards such as mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil; nitrosoureas such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU); ethylenimines / methylmelamines such as Temodar™ (temozolamide), triethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), and hexamethylmelamine (HMM, altretamine); alkylsulfonic acids such as busulfan; alkylating agents, including triazines such as dacarbazine (DTIC); folic acid analogs such as methotrexate and trimetrexate, 5-fluorouracil (5FU), fluorodeoxyuridine, gemcitabine, cytosine arabinoside. antimetabolites, including pyrimidine analogues such as 5-azacytidine (AraC, cytarabine), 5-azacytidine, and 2,2-difluorodeoxycytidine; purine analogues such as 6-mercaptopurine, 6-thioguam, azathioprine, T-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, and 2-chlorodeoxyadenosine (cladribine, 2-CdA); and antimitotics, including paclitaxel. natural products; vinca alkaloids, including vinblastine (VLB), vincristine, and vinorelbine, taxotere, estramustine, and estramustine phosphate; podophyllotoxins, such as etoposide and teniposide; antibiotics, such as actinomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycin, plicamycin (mithramycin), mitomycin C, and actinomycin; enzymes such as L-asparaginase; biological response modifiers such as interferon-α, IL-2, G-CSF, GM-CSF; platinum coordination compounds such as oxaliplatin, cisplatin and carboplatin, anthracenediones such as mitoxantrone, substituted ureas such as hydroxyurea, methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine, adrenal cortical suppressants such as mitotane (o,p-DDD) and aminoglutethimide;Hormones and antagonists, including corticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; progestins, such as Gemzar™ (gemcitabine), hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogens, such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogens, such as tamoxifen; androgens, including testosterone propionate and fluoxymesterone / equivalents; antiandrogens, such as flutamide, gonadotropin-releasing hormone analogs and leuprolide; and nonsteroidal antiandrogens, such as flutamide. Epigenetic mechanism-targeted therapies, including, but not limited to, histone deacetylase inhibitors, demethylating agents (e.g., Vidaza® and releasing transcription repression (ATRA) therapeutics, may also be combined with the antibodies of the invention.

[0084] In certain aspects, the chemotherapeutic agent may be selected from the group consisting of taxanes (e.g., paclitaxel (Taxol®), docetaxel (Taxotere®), modified paclitaxel (e.g., Abraxane and Opaxio®), doxorubicin, sunitinib (Sutent®), sorafenib (Nexavar®), and other multi-targeted kinase inhibitors, oxaliplatin, cisplatin and carboplatin, etoposide, gemcitabine, and vinblastine. In one embodiment, the chemotherapeutic agent is selected from the group consisting of taxanes (e.g., Taxol (paclitaxel), docetaxel (Taxotere), modified paclitaxel (e.g., Abraxane and Opaxio), etc.).

[0085] In an embodiment of the present disclosure, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), leucovorin, irinotecan, or oxaliplatin. In a particular embodiment, the chemotherapeutic agent is 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI). In another embodiment, the chemotherapeutic agent is 5-fluorouracil and oxaliplatin (FOLFOX). In an embodiment of the present disclosure, the chemotherapeutic agent is selected from a taxane (e.g., docetaxel or paclitaxel) or modified paclitaxel (e.g., Abraxane or Opaxio), doxorubicin, capecitabine and / or bevacizumab (Avastin®) for the treatment of breast cancer; a therapy with carboplatin, oxaliplatin, cisplatin, paclitaxel, doxorubicin (or modified doxorubicin (Caelyx® or Doxil®)), or topotecan (Hycamtin®) for the treatment of ovarian cancer; a therapy with multiple kinase inhibitors, MKI (Sutent, Nexavar, AMG706) and / or doxorubicin for the treatment of kidney cancer, a therapy with oxaliplatin, cisplatin and / or radiation for the treatment of squamous cell carcinoma, a therapy with taxol and / or carboplatin for the treatment of lung cancer.

[0086] Therapeutic agents may be administered according to any standard dosing regimen known in the art. For example, therapeutic agents may be administered at doses ranging from 1 to 500 mg / m 2 The concentration (volume) in the range of the patient surface area (m 2 For example, an exemplary dosage of the chemotherapy agent paclitaxel is 15 mg / m 2 ~275mg / m 2 and an exemplary dosage of docetaxel is 60 mg / m 2 ~100mg / m 2 and an exemplary dosage of epothilone is 10 mg / m 2 ~20mg / m 2 and an exemplary dosage of calicheamicin is 1 mg / m 2 ~10mg / m 2 Exemplary dosage amounts are described herein, however, these are provided for reference only and are not intended to limit the dosage ranges of the drugs of the present disclosure.

[0087] Exemplary anti-inflammatory agents may be selected from steroidal drugs and NSAIDs (non-steroidal anti-inflammatory drugs). Other anti-inflammatory agents include aspirin and other salicylates, Cox-2 inhibitors (such as rofecoxib and celecoxib), NSAIDs (such as ibuprofen, fenoprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, and indomethacin), anti-IL6R antibodies, anti-IL8 antibodies, anti-IL15 antibodies, anti-IL15R antibodies, anti-CD4 antibodies, anti-CD11a antibodies (e.g., efalizumab), anti-IL15R antibodies, anti-IL2R antibodies, ... The therapeutic agent may be selected from alpha4 / beta1 integrin (VLA4) antibodies (e.g., natalizumab), CTLA4-1g antibodies for the treatment of inflammatory diseases, disease-modifying antirheumatic drugs (DMARDs) such as prednisolone, prednisone, methotrexate, hydroxychloroquine, sulfasalazine, pyrimidine synthesis inhibitors (such as leflunomide), IL-1 receptor blockers (such as anakinra), TNF-alpha blockers (such as etanercept, infliximab, adalimumab), and similar agents.

[0088] Exemplary immunosuppressants and / or immunomodulators include cyclosporine, azathioprine, mycophenolic acid, mycophenolate mofetil, corticosteroids such as prednisone, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, 15-deoxyspergualin, 6-mercaptopurine, cyclophosphamide, rapamycin, tacrolimus (FK-506), OKT3, antithymocyte globulin, thymopentin, thymosin-α, and similar agents.

