Conjugates for targeted radiotheranostics

Abstract

The present disclosure provides, inter alia, a conjugate that can be radiolabeled and administered to a subject for diagnosing and treating a cancer.

Description

Attorney Docket No.: 3014529.000044CONJUGATES FOR TARGETED RADIOTHERANOSTICSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Provisional Patent Application Serial No. 63 / 691 ,293, filed on September 5, 2024, the entire content of which is hereby incorporated by reference.FIELD OF DISCLOSURE

[0002] The present disclosure relates to, inter alia, a conjugate for radiotheranostics and methods for diagnosing and treating a cancer, in a subject in need thereof using the same.

[0003] Targeted radionuclide therapy (TRT) is a widely used cancer treatment option that employs radiopharmaceuticals to target and deliver ionizing radiation to kill cancer cells (1 -3). TRTs have been used for cancer therapy demonstrating increased overall survival as exemplified in patients with thyroid cancer, prostate cancer, and neuroendocrine tumours (4). As a frontline type of current cancer therapy, TRT delivers a therapeutic dose of radiation to cancer cells using radioactive drugs (radiopharmaceuticals) labelled with radionuclides such as alpha(a)- or beta([3')-emitting radioisotopes (3,5). TRT with a emitters (a-TRT) offers several advantages compared to P’ emitters, mainly due to the delivery of high-energy a-particles (5-9 MeV) to the tumour with a short pathlength (50-100 pm) and high linear energy transfer (LET), causing less toxicity to neighbouring healthy tissues (6). However, radiopharmaceuticals for a-TRT cannot directly be used for imaging applications in vivo to assess their biodistribution and target binding and retention profile as crucial criteria for patient selection and dose calculation in the clinical setting (1 ). The development and application of radiopharmaceuticals combining targeted imaging and therapy, alsocalled radiotheranostics, represent a rapidly evolving field in oncologic nuclear medicine (8,9). Ideal radiotheranostics use different radioisotopes for imaging and therapy of the same chemical element to ensure similar pharmacokinetics, metabolism and biodistribution patterns (1 ,8). Typical examples of ideal radionuclide pairs in radiotheranostics include64Cu / 67Cu, ^Y / ^Y,124l / 131l,152Tb / 161Tb,133La / 135La and203Pb / 212Pb (11-14). In addition, physical half-life, availability, and production costs also require special consideration in the design and development of radiotheranostics (10).

[0004] The203Pb / 212Pb radionuclide pair has recently gained much attention for developing radiotheranostics for TRT (12,13).203Pb emits y-photons through electron capture, allowing detection with single-photon emission computed tomography (SPECT) for diagnostic imaging, whereas212Pb decays by emitting P'-particles and a-particles suitable for delivering therapeutic doses of radiation to cancer cells (13,14).

[0005] Accordingly, there is a need for developing radiotheranostics compounds, compositions, and methods for a-TRT that targets various cancers. Aspects of this disclosure are directed to meeting these and other needs.SUMMARY

[0006] Aspects of the present disclosure relate to a conjugate having the formula A-(L-C)n, wherein A is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein that is selective for a target other than epidermal growth factor receptor (EGFR), L is a bond or a linker, C is a lead specific chelating moiety according to Formula 5a,Formula 5a each Ri is independently hydrogen or an alkyl group,R2 is -OR1, -NH2 or a bond connecting the lead specific chelating moiety,C, to the linker, L,R4 and Rs are independently hydrogen or a bond connecting the lead specific chelating moiety to the linker, L, provided (i) at least one of R4 and Rs is hydrogen, and (ii) each of R4 and Rs is hydrogen when R2 is a bond connecting the lead specific chelating moiety, C, to the linker, L, and n is at least 1 .

[0007] In one embodiment, in a case where the other OR1 groups in Formula 5a are each OH, R2 is other than an OH group, such as -NH2, -OR1 where R1 is an alkyl group, or a bond connecting the lead specific chelating moiety, C, to the linker, L.