[0089] In certain aspects of the present disclosure, the additional therapeutic agent may include an anti-myeloma drug. Exemplary anti-myeloma drugs include dexamethasone, melphalan, doxorubicin, bortezomib, lenalidomide, prednisone, carmustine, etoposide, cisplatin, vincristine, cyclophosphamide, and thalidomide, some of which are set forth above as chemotherapeutic, anti-inflammatory, or immunosuppressive agents. In certain aspects of the present disclosure, additional therapeutic agents may include allopurinol administered orally at a dose of 300-600 mg / day beginning on day 1 of the treatment period and continuing for at least 7 days after administration of the CD33-targeted drug. Prophylactic antibiotic and antifungal therapy may be introduced for patients with absolute neutrophil counts below 500 / ul. Painkillers and antihistamines may also be introduced prior to administration of the CD33-targeted drug by infusion to reduce infusion-related reactions. The additional therapeutic agent may be administered according to any standard dosing regimen known in the art. For example, the therapeutic agent may be administered at a dose of 1-500 mg / m 2 The concentration (volume) in the range of the patient surface area (m 2 For example, an exemplary dosage of paclitaxel is 15 mg / m 2 ~275mg / m 2 and an exemplary dosage of docetaxel is 60 mg / m 2 ~100mg / m 2 and an exemplary dosage of epothilone is 10 mg / m 2 ~20mg / m 2 and an exemplary dosage of calicheamicin is 1 mg / m 2 ~10mg / m 2 Exemplary dosage amounts are described herein, however, these are provided for reference only and are not intended to limit the dosage ranges of the drugs of the present disclosure.

[0090] The following inventive aspects are also provided by the present disclosure, without being limited thereto: Embodiment 1: A therapeutic composition for the treatment of cancer in a mammalian, such as a human, subject, comprising: a radiotherapeutic agent, such as a radiolabeled cancer targeted agent, such as a radiolabeled antigen targeted agent, e.g., a radiolabeled antibody, e.g., a radiolabeled antibody, e.g., a CD47 blocking agent; and a CD47 blocking agent. Aspect 2: The composition of aspect 1, wherein the radiotherapeutic agent comprises a radiolabeled CD33, DR5, 5T4, HER2, HER3, or TROP2 targeted agent, such as a radiolabeled anti-CD33, anti-DR5, anti-5T4, anti-HER2, anti-HER3, or anti-TROP2 monoclonal antibody, or a radiolabeled antigen-binding fragment of any of the foregoing monoclonal antibodies. Aspect 3: The radiation therapeutic agent is 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Bi, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb and 103 3. The composition of any one of the preceding claims, further comprising a radiolabel selected from Pd, Pd, or a combination thereof. Aspect 4: The composition of any one of aspects 1-3, wherein the radiotherapeutic agent comprises a CD33 targeted agent selected from radiolabeled lintuzumab, gemtuzumab, vadastuximab, or combinations thereof, such as actinium-225 or lutetium-177 labeled lintuzumab, gemtuzumab, vadastuximab, or combinations thereof. Aspect 5: The composition of any one of aspects 1-4, wherein the radiotherapeutic agent comprises a radiolabeled DR5 targeted agent selected from radiolabeled mapatumumab, conatumumab, lexatumumab, tigatuzumab, drozitumab, LBY-135, or combinations thereof, e.g., any of the above targeted agents labeled with actinium-225 or lutetium-177, or any combination thereof. Aspect 6: The composition of any one of aspects 1-5, wherein the radiotherapeutic agent comprises a radiolabeled 5T4 targeted agent selected from radiolabeled MED10641, ALG.APV-527, Tb535, H6-DM5, ZV0508, or a combination thereof, e.g., any of the above targeted agents labeled with Actinium-225 or Lutetium-177, or any combination thereof. Aspect 7: The composition of any one of aspects 1-6, wherein the radiotherapeutic agent comprises a radiolabeled HER3 targeted agent selected from radiolabeled patritumab, seribantumab, lumuletuzumab, elgemtumab, AV-203, GSK2849330, or combinations thereof, e.g., any of the aforementioned targeted agents labeled with Actinium-225 or Lutetium-177, or any combination thereof. Aspect 8: The composition of any one of aspects 1-7, wherein the effective amount of the Actinium-225 labeled radiotherapeutic agent comprises a radiation dose of 0.1-10 μCi / kg of subject body weight and a protein dose of less than 10 mg / kg of subject body weight. Aspect 9: The composition of any one of aspects 1 to 8, wherein the effective amount of the actinium-225 labeled radiotherapeutic agent comprises a radiation dose of 0.1-2 μCi / kg of subject body weight and a protein dose of less than 5 mg / kg of subject body weight. Embodiment 10: A composition according to any one of embodiments 1 to 9, wherein the CD47 blocking agent comprises a monoclonal antibody that interferes with the binding of CD47 to SIRPα. Embodiment 11: The composition of any one of embodiments 1 to 10, wherein the CD47 blocking agent comprises magrolimab, lemzoparimab, AO-176, TTI-621, TTI-622, ALX148, RRx-001, azelnidipine, any CD47 blocking agent disclosed herein, or any combination thereof. Aspect 12: The composition according to any one of aspects 1 to 11, wherein the effective amount of the CD47 blocking agent is 0.05 to 5 mg / kg (drug mass / body weight). Aspect 13: The radiotherapeutic agent has a protein dosage of 0.1-2 μCi / kg of subject's body weight and less than 5 mg / kg of subject's body weight 225 13. The composition according to any one of aspects 1 to 12, comprising Ac Lintuzumab. Embodiment 14: The composition according to any one of embodiments 1 to 13, wherein the cancer is a solid tumor cancer. Embodiment 15: The composition according to any one of embodiments 1 to 14, wherein the cancer is a blood cancer. Embodiment 16: The composition of embodiment 15, wherein the hematological cancer is a myeloid malignancy. Embodiment 17: The composition of embodiment 15, wherein the hematological cancer comprises multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Embodiment 18: The composition according to any one of embodiments 14 to 17, wherein the hematological cancer is relapsed / refractory acute myeloid leukemia. Embodiment 19: The composition according to any one of embodiments 1 to 18, wherein the cancer is a CD33 positive, DR5 positive, 5T4 positive, HER2, HER3, and / or TROP2 positive cancer. Embodiment 20: The composition according to embodiment 19, wherein the CD33 positive cancer comprises cells expressing CD33, and wherein the CD33 expressing cells comprise myeloblast cells or malignant plasma cells. Embodiment 21: The composition according to any one of embodiments 1 to 20, further comprising at least one pharma- ceutically acceptable excipient. Embodiment 22: A method for treating cancer in a mammalian subject, such as a human, comprising administering a composition according to any one of embodiments 1 to 21. Embodiment 23: A method of treating cancer in a mammalian subject, such as a human, comprising administering (i) a radiolabeled cancer targeting agent, such as any of those disclosed herein, e.g., a radiolabeled antigen targeting agent that targets a preselected cancer associated antigen, such as any of those disclosed herein, e.g., a radiolabeled antibody that targets a preselected cancer associated antigen, such as any of those disclosed herein; and (ii) a CD47 blocking agent. Embodiment 24: The method of embodiment 22 or 23, wherein the radiotherapeutic agent comprises a radiolabeled form of an anti-CD33 monoclonal antibody or a CD33 binding fragment thereof, and the cancer is a hematological disease or disorder selected from one or more of multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, or a solid tumor cancer, such as any of those disclosed herein; or an anti-5T4 monoclonal antibody or a 5T4-binding fragment thereof, and the cancer is colorectal cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, renal cancer, or any combination thereof; or the anti-DR5 monoclonal antibody or a DR5-binding fragment thereof, and the cancer is breast cancer, triple-negative breast cancer, ovarian cancer, or prostate cancer; the anti-HER2 monoclonal antibody or a HER2-binding fragment thereof, and the cancer is pancreatic cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, or ovarian cancer; an anti-HER3 monoclonal antibody or a HER3-binding fragment thereof, and the cancer is pancreatic cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, or ovarian cancer; or The anti-TROP2 monoclonal antibody or TROP2-binding fragment thereof, and the cancer is pancreatic cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, or ovarian cancer. Embodiment 25: The method of embodiment 22 or 23, wherein the radiotherapeutic agent is a radiolabeled CD33, DR5, HER2, HER3, or anti-TROP2 targeted agent, such as a radiolabeled anti-CD33, anti-DR5, anti-5T4, anti-HER2, anti-HER3, or anti-TROP2 monoclonal antibody. Aspect 26: The radiation therapeutic agent comprises: 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Bi, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb or 103 26. The method of any one of aspects 22 to 25, comprising a radiolabel selected from Pd, Pd, or a combination thereof. Aspect 27: The method of any one of aspects 22 to 26, wherein the radiotherapeutic agent comprises a CD33 targeted agent selected from radiolabeled lintuzumab, gemtuzumab, vadastuximab, or a combination thereof, such as actinium-225 or lutetium-177 labeled lintuzumab, gemtuzumab, vadastuximab, or a combination thereof. Aspect 28: The method of any one of aspects 22 to 27, wherein the radiotherapeutic agent comprises a radiolabeled DR5 targeted agent selected from radiolabeled mapatumumab, conatumumab, lexatumumab, tigatuzumab, drozitumab, LBY-135, or a combination thereof, e.g., any of the above targeted agents labeled with actinium-225 or lutetium-177, or any combination thereof. Aspect 29: The method of any one of aspects 22 to 28, wherein the radiotherapeutic agent comprises a radiolabeled 5T4 targeted agent selected from radiolabeled MED10641, ALG.APV-527, Tb535, H6-DM5, ZV0508, or a combination thereof, e.g., any of the above-mentioned targeted agents labeled with Actinium-225 or Lutetium-177, or any combination thereof. Aspect 30: The method of any one of aspects 22-29, wherein the radiotherapeutic agent comprises a radiolabeled HER3 targeted agent selected from radiolabeled patritumab, seribantumab, lumuletuzumab, elgemtumab, AV-203, GSK2849330, or a combination thereof, e.g., any of the aforementioned targeted agents labeled with actinium-225 or lutetium-177, or any combination thereof. Aspect 31: The method of any one of aspects 22 to 29, wherein the effective amount of the actinium-225 labeled radiotherapeutic agent comprises a radiation dose of 0.1-10 μCi / kg of subject body weight and a protein dose of less than 10 mg / kg of subject body weight. Aspect 32: The method of aspect 31, wherein the effective amount of the actinium-225 labeled radiotherapeutic agent comprises a radiation dose of 0.1-2 μCi / kg of subject body weight and a protein dose of less than 5 mg / kg of subject body weight. Embodiment 33: A method according to any one of embodiments 22 to 30, wherein the CD47 blocking agent comprises a monoclonal antibody that prevents binding of CD47 to SIRPα. Embodiment 34: The method of any one of embodiments 22 to 30, wherein the CD47 blocking agent comprises magrolimab, lemzoparimab, AO-176, TTI-621, TTI-622, ALX-148, RRx-001, azelnidipine, any CD47 blocking agent disclosed herein, or any combination thereof. Aspect 35: A method according to any one of aspects 22 to 34, wherein the effective amount of the CD47 blocking agent is 0.05 to 5 mg / kg (drug mass / body weight). Aspect 36: The radiotherapeutic agent has a protein dosage of 0.1-2 μCi / kg of subject's body weight and less than 5 mg / kg of subject's body weight. 225 The method according to any one of aspects 22 to 35, comprising Ac Lintuzumab. Embodiment 37: The method according to any one of embodiments 22 to 36, wherein the cancer is a solid tumor cancer. Embodiment 38: A method according to any one of embodiments 22 to 37, wherein the cancer is a blood cancer. Embodiment 39: The method of embodiment 38, wherein the hematological cancer is a myeloid malignancy. Embodiment 40: The method of embodiment 38, wherein the hematological cancer comprises multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Embodiment 41: The composition according to any one of embodiments 38 to 40, wherein the hematological cancer is relapsed / refractory acute myeloid leukemia. Embodiment 42: The composition according to any one of embodiments 22 to 41, wherein the cancer is a CD33 positive, DR5 positive, 5T4 positive, HER2, HER3, and / or TROP2 positive cancer. Embodiment 43: The composition according to embodiment 42, wherein the cancer comprises a CD33-positive cancer comprising either or both of CD33-positive myeloblast cells and CD33-positive malignant plasma cells. Embodiment 44: Use of a therapeutically active radiolabeled cancer targeting agent, such as a radiolabeled agent that targets a cancer associated antigen, such as any of those disclosed herein, or that targets cancer cells, in combination with a CD47 blocking agent, such as any of those disclosed herein, in the preparation of a medicament for the treatment of a cancer or precancerous proliferative disorder, such as any of those disclosed herein, in a mammalian subject, such as a human patient. Embodiment 45: Use of a CD47 blockade / blocking agent, such as any of those disclosed herein, in combination with a therapeutically active radiolabeled cancer targeting drug that targets a cancer associated antigen, such as any of those disclosed herein, or that targets cancer cells, in the preparation of a medicament for the treatment of a cancer or precancerous proliferative disorder, such as any of those disclosed herein, in a mammalian subject, such as a human patient. Embodiment 46: Use of a therapeutically active radiolabeled cancer targeting agent that targets a cancer associated antigen, such as any of those disclosed herein, or that targets cancer cells, in combination with a CD47 blocking agent, such as any of those disclosed herein, for the treatment of a cancer or precancerous proliferative disorder, such as a hematological malignancy or solid cancer, such as any of those disclosed herein, in a mammalian subject, such as a human patient. Embodiment 47: The embodiment of any of embodiments 1-46, wherein the radiolabeled targeting agent comprises a targeting agent chemically conjugated to a chelating agent, the chelating agent chelating a radionuclide, such as any of those disclosed herein. Embodiment 48: The embodiment of embodiment 47, wherein the chelating agent comprises DOTA or a DOTA derivative. Aspect 49: The radionuclide is 177 Lu, 225 Ac, 131 I, or 90 The embodiment according to any one of embodiments 1 to 48, wherein Y is