[0008] Aspects of the present disclosure relate to a process for the preparation of a compound suitable for radiolabeling comprising reacting a binding moiety A that is selective for a target other than epidermal growth factor receptor (EGFR), and that is any of a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein, and comprises one or more lysine residues, with a lead specific chelating moiety C corresponding to any of Formulas 3a, 3b and 3cFormula 3bwhereinRi is hydrogen or an alkyl group.

[0009] Aspects of the present disclosure relate to a method of radiolabeling a conjugate corresponding to any of Formula 1a, Formula 1 b or Formula 1 cwhereinA is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein that is selective for a target other than epidermal growth factor receptor (EGFR),L is a bond or linker,R3 is -OR1 or -NH2, wherein R1 is an alkyl group, and n is at least 1 , the method comprising:combining the conjugate with a lead radioisotope in aqueous solution at a temperature of no more than 60°C.

[0010] Aspects of the present disclosure relate to a method of imaging or diagnosing a subject suffering from a cancer associated with overexpression of a target that is other than epidermal growth factor receptor (EGFR), the method comprising administering a conjugate as described herein, as radiolabeled with203Pb (Pb-203), to the subject, and imaging tissue having the radiolabeled conjugate compound bound thereto.

[0011] Aspects of the present disclosure relate to a method of treating a subject suffering from a cancer or other diseases associated with overexpression of a target that is other than epidermal growth factor receptor (EGFR), the method comprising administering a conjugate as described herein, as radiolabeled with212Pb (Pb-212), to the subject, in a dosage sufficient to kill tumor cells or diseased cells or tissues.

[0012] A method of diagnosing and treating a subject suffering from a cancer associated with overexpression of a target other than EGFR, the method comprising: diagnosing the subject by administering conjugate described herein, as radiolabeled with203Pb (Pb-203), and imaging tissue having the radiolabeled conjugate compound bound thereto to diagnose the subject as being afflicted with the cancer; and treating the subject diagnosed as being afflicted by the cancer, by administering a conjugate as described herein, as radiolabeled with212Pb (Pb-212), in a dosage sufficient to kill cancer cells.

[0013] Aspects of the present disclosure relate to the use of the conjugates as described herein, as radiolabeled with203Pb (Pb-203), to the subject for medical imaging and / or diagnosis or monitoring of a subject suffering from cancer.

[0014] Aspects of the present disclosure relate to the use of the conjugates as described herein, as radiolabeled with212Pb (Pb-212), for treatment of a subject suffering from cancer.

[0015] Aspects of the present disclosure relate to an aqueous formulation comprising a conjugate as described herein, as radiolabeled with a lead radioisotope, wherein the formulation comprises a buffer and optionally further comprises a stabilizercomprising any one or more of ascorbic acid, sodium acetate, gentisic acid, a chelator (e.g. DTPA or DSMA), and ethanol.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIGS. 1A-1C show the LC-MS chromatograms of PSC-trastuzumab (A), PSC-sacituzumab (B) and PSC-M5A (C) conjugates in accordance with Example 3.

[0017] FIGS. 2A-2C show the deconvoluted mass spectra of PSC-trastuzumab (A), PSC-sacituzumab (B) and PSC-M5A (C) conjugates in accordance with Example 3.

[0018] FIGS. 3A-3C illustrates the binding specificity of [203Pb]Pb-PSC- trastuzumab (A), [203Pb]Pb-PSC-sacituzumab (B) and [203Pb]Pb-PSC-M5A (C) in accordance with Example 5.

[0019] FIGS. 4A-4B illustrate the binding kinetics of sacituzumab (A) and sacituzumab-PSC (B) to human TROP2 protein in accordance with Example 6.

[0020] FIG. 5 is a graph showing the % ID / g of [203Pb]Pb-PSC-M5A in accordance with Example 7.DETAILED DESCRIPTION

[0021] As used herein, the terms “comprising”, “having”, “including”, and “containing” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps, even if a feature / component defined as a part thereof consists or consists essentially of specified feature(s) / component(s). The term “consisting essentially of” if used herein in connection with a compound, composition, use or method, denotes that additional elements and / or method steps may be present, but that these additions do not materially affect the manner in which the recited compound, composition, method or use functions. The term “consisting of” if used herein in connection with a feature of a compound, composition, use or method, excludes the presence of additional elements and / or method steps in that feature. A compound, composition, use or methoddescribed herein as comprising certain elements and / or steps may also, in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps, whether or not these embodiments are specifically referred to. A use or method described herein as comprising certain elements and / or steps may also, in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps, whether or not these embodiments are specifically referred to.

[0022] A reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one” and “one or more than one”.

[0023] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range including all whole numbers, all integers and, where suitable, all fractional intermediates (e.g., 1 to 5 may include 1 , 1.5, 2, 2.75, 3, 3.80, 4, and 5 etc.).

[0024] Unless otherwise specified, “certain embodiments”, “various embodiments”, “an embodiment” and similar terms includes the particular feature(s) described for that embodiment either alone or in combination with any other embodiment or embodiments described herein, whether or not the other embodiments are directly or indirectly referenced and regardless of whether the feature or embodiment is described in the context of a method, product, use, composition, compound, et cetera.

[0025] As used herein, the terms “treat”, “treatment”, “therapeutic” and the like include ameliorating symptoms, reducing disease progression, improving prognosis and reducing recurrence.

[0026] As used herein, the term “conjugate” refers to a compound having a binding moiety that is linked to a chelating moiety, such as a metal chelating moiety,either via direct bond or via a linker. For example, the chelating moiety may be a compound capable of chelating radionuclides, such as203Pb and / or212Pb. The binding moiety may be capable of selectively binding to a cellular target, and may for example be any of a peptide, protein, monoclonal antibody, polyclonal antibody, antibody fragment, or a synthetic protein. According to certain embodiments, a conjugate that includes an antibody or antibody fragment may be an “immunoconjugate”.

[0027] As used herein, the term “radiopharmaceutical” refers to a compound that is labeled with a radionuclide and is suitable for medical purposes, including treatment and diagnostic purposes, such as treatment of a disease state, including cancer (a radiotherapeutic), or diagnostic or imaging applications (a radiodiagnostic).

[0028] As used herein, the term “antibody” is used in the broadest sense and includes polyclonal antibodies and fragments thereof, monoclonal antibodies and fragments thereof, and includes intact antibodies and antibody fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific and trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di- scFv, tandem tri-scFv. As used herein, the “antibody fragment ” should be understood to encompass functional antibody fragments thereof, including functional (antigen-binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragment. The term “antibody” also encompasses intact or full- length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.

[0029] The term “amino acid residue” or “amino acid” includes reference to an amino acid that is incorporated into a protein, polypeptide, and / or peptide. The term “polypeptide” includes any polymer of amino acids or amino acid residues. The term “polypeptide sequence” refers to a series of amino acids or amino acid residues which physically comprise a polypeptide. A “protein” is a macromolecule comprising one ormore polypeptides or polypeptide “chains,” such as for example a naturally occurring or synthetic protein. A “peptide” is a small polypeptide of a size of 2 to 20 amino acid residues. The term “amino acid sequence” refers to a series of amino acids or amino acid residues which physically comprise a peptide or polypeptide or protein depending on the length.

[0030] The terms “amino acid,” “amino acid residue,” “amino acid sequence,” or polypeptide sequence include naturally occurring amino acids (including L and D isosteriomers) and, unless otherwise limited, also include known analogs of natural amino acids that can function in a similar manner as the common natural amino acids, such as selenocysteine, naphthylalanine, norleucine, pyrrolysine, N-formylmethionine, gamma-carboxyglutamate, hydroxyprolinehypusine, pyroglutamic acid, and selenomethionine (see, e.g., Ho J et al., ACS Synth Biol 5: 163-71 (2016); Wang Y, Tsao M, Chembiochem 17: 2234-9 (2016)).

[0031] As used herein, the term “immunoconjugate” refers to a compound comprising at least one antigen binding region derived from an antibody (e.g., variable regions or complementarity determining regions) further coupled to at least one chelating moiety, such as the lead (Pb) specific chelating moiety described herein. The chelating moiety may, for example be conjugated to one or more lysine or cysteine resides of an antibody or antibody fragment having the antigen binding region.