[0091] In one variation, various aspects of the embodiments of the invention and embodiments of the invention are not part of, and are not used in combination with, or with, cell therapy, such as engineered cell therapy, such as CAR-T therapy. Thus, in one variation, the therapeutic methods of the invention do not include cell therapy, such as engineered cell therapy, such as CAR-T therapy.

[0092] In various aspects of the invention and in one variation of the invention, the CD47 blocking agent, such as an anti-CD47 mAb or an anti-SIRPα mAb or a SIRPα-Fc fusion protein, is not radiolabeled. In various aspects of the invention and in another variation of the invention, the CD47 blocking agent and the radiolabeled targeted or radiotherapeutic agent are separate, distinct molecules, i.e., are not part of the same molecule. Advantageously, the CD47 blocking agent increases the overall tolerance and survivability of the mammalian subject to the radiation dose delivered by the radiolabeled drug (and any external beam radiation and / or brachytherapy) without substantially reducing the lethality of the concomitant treatment against the targeted cancer cells (or targeted precancerous disorder cells), thereby allowing for the use of higher, more effective radiation doses, and / or more frequent administrations, and / or longer courses of treatment than would be used without the CD47 blocking agent. EXAMPLES

[0093] Example 1: Preparation of radiolabeled targeted drugs Targeting agents, such as antibodies or other proteins or peptides, can be prepared by, for example, combining the antibodies or other proteins or peptides with the targeting agents according to the methods described in any of U.S. Pat. Nos. 10,420,851, 9,603,954, WO 2017 / 155937, and U.S. Provisional Patent Application No. 63 / 042,651, filed December 9, 2019, entitled "Compositions and methods for preparation of site-specific radioconjugates." 131 I or 225 It may be labeled with a radionuclide such as Ac.

[0094] Radiolabeling: The antibody may be conjugated to a linker, such as any of the linkers described in the patent applications noted above. An exemplary linker includes at least dodecanetetraacetic acid (DOTA), with the goal of the conjugation reaction being to achieve a DOTA-antibody ratio of 3:1 to 5:1. 177 Lu, 90 Y, or 225 Chelation with a radionuclide such as Ac can be performed, and the efficiency and purity of the resulting radiolabeled antibody, such as an anti-CD33 antibody, can be determined by HPLC and iTLC. 225 An exemplary labeling reaction for Ac is as follows: A reaction containing 15 μl of 0.15 M NH4OAc buffer, pH=6.5 and 2 μl (10 μg) of DOTA-anti-CD33 (5 mg / ml) was mixed in an Eppendorf reaction tube and 4 μL of 0.05 M HCl. 225 Ac (10 μCi) may be added subsequently. The contents of the tube may be mixed with a pipette tip and the reaction mixture may be incubated at 37° C. for 90 minutes with shaking at 100 rpm. At the end of the incubation period, 3 μL of 1 mM DTPA solution may be added to the reaction mixture and incubated at room temperature for 20 minutes to remove unreacted DTPA. 225 Ac 225 The free DTPA can be bound in an Ac-DTPA complex using instant thin layer chromatography with a 10 cm silica gel strip and a 10 mM EDTA / saline mobile phase. 225 Ac( 225 Ac-DTPA) 225 Ac-labeled anti-CD33 ( 225 Ac-DOTA-anti-CD33) 225 The radiochemical purity of Ac-DOTA-anti-CD33 can be measured. In this system, the radiolabeled antibody remains intact at the time of application. 225 Ac-DTPA migrates with the solvent front. The strip is cut in half and analyzed in a gamma counter equipped with a pulse height analyzer. 225 Counting can be performed using channels 72 to 110 for Ac, and its daughter isotopes can be excluded.

[0095] purification:225 Exemplary radiolabeled targeting agents such as Ac-DOTA-antibodies can be purified on a PD10 column preblocked with 1% HSA or using a Vivaspin centrifugal concentrator with a 50 kDa MW cut-off, 2 x 1.5 ml washes, 3 min / spin. 225 HPLC analysis of Ac-DOTA-antibodies may be performed using a Waters HPLC system equipped with a flow-through Waters UV and Bioscan Radiation detector, using a TSK3000SW XL column eluted with PBS pH=7.4 and a flow rate of 1 ml / min.