[0032] As used herein, “linker” refers to any chemical group that serves to couple a binding moiety to a chelating moiety, such as a lead specific chelating moiety. That is, the “linker” may correspond to the moiety “L” in any of the Formulas 1 a, 1 b, and 2b herein (“L” may also simply be a direct bond between the lead specific chelating moiety and the binding moiety A, in certain embodiments). For example, in certain embodiments, the linker can comprise an isothiocyanate group that is capable of forming a thiourea linkage with lysine residues present in a binding moiety A corresponding to an antibody.

[0033] A binding moiety or conjugate having the binding moiety that “binds” a cellular target of interest is one that binds the cellular target with sufficient affinity that is measurably different from a non-specific interaction. Selective binding can bemeasured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. “Selective” binding refers to binding moiety or conjugate comprising the binding moiety that is capable of binding a cellular target with sufficient affinity such that the binding moiety and / or conjugate is useful as a diagnostic and / or therapeutic agent with respect to the target. Conversely, a binding moiety or conjugate comprising the binding moiety that is not selective for a certain cellular target is one that does not bind the cellular target with sufficient affinity to be useful as a diagnostic and / or therapeutic agent with respect to the target. For example, a binding moiety or conjugate comprising the binding moiety that is not selective for EGFR is one that does not bind to EGFR with sufficient affinity to be useful as a diagnostic and / or therapeutic agent with respect to cancer and / or tumor cells expressing EGFR, even though it may be selective for other targets that may be suitable for cancer diagnosis and / or treatment. The “target” as used herein may be any biological target that is associated with a disease state, such as cancer, and may be for example be understood to be a protein, peptide, sequence, antigen, epitope, polysaccharide, lipid, or other biological structure that is associated with the disease state, and that may be overexpressed in certain types of cancers. In one embodiment, the extent of binding of the binding moiety and / or conjugate to an unrelated target is less than about 10% of the binding of the binding moiety and / or conjugate to its target as measured, e.g., by a radioimmunoassay. A “target selective” binding moiety, as used herein, is one that specifically binds to the target with sufficient specificity and affinity to be useful in targeting a therapeutic, targeting a diagnostic, or method of detecting the target in a biological sample or tissue from a subject. For example, an “antigen specific” antibody or immunoconjugate, as used herein, is one that specifically binds to the antigen with sufficient specificity and affinity to be useful in targeting a therapeutic, targeting a diagnostic, or method of detecting the antigen in a biological sample or tissue from a subject. In some embodiments, binding moiety and / or conjugate, such as an immunoconjugate or antibody construct or target imaging complex or radioimmunoconjugate that binds to its target has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10'8M to 10'10M, e.g., from 10'8M to 10'13M).

[0034] As used herein, the term “diagnostic agent” includes an “imaging agent”. As such, a “diagnostic radionuclide” includes radionuclides that are suitable for use in imaging agents.

[0035] The term “subject” refers to an animal (e.g. a mammal or a non-mammal animal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal (e.g., mouse, rat, rabbit, hamster and the like). The subject may be an agricultural animal (e.g., equine, ovine, bovine, porcine, camelid and the like) or a domestic animal (e.g., canine, feline and the like). In some embodiments, the subject is a human.

[0036] The terms “cancer” and “cancerous” as used herein refer to or describe the pathological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, melanoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), skin cancer, melanoma, lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), glioblastoma, cervical cancer, ovarian cancer (e.g., high grade serous ovarian carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC)), bladder cancer (e.g., urothelial bladder cancer), testicular (germ cell tumor) cancer, hepatoma, breast cancer, brain cancer (e.g., astrocytoma), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (e.g., renal cell carcinoma, nephroblastoma or Wilms’ tumor), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer. Additional examples of cancer include, without limitation, retinoblastoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including nonHodgkins lymphoma (NHL), multiple myeloma and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas,hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi’s sarcoma, melanoma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, anaplastic astrocytoma, basal cell carcinoma (basal cell epithelioma), bile duct cancer, small cell bladder cancer, metastatic breast cancer, metastatic colorectal cancer, epithelial ovarian cancer, fallopian tube cancer, gastric adenocarcinoma, glioblastoma multiforme (GBM), recurrent glioblastoma multiforme (GBM), gliomas, gliosarcoma, head and neck squamous cell carcinoma (HNSCC), recurrent head and neck squamous cell carcinoma, malignant pleural mesothelioma head and neck cancer, Hodgkin lymphoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma, squamous nonsmall cell lung cancer, squamous carcinoma of the lung, relapsed or refractory small-cell lung cancer, treatment-resistant melanoma, metastatic melanoma, Merkel cell carcinoma, neuroendocrine cancer, large cell neuroendocrine cancer, neuroendocrine tumors (NETS), ovarian carcinoma, papillary carcinoma, peritoneal cancer, neuroendocrine prostate cancer, hormone- refractory prostate cancer, castrationresistant prostate cancer, soft tissue sarcoma, and squamous cell carcinoma.

[0037] As used herein, the term “epidermal growth factor receptor (EGFR)” refers to a type 1 membrane protein of 170 kDa, which is used interchangeably with an epithelial cell proliferation factor receptor or epidermal cell growth factor receptor, and is a cell surface receptor for extracellular protein ligands of the epidermal growth factor family, a subfamily of four closely related kinases, EGFR, HER2 / c-neu, HER3, and HER4. As used herein, “EGFR+” or “EGFR positive” refers to cells or tissues that express EGFR. EGFR+ tumors or EGFR+ cancers refer to tumors or cancers express EGFR.

[0038] As used herein, the terms “salt” and “solvate” have their usual meaning in chemistry. As such, when the compound is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free baseforms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts, solvates and counter-ions are intended, unless a particular form is specifically indicated.

[0039] In certain embodiments, the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject. As used herein, “pharmaceutically acceptable” means suitable for in vivo use in a subject, and is not necessarily restricted to therapeutic use, but also includes diagnostic use. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffers, stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66:1 -19), or Remington-The Science and Practice of Pharmacy, 21 st edition (Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia), each of which is incorporated by reference in its entirety.

[0040] As used herein, the term “alkyl group” encompasses saturated linear or branched carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In other embodiments, alkyl groups are "lower alkyl" groups having one to about six carbon atoms. Examples of such groups include, but are not limited thereto, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, ethylhexyl, octyl and the like.

[0041] As used herein, the term “radionuclide” or “radioisotope” includes, but is not limited to, an alpha emitting radionuclides, beta-emitting radionuclides, and / or gamma-emitting radionuclides, such as, e.g., any one of Y-86, Y-90, Lu-177, In-111 , Re-186, Re-188, Sr-89, Sm-153, Ac-225, Bi-213, Po-213, Bi-212, Ra-223, Ra-224, Tc- 99m, Th-227, Tb-149, Tb-161 , Ga-68, Cu-64, Cu-67, Zr-89, Cs-137, Pb-203, Pb-212, and Pd-103, among others. For example, lead radionuclides can include any of Pb-196,Pb-197, Pb-198, Pb-199, Pb-200, Pb-201 , Pb-202, Pb-203, Pb-204, Pb-205, Pb-206, Pb-207, Pb-208, Pb-209, Pb-210, Pb- 211 , Pb-212, Pb-213, Pb-214, Pb-215, and Pb- 216. As used herein, the expressions “XE” and “E-x”, where “E” represents the element and “x” represents the particular elemental isotope, are equivalent and have the same meaning. For example, “xPb” and “Pb-x” (and “lead-x”) are equivalent and have the same meaning, such that “203pb” is equivalent to “Pb-203” (and to “lead-203”), and “212Pb” is equivalent to “Pb-212” (and “lead-212”).

[0042] As used herein, lead (Pb) refers to the lead element and includes isotopes of both radioactive and observationally stable. The isotopes of Pb include, but are not limited to, Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb-201 , Pb-202, Pb-203, Pb-204, Pb-205, Pb-206, Pb-207, Pb-208, Pb-209, Pb-210, Pb- 211 , Pb-212, Pb-213, Pb-214, Pb-215, and Pb-216.