[0096] Example 2: Specificity and stability of CD33 ARC Actinium-225( 225 The cytotoxicity of lintuzumab conjugated with radiolabeled lintuzumab (Lintuzumab-Ac) against certain cell types expressing CD33 was tested. For example, suspensions of HL60 (leukemia cells) were conjugated with various doses of radiolabeled lintuzumab (Lintuzumab-Ac). 225 ) and incubated with the dose at which 50% of the cells die (LD 50 ) was found to be 8 pCi per mL of cell suspension. In studies assessing the reactivity of radiolabeled lintuzumab with peripheral blood and bone marrow cells from non-human primates and human frozen tissues, radiolabeled lintuzumab showed reactivity only with mononuclear cells, demonstrating specificity. In further studies measuring the stability of the radiolabel on the antibody, 10 normal mice (8-week-old Balb / c female mice from Taconic Germantown, New York) were injected in the tail with 300 nCi radiolabeled lintuzumab (in 0.12 ml). Serum samples taken over a 5-day period showed that actinium-225 remained bound to lintuzumab, demonstrating the stability of the radiolabel on the antibody in vivo.

[0097] The maximum tolerated dose (MTD) of a single injection of radiolabeled lintuzumab was determined to be 3 μCi / kg of patient body weight. As a fractionated dose (e.g., two equivalent doses administered 4-7 days apart), the MTD was determined to be 2 μCi / kg per dose or 4 μCi / kg for a total dose. This data was determined by injection in patients with relapsed / refractory AML: 21 patients were injected with escalating doses of radiolabeled lintuzumab - 0.5 μCi / kg to 4 μCi / kg. The determination of the MTD was based on the severity of adverse effects observed at each dose level. Anti-leukemic effects included disappearance of peripheral blood blasts in 13 of 19 evaluable patients. Twelve of 18 patients evaluated 4 weeks after treatment had a reduction in bone marrow blasts, of which 9 had a reduction of 50% or more. Three patients were treated with 1 μCi / kg, 3 μCi / kg, and 4 μCi / kg, respectively, and had 5% or less blasts after treatment.

[0098] Example 3: Maximum Tolerated Dose in Humans and Efficacy of CD33 ARC Split-dose Lintuzumab-Ac 225 The maximum tolerated dose (MTD) of granulocyte colony stimulating factor (GCSF) support at each cycle can be determined using a dosing cycle of approximately 42 days. 225 A cycle is initiated with administration of a split dose of 1 μCi / kg of lintuzumab-Ac followed by administration of GCSF on day 9 and continuing GCSF administration according to appropriate dosing instructions until absolute neutrophil count (ANC) is greater than 1,000, which is expected to occur within 5-10 days. Peripheral blood paraprotein levels may be assessed on days 14, 21, 28, 35, and 42. Bone marrow aspirates are performed and plasma cell infiltration assessed on day 42. If the response is partial or better but less than complete remission on day 42 and the patient remains otherwise eligible, the patient will be re-administered with a new cycle at the same dose level as soon as 60 days after day 1 of the first cycle. In the absence of dose-limiting toxicity, cycles begin with the patient receiving 4 μCi / kg of lintuzumab-Ac. 225 The algorithm described above continues until a cumulative dose of

[0099] Example 4: Syngeneic Mouse Model for 5T4 Targeted Drugs Syngeneic mouse models can be used to investigate 5T4 targeting in models where the antibody is also able to react with 5T4 expressed on normal tissues. Such models provide an opportunity to observe any toxicity that may result from targeting this protein with a radioisotope warhead. Woods (Woods, AM et al. (2002) Biochem. J. 366, 353-365) reported the discovery of an antibody (9A7) reactive to mouse 5T4 and used it to screen mouse tumor lines for 5T4 expression (see Table 4; cited in Woods, 2002). Among the cell lines reported to be positive for 5T4 expression, the EMT6 breast adenocarcinoma cell line has high levels of 5T4 expression and is readily available for purchase from commercial sources to perform experiments. Furthermore, this cell line has been reported to be sensitive to irradiation. Specific mouse 5T4-reactive antibodies are available, including B3F1 (Southgate, TD et al. (2010) PLoS One 5, e9982). This antibody showed strong binding to 5T4 in ELISA, FACS, and Western blot assays, making it suitable as a targeted agent in preclinical proof-of-concept studies. Therefore, the B3F1 anti-mouse 5T4 antibody is utilized for radiotargeting to the 5T4-expressing tumor cell line EMT6.

[0100] Experimental Design: An exemplary experimental design involves conjugation of the 5T4 antibody B3F1 with the chelator DOTA, followed by 111 In or 225 The specific activity, labeling efficiency, and stability of the radiolabeled antibodies can be determined as shown in Examples 1 and 2. [Table 4]

[0101] In vitro cell killing assay 225 Ac radiolabeled B3F1 antibody. EMT6 cells were used as a positive control for 5T4 expressing cells. 225Expose to a dilution series of Ac-labeled and unlabeled DOTA-B3F1 for 1 hour. Cell viability can be measured using the XTT assay described previously herein. If necessary, a cell line that does not express 5T4, such as LL / 2 cells, can be used as a negative control (see Table 4, cited in Woods, 2002). Table 4 shows fluorescence activated cell sorting (FACS) analysis of the 9A7 antibody against a panel of mouse cell lines, where 105 cells of each cell line were stained with 9A7. The last column shows the relative reactivity of 9A7 against the panel of cell lines, with the breast cell line EMT6 being highly reactive and the lung cancer cell line LL / 2 being non-reactive.

[0102] Biodistribution experiments: To assess the binding of any antibody to normal tissues and to calculate the radiation dose absorbed in the organs. 111 The In-labeled B3F1 antibody can be used in a first round of biodistribution experiments carried out in tumor-free BALB / c mice. A second round of biodistribution experiments can be carried out using EMT6 tumor-bearing BALB / c mice to assess the specific targeting of the antibody to 5T4-expressing tumors, allowing calculation of the radiation dose absorbed in the tumor and other organs. After biodistribution experiments, tumor-bearing mice were treated with ascending single doses of 225 Treatment with Ac-DOTA-B3F1 can be used to establish the maximum tolerated dose (MTD) of the antibody. Dose ranges can be from 50 nCi to 400 nCi. Tolerability of the antibody can be determined by measurements of body weight, behavior, and blood chemistry / blood counts.