[0043] Targeting vectors in radiotheranostics for TRT encompass small molecules, peptides, antibodies, and nanoparticles, among other things (4). Among the targeting vector landscape, monoclonal antibodies (mAb) display exceptional target specificity, making mAb excellent candidates for TRT.Conjugate

[0044] Accordingly, one aspect of the present disclosure is directed to a conjugate for radiotheranostics. Generally speaking, the conjugate comprises a binding moiety A that is bound to a lead specific chelating moiety, either via a direct bond or via a linker, having the formula A-(L-C)n, where n is at least 1 , A is the binding moiety, L is a bond or linker, and C is a lead specific chelating moiety. According to one embodiment, the lead specific chelating moiety C has a formula according to Formula 5a,Formula 5a

[0045] where in Formula 5a, each Ri is independently hydrogen or an alkyl group,R2 is -ORi, -NH2 or a bond connecting the lead specific chelating moiety, C, to the linker, L,R4 and Rs are independently hydrogen or a bond connecting the lead specific chelating moiety to the linker, L, provided (i) at least one of R4 and Rs is hydrogen, and (ii) each of R4 and Rs is hydrogen when R2 is a bond connecting the lead specific chelating moiety, C, to the linker, L, and n is at least 1 .

[0046] In one embodiment, in a case where the other OR1 groups in Formula 5a are each OH, R2 is other than an OH group, such as -NH2, -OR1 where R1 is an alkyl group, or a bond connecting the lead specific chelating moiety, C, to the linker, L.

[0047] According to one embodiment, a conjugate according to the present disclosure is shown in any of Formulas 1 a, 1 b and 1 c below:Formula 1b

[0048] In Formulas 1 a, 1 b and 1c,

[0049] A is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein that is selective for a target that is other than epidermal growth factor receptor (EGFR),L is a bond or a linker,Rs is -ORi or -NH2, wherein R1 is an alkyl group; and n is at least 1 .

[0050] The chelating moiety in Formulas 5a and 1a-1c is a lead-specific chelating moiety derived from 1 ,4,7,10-tetraazacyclododecane-7-acetamide-1 ,4,10-triacetic acid (lead specific chelator (PSC)), as described in further detail below. Furthermore, the binding moiety A is one that is selective for a target other than epidermal growth factor receptor (EGFR), and may be any selected from the group consisting of a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein. The number of chelating moieties bound to the antibody A via L (which is a bond or linker) is at least 1 , but may be at least 2, at least 3, at least 4, at least 6, at least 7, at least 8, and / or at least 10 (e.g., n in Formula 1a above is an integer between 1 -20, such as between 1-8). In one embodiment, the average number of chelating moieties bound tothe antibody A in a formulation containing the conjugate is in the range of 3-5 (e.g. n is from 3-5, such as from 4-5). In another embodiment, the average number of chelators bound to the antibody A in a formulation containing the conjugate is in the range of 3-20 (e.g. n is from 5-15, such as from 7-12).

[0051] According to one embodiment, the chelating moiety in any of Formulas 5a and 1a-1c is bound to the binding moiety A via a linker L comprising a thiourea linkage, as shown for example in Formula 2a, 2b and 2c below, where n is any integer between 1 -20, such as between 1-8, as described above. In Formula 2a, 2b and 2c, Z is -NH- and is the residue of a primary amine moiety comprised by A, which NH group is contributed by the binding moiety A to participate in the thiourea linkage. As shown, the binding moiety may contribute a plurality of NH groups to form thiourea linkages with the linker L, in a case where n is greater than 1.

[0052] The conjugate A-(L-C)n, such as any of the conjugates according to any ofFormulas 5a, 1 a-1 c and / or 2a-2c may be further labeled, such as with a lead (Pb)isotope, and specifically with a lead radioisotope, to provide a theranostic compound that can be used for diagnostic and / or therapeutic purposes. Examples of the labeled conjugates are shown in Formulas 1 a-1 , 2a-1 , 2b-1 and 2c-1 below.Formula 1 a-1

[0053] In Formula 1a-1 above,xPb is a lead isotope, n is at least 1 , A is the binding moiety, and L is a bond or linker. The corresponding Formulas 1 b and 1 c shown above can be similarly labeled with a lead isotope, analogously to the structure shown in Formula 1a-1.

[0054] In Formula 2a-1 above, A is the binding moiety, the adjacent -NH- group is the residue of a primary amine moiety comprised by A, n is at least 1 , andxPb is an isotope of lead.

[0055] In Formula 2b-1 above, A is the binding moiety, the adjacent -NH- group is the residue of a primary amine moiety comprised by A, n is at least 1 , andxPb is an isotope of lead.Formula 2c- 1

[0056] In Formula 2c-1 , A is the binding moiety, the adjacent -NH- group is the residue of a primary amine moiety comprised by A, n is at least 1 , andxPb is an isotope of lead.

[0057] Further disclosure of the conjugate, compounds, formulations, and methods therewith, are disclosed below.Chelating Moiety

[0058] The chelating moiety used to prepare the conjugate described herein is a lead specific chelating moiety that is based on the lead specific chelator (PSC) 2,2’- (4, 10-bis(2-amino-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecane-1 , 7-d iy l)d iacetic acid compound shown in Formula 4 below.Formula 4

[0059] The chelating moiety can be modified and / or derivatized to link to the binding moiety A, such as by connecting the chelating moiety at any one or more of the locations *, ** or *** in the Formula 5b below.

[0060] In Formula 5b above, each Ri may independently be hydrogen, an alkyl group, or a protecting group, such as a tert-butyl group. R2 in Formula 5b can be OR1 or can be NH2. For example, tert-butyl groups may be provided as protecting groups during synthesis of the derivatized chelating moiety and / or conjugate, and may be removed at an appropriate point during synthesis or after forming the final conjugate. In one embodiment, in a case where the other OR1 groups in Formula 5b are each OH, R2 is other than an OH group, such as NH2 or OR1 where R1 is an alkyl group According to certain embodiments, for example, a derivatized PSC can be prepared from a 1 ,4,7,10-tetraacecyclododecane-1 ,7-bis(t-butyl acetate) precursor via a monoamide (43).

[0061] According to certain embodiments, the lead specific chelator (PSC) can be derivatized to add an isothiocyanate moiety (NCS) that is linked to the chelator through a benzyl group, as shown for example in Formula 3a below (as connected at point * in Formula 5b):

[0062] Formulas 3b and 3c further depict the chelator (PSC) as derivatized at the connection points ** and ***, respectively, in Formula 5b.

[0063] In each of Formulas 3a-3c above, each Ri may independently be hydrogen, an alkyl group, or a protecting group, such as a tert-butyl group, as described for Formula 5a above. Accordingly, in some embodiments of the present disclosure, the derivatized chelator that is used to prepare the conjugate is PSC is 2,2'-(4-(2-amino- 2-oxoethyl)-10-(2-((4-isothiocyanatobenzyl)amino)-2-oxoethyl)-1 ,4,7,10 tetraazacyclododecane-1 ,7-diyl) diacetic acid (PSC-NCS), corresponding to Formula 3a above, where each Ri is hydrogen (11 ). Other derivatized lead-specific chelating moieties may also be used.

[0064] According to certain embodiments, the isothiocyanate group of the derivatized lead-specific chelators of any of Formulas 3a-3c may be reacted with a suitable site on the binding moiety A, to form a thiourea linkage with the binding moiety. For example, the isothiocyanate group may react with a lysine residue, or other suitable residue (e.g. a residue having an amine group), that may be present in the binding moiety A. Furthermore, as described above, in certain embodiments a plurality of chelating moieties may be linked to the binding moiety A, such as for example byreaction of a plurality of NCS-derivatized lead specific chelators with a plurality of lysine residues in the binding moiety A. Formulas 2a-2b below show general formulas for a conjugate having a moiety A which is bound to at least one, or a plurality, of lead specific chelating moieties, via a thiourea linkage formed via reaction of a primary amine moiety comprised by binding moiety A with an isothiocyanate group on the PSC-NCS derivatized lead-specific chelator of any of Formulas 3a, 3b and 3c. As shown in Formulas 2a-2b below, Z is -NH- and is the residue of a primary amine moiety comprised by A, and participates in the thiourea linkage, to link the chelating moiety to the binding moiety A via the thiourea group.

[0065] In Formulas 2a-2c above, A is the binding moiety, n is at least one, as described above, and Z is -NH- and is the residue of a primary amine moiety comprised by A.Radionuclide

[0066] The lead specific chelating moiety is capable of chelating a lead isotope, such as a lead radionuclide. The conjugate having the chelated lead radionuclide may be suitable for theranostic methods, such as imaging and diagnosis, as well as therapeutic treatments. Lead isotopes that the lead specific chelating moiety may be capable of chelating can include both radioactive (radionuclide) and non-radioactive isotopes, for example, any of Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb-201 , Pb- 202, Pb-203, Pb-204, Pb-205, Pb-206, Pb-207, Pb-208, Pb-209, Pb-210, Pb- 211 , Pb- 212, Pb-213, Pb-214, Pb-215, and Pb-216. Of these, the lead radionuclides (e.g. radioactive lead isotopes) that the lead specific chelating moiety is capable of chelating include any selected from the group consisting of Pb-196, Pb-197, Pb-198, Pb-199, Pb- 200, Pb-201 , Pb-202, Pb-203, Pb-205, Pb-209, Pb-210, Pb- 211 , Pb-212, Pb-213, Pb- 214, Pb-215, and Pb-216. According to certain embodiments, the lead radionuclide that is conjugated by the lead specific chelating moiety comprises any of Pb-203 or Pb-212. Pb-203 emits y-photons through electron capture, allowing detection with single-photon emission computed tomography (SPECT) for diagnostic imaging, whereas Pb-212 decays by emitting |3’-particles and a-particles suitable for delivering therapeutic doses of radiation to cancer cells (13,14). Accordingly, in one embodiment, the conjugate comprises a lead specific chelating moiety that is labeled with lead-203, for diagnostic and / or imaging applications. In another embodiment, the conjugate comprises a lead specific chelating moiety that is labeled with lead-212, for therapeutic treatment applications, such as in the treatment of cancer.

[0067] Formulas 1a-1 , 2a-1 , 2b-1 and 2c-1 below show: the general conjugate of Formula 1a containing the lead specific chelating moiety as radiolabeled with a lead isotope such as a lead radionuclide (Formula 1 a-1 ); and the more specific conjugate (Formulas 2a, 2b and 2c) containing the lead specific chelating moiety that is linked via a thiourea group to the binding moiety A (Formula 2a-1 , 2b-1 , 2c- 1 ), where x may represent any of the lead isotopes or radionuclides herein, such as for example 203 for203Pb, or 212 for212Pb.Formula 2c- 1

[0068] More generally, the conjugate A-(L-C)n, where C is the chelating moiety in Formula 5a above, can be radiolabeled with a lead radioisotopexPb, such as for example203Pb, or212Pb.Binding Moiety

[0069] According to certain embodiments, the binding moiety A may be any of a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein, that is selective for a cellular target that is associated with overexpression in cancer cells. According to certain embodiments, the binding moiety A is selective for a cellular target that is other than epidermal growth factor receptor (EGFR).

[0070] According to one embodiment, the binding moiety comprises an antibody or antibody fragment that is selective for a target that is other than EGFR, such as for example any one or more ofrituximab, ibritumomab, tiuxetan, tositumomab, ofatumumab, oblinutuzumab (glycoengineered), inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, gemtuzumab ozogamicin, daratumumab, isatuximab, blinatumomab, teclistamab, belantamabmafodotin, tafasitamab, loncastuximabtesirine, alemtuzumab, trastuzumab, ado- trastuzumabemtansine, M5A, pertuzumab, atezolizumab, avelumab, durvalumab, bevacizumab, ramucirumab, ipilimumab, tremelimumab, pembrolizumab, nivolumab, cemiplimab, dostarlimab, denosumab, dinutuximab, naxitamab, elotuzumab, olaratumab, sacituzumab govitecan, and mirvetuximabsoravtansine-gynx. Other antibodies, antibody fragments, or synthetic proteins, such as antibody derivatives, may also be used. In certain embodiments, the antibody is a full-length immunoglobulin. In certain embodiments, the