[0103] Example 5: Xenograft Mouse Model for 5T4 Targeted Drugs Xenograft mouse models can be used to determine whether therapeutic targeted drugs have an effect on human-derived cancer cells, but if the targeted drug does not cross-react with the mouse target, it mainly only provides information about the drug's cell-killing ability on the xenograft cells, and may not provide information about on-target but off-tumor effects. A number of anti-human 5T4 therapeutics have been developed against 5T4-expressing cancers, some of which are summarized in Table 1. The original description of anti-5T4 antibody sequences was provided by Hole & Stern (Hole, 1988). Antibodies for use as 5T4 targeting agents according to the present disclosure, such as in preclinical trials, may be produced using the sequences provided by Hole & Stern. Alternatively, other 5T4 antibodies that may be used may include the following antibodies or antibody portions: Mediimmune / AstraZeneca (MED10641), Aptevo Therapeutics / Alligator Bioscience (ALG.APV-527), Biotecnol / Chiome Bioscience (Tb535), Guangdong Zhongsheng Pharmaceuticals (H6-DM5), and Zova Biotherapeutics (ZV0508). Additional antibodies available as bispecific or antibody drug conjugates are listed in Table 1, providing additional 5T4 targeting agents, ie, 5T4-specific binding moieties.

[0104] The Medimmune / Astrazeneca antibodies contain engineered cysteines that can be used for site-specific conjugation of DOTA and subsequent chelation with radioisotopes such as those described in U.S. Provisional Patent Applications Nos. 62 / 945,383, filed December 9, 2019, and 63 / 119,093, filed November 30, 2020, entitled "Compositions and methods for preparation of site-specific radioconjugates," respectively. These provisional patent applications are incorporated herein by reference.

[0105] Tumor dose Biodistribution studies can be performed in 4T1 tumor-bearing mice to establish normal tissue distribution and dosimetry profiles of DR5-targeted ARC and to confirm selective uptake of radiolabeled MD5-1 antibody into the tumor. 225 As a substitute for Ac 111In because of the similar radiochemical properties of the two isotopes, and 225 This doesn't happen with Ac 111 Used again for gamma radiation from In, 111 To test the increased sensitivity and reliability of in vivo detection of In radiolabeled drugs, five groups of four female mice (6-8 weeks old) were each 111 In-labeled MD5-1 is injected and one group of mice is euthanized at each of the following time points: 2, 24, 48, 96, and 168 hours. Organs (liver, lung, kidney, spleen, brain, stomach, muscle, and tumor) can then be harvested and gamma counts measured. These measurements are used in dosimetry calculations to determine the radiation dose absorbed in each organ, including the dose delivered to the tumor.

[0106] Example 7: 225 Determination of MTD and single agent activity of Ac-MD5-1 Established subcutaneous 4T1 tumors (approximately 150–200 mm 3 Six groups, each with 6 mice, were treated with either unlabeled MD5-1 (500 ng) or increasing doses of 225 Ac-MD5-1 (50, 100, 200, 400, 500 nanocuries (nCi), 500 ng total antibody) will be injected to identify the maximum tolerated dose (MTD), defined as the highest administered activity that allows survival without more than 20% mass loss in all treated mice. Body weight and tumor measurements will be taken twice weekly for the 6-week study period, beginning upon arrival of the animals at the Invicro facility. Blood biochemistry (alanine aminotransferase, alkaline phosphatase, total bilirubin, blood urea nitrogen, calcium, phosphorus, total protein, albumin, globulin, albumin / globulin ratio, amylase, glucose, total cholesterol, lipase) and complete blood counts (CBC) will be evaluated in animals at baseline, week 3, and terminal time points during the study. Humane euthanasia criteria include a loss of more than 20% body weight or a gain of more than 10% body weight due to ascites. Any sign of pain or distress may be considered. Animal health measurements and observations can be used to determine the MTD. Observations on tumor volume and survival are recorded and 225The toxicity / tolerability profile will be considered to determine the MTD of Ac-MD5-1. During this experimental phase, preliminary antitumor efficacy can be determined by tumor measurements and survival can be used as a surrogate for lung metastasis as previously reported (Demaria, S. et al. (2005) Clin. Cancer Res. 11, 728-34).

[0107] Example 8: Combination of HER2-targeted ARC and CD47 blocking antibodies in human solid tumor cancer models These studies investigated the effect of a combination of HER2-specific targeting ARC and CD47 blocking antibodies on the human HER2-expressing ovarian cancer cell line SK-OV3. The anti-HER2 antibody trastuzumab was conjugated with p-SCN-DOTA. 225 Ac or 177 Both radioconjugates were radiolabeled with Lu. The biological activity of both radioconjugates was evaluated using human recombinant HER2 and receptor positive tumor cell lines. The cytotoxic effect of the radioconjugates and their ability to upregulate calreticulin (CRT) were evaluated on SK-OV3 cells using XTT assay and flow cytometry, respectively. To evaluate the effect of the combination of anti-HER2 ARC and CD47 antibodies in vitro, a flow cytometric macrophage phagocytosis assay was developed.

[0108] result Trastuzumab ARC has similar binding properties to natural antibodies and demonstrated specific cytotoxicity. Importantly, ARC-mediated CRT upregulation in HER2-expressing cells was demonstrated. Furthermore, the combination of HER2-targeted ARC and a CD47-blocking antibody enhanced in vitro macrophage-mediated tumor cell phagocytosis at radiation doses below the maximum tested, compared to the effect of each agent alone on phagocytosis. These findings suggest that ARC-mediated upregulation of CRT enhances stimulatory phagocytic signals and the anti-CD47 mode of action, thereby enhancing antitumor activity. Tumor xenograft studies investigating the effect of ARC treatment in combination with CD47 blockade on tumor growth were also performed. Figure 1 shows the efficacy and safety of SK-OV3 human ovarian cancer cell line in NGS mouse xenograft model with vehicle alone (control), magrolimab alone (10 mg / kg), 225 Ac-trastuzumab alone (0.025 μCi / animal) and magrolimab (10 mg / kg) 225 Graph showing the comparative effect of Ac-Trastuzumab (0.025 μCi / animal) combination on tumor growth. Each cohort consisted of 8 animals. Figure 2 shows the efficacy and safety of SK-OV3 human ovarian cancer cell line in NGS mouse xenograft model with vehicle alone (control), magrolimab alone (10 mg / kg), 117 Lu-trastuzumab alone (25 μCi / animal) and magrolimab (10 mg / kg) 117 FIG. 1 is a graph showing the comparative effect of Lu-Trastuzumab (25 μCi / animal) combinations on tumor growth. Each cohort consisted of 8 animals.

[0109] Example 9: Combination of CD33-targeted ARC and CD47 blocking antibodies in AML models These tests are 225 Ac or lutetium-177( 177 The effect of the combination of anti-CD33 ARC and CD47 blocking antibodies armed with Lu) was investigated using the in vitro human AML model cell lines U937 and HL-60. The anti-CD33 antibody lintuzumab was conjugated with p-SCN-DOTA. 225 Ac or 177The radioconjugates were radiolabeled with Lu. The biological activity of both radioconjugates was investigated using human recombinant CD33 and receptor positive cell lines U937 and HL-60. The cytotoxic effect of the radioconjugates and their ability to upregulate calreticulin (CRT) were evaluated in CD33 expressing cell lines using XTT assay and flow cytometry, respectively. To evaluate the therapeutic combination of anti-CD33 ARC and CD47 antibodies in vitro, a flow cytometric macrophage phagocytosis assay was used.

[0110] result Anti-CD33 ARC has similar binding properties to native antibodies and exhibits specific cytotoxicity. ARC-mediated upregulation of cell surface CRT in both CD33-expressing AML cells was demonstrated. Furthermore, the in vitro combination of CD33-targeting ARC and a CD47-blocking antibody enhanced macrophage-mediated tumor cell phagocytosis in both AML cell lines at radiation doses below the maximum dose tested, compared to the effect of each agent alone on phagocytosis. 4A and 4B are 225 Figure 1 shows that Ac-labeled lintuzumab induces an increase in cell surface calreticulin in human leukemia cell lines at different time points compared to control untreated cells. 225 Cell surface calreticulin (CRT) levels in AML cells (MV-4-11 and HL-60 in Fig. 4A and U937 in Fig. 4B) treated with Ac-labeled lintuzumab and untreated control cells were detected by flow cytometry at 72 hours (Fig. 4A) or 96 hours (Fig. 4B). Statistical analysis was performed using two-way ANOVA (*p<0.05). 5A, 5B, and 5C are 225 We show that combination therapy of Ac-labeled lintuzumab and anti-CD47 antibody, B6.H12 (BioXCell, Lebanon, NH, USA), enhances the phagocytosis of three human leukemia cell lines. 225Cells were treated with Ac-labeled lintuzumab for 96 h. Cells were labeled with DiD and co-cultured with DiO-labeled human macrophages in the presence of anti-CD47 mAb (1 μg / ml) for 2 h. The percentage of phagocytosis was measured by flow cytometry (macrophage DiO+ / DiD+). Statistical analysis was performed using one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001 and ****p<0.0001). In each of Figures 5A-5C, bar 1 shows the results of a nonspecific IgG control, bar 2 shows the results of anti-CD47 mAb only, and bar 3 shows the results of 100 nCi. 225 Bar 3 shows the results of Ac-labeled lintuzumab alone, and bar 4 shows the results of anti-CD47 mAb and 100 nCi 225 The results of the combination of Ac-labeled lintuzumab are shown. These findings support a novel synergistic mechanism by which CD33 ARC-targeted irradiation induces upregulation of CRT, thereby enhancing pro-phagocyte innate immune responses in combination with anti-CD47 blocking antibodies.

[0111] Example 10: Effect of a combination of HER3-targeting ARC and CD47 blocking antibodies on phagocytosis of human BxPC3 pancreatic cells FIG. 3 shows the results of the assay using non-radiolabeled anti-human HER3 IgG monoclonal antibody AT-02 alone ("HER3 mAb"), anti-human CD47 antibody alone (10 μg / mL; clone B6.H12; BioXCell catalog no. BE0019-1; "CD47 mAb"); 225 Ac-labeled AT-02 anti-HER3 mAb alone (100 nCi / mL; 225 AC-HER3 mAb), and anti-CD47 mAb (10 μg / mL). 225 1 is a graph showing the comparative effect of the combination of Ac-labeled AT-02 anti-HER3 mAb (100 nCi / mL) on phagocytosis of BxPC3 human pancreatic cancer cell line (adenocarcinoma) cells by human macrophages. As shown in the figure, the combination significantly enhanced phagocytosis of BxPC3 cells compared to either individual agent.

[0112] While various specific aspects and embodiments have been illustrated and described herein, it will be understood that various changes can be made without departing from the spirit and scope of the invention. Moreover, features described in connection with one aspect or embodiment of the invention may be used in combination with other aspects and embodiments of the invention, even if not explicitly illustrated in that combination.

Claims

1. 1. A pharmaceutical composition for treating cancer or a precancerous proliferative disorder in a mammalian subject, comprising: The pharmaceutical composition comprises an effective amount of one or more therapeutic radiolabeled cancer targeted drugs; and comprising an effective amount of one or more CD47 blocking agents; The pharmaceutical composition, wherein the one or more CD47 blocking agents comprise one or more of an anti-CD47 antibody, an anti-SIRPα antibody, a SIRPα Fc fusion protein, a CD47 antisense phosphorodiamidate morpholino oligomer (PMO), and 1-bromoacetyl-3,3 dinitroazetidine, or a pharma- ceutically acceptable salt thereof.

2. 2. The pharmaceutical composition of claim 1, wherein at least one of the one or more radiolabeled cancer targeting drugs is labeled with an alpha particle-emitting radionuclide.

3. 2. The pharmaceutical composition of claim 1, wherein at least one of the one or more radiolabeled cancer targeting drugs is labeled with a beta particle-emitting radionuclide.

4. 2. The pharmaceutical composition of claim 1, wherein the one or more radiolabeled cancer targeting drugs comprise one or more of a monoclonal antibody against CD33 or an antigen-binding fragment thereof, a monoclonal antibody against DR5 or an antigen-binding fragment thereof, a monoclonal antibody against 5T4 or an antigen-binding fragment thereof, a monoclonal antibody against HER2 or an antigen-binding fragment thereof, or a monoclonal antibody against HER3 or an antigen-binding fragment thereof, a monoclonal antibody against TROP2 or an antigen-binding fragment thereof, and a monoclonal antibody against MUC1 or an antigen-binding fragment thereof.

5. The one or more radiolabeled cancer targeting drugs include: 225 and / or a composition of Ac-labeled antibody and a non-radiolabeled antibody, said composition comprising a radiation dose of 0.1-2.0 μCi / kg of said subject's body weight and a protein dose of 0.1-5.0 mg / kg of said subject's body weight.

5. The pharmaceutical composition of claim 4, wherein the CD47 blocking agent comprises a total dosage of 0.05-5.0 mg / kg of the subject's body weight.

6. 5. The pharmaceutical composition of claim 4, wherein the monoclonal antibody is an anti-CD33 antibody and the cancer or precancerous proliferative disorder is a solid tumor, osteosarcoma, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm.

7. 5. The pharmaceutical composition of claim 4, wherein the monoclonal antibody is an anti-5T4 antibody and the cancer or precancerous proliferative disorder is colorectal cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, renal cancer, or any combination thereof.

8. 5. The pharmaceutical composition of claim 4, wherein the monoclonal antibody is an anti-DR5 antibody and the cancer or precancerous proliferative disorder is breast cancer, triple negative breast cancer, ovarian cancer, or prostate cancer.

9. 5. The pharmaceutical composition of claim 4, wherein the monoclonal antibody is an anti-HER3 antibody and the cancer or precancerous proliferative disorder is pancreatic cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, or ovarian cancer.

10. 5. The pharmaceutical composition of claim 4, wherein the monoclonal antibody is an anti-HER2 antibody and the cancer or precancerous proliferative disorder comprises HER2-expressing cancer cells.

11. The pharmaceutical composition of claim 10, wherein the cancer or precancerous proliferative disorder is breast cancer or ovarian cancer.

12. The pharmaceutical composition of claim 4 , wherein the monoclonal antibody is an anti-TROP2 antibody and the cancer or precancerous proliferative disorder comprises TROP2-expressing cancer cells.

13. 13. The pharmaceutical composition of claim 12, wherein the cancer or precancerous proliferative disorder is pancreatic cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, or ovarian cancer.

14. 2. The pharmaceutical composition of claim 1, wherein the one or more radiolabeled cancer targeting drugs comprise a radiolabeled PSMA targeting drug.

15. The pharmaceutical composition of claim 14, wherein the cancer or precancerous proliferative disorder is prostate cancer.

16. 2. The pharmaceutical composition of claim 1, wherein the cancer or precancerous proliferative disorder is a solid cancer or a hematological malignancy.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein said one or more CD47 blocking agents are separate and distinct molecules from said one or more therapeutic radiolabeled cancer targeting agents.

18. Use of a therapeutic radiolabeled cancer targeted drug in combination with a CD47 blocking agent for the treatment of a solid tumor cancer or hematological malignancy in a non-human mammalian subject.

19. The therapeutic radiolabeled cancer targeting agent is selected from the group consisting of CD33, DR5, 5T4, HER2 (ErbB2; HER2 / neu), HER3, TROP2, mesothelin, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL-1, GD2, GD3, B-cell maturation antigen (BCMA), TnAg, prostate-specific membrane antigen (PSMA), ROR1, FLT3, fibroblast activation protein (FAP), somatostatin receptor, somatostatin receptor 2 (SSTR2), somatostatin receptor 5 (SSTR5), gastrin-releasing peptide receptor (GRPR), NKG2D ligands (e.g., MICA, MICB, RAET1E / ULBP4, RAET1G / ULBP5, RAET1H / ULBP2, RAET1 / ULBP1, RAET1L / ULBP6, and RAET1N / ULBP3), LYPD3 (C4. 4A), nectin 4, urokinase plasminogen activator receptor (uPAR), folate receptor alpha (FOLR1), CUB-domain-containing protein 1 (CDCP1), glypican-3 (GPC3), tenascin, tenascin-C, CEACAM5, cadherin-3, CCK2R, neurotensin receptor type 1 (NTSR1), human kallikrein 2 (hK2), norepinephrine transporter, integrin alpha-V-beta-6, CD37, CD66, CXCR4, fibronectin extradomain EBV-derived dehydrogenase B (EBD), LAT-1, carbonic anhydrase IX (CAIX), B7-H3 (also known as CD276), disialoganglioside GD2 antigen (GD2), calreticulin, phosphatidylserine, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, interleukin-11 receptor a (IL-11Ra), PSCA, PRSS21, VEGFR2, LewisY, CD24, platelet-derived growth factor receptor-beta (PDGFRβ), SSEA-4 , CD20, folate receptor alpha (FRa), MUCl, epidermal growth factor receptor (EGFR), EGFRvIII, NCAM, prostase, PAP, ELF2M, ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, fucosyl GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1 / CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE A1, MAGEA3, MAGEA3 / A6, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, prostein, survivin and telomerase, PCTA-1 / galectin 8, KRAS, MelanA / MART1, Ras mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, TRP-2, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxylesterase, mut 19. The use of claim 18, which targets a cancer-associated antigen selected from hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, GPA7, and IGLL1.

20. 20. The use according to claim 18 or 19, wherein said therapeutic radiolabeled cancer targeting drug is labeled with an alpha particle emitting radionuclide.

21. 20. The use according to claim 18 or 19, wherein the therapeutic radiolabeled cancer targeting drug is labeled with a beta particle emitting radionuclide.

22. 20. The use of claim 18 or 19, wherein the therapeutic radiolabeled cancer targeting drug and the CD47 blocking agent are separate and distinct molecules.

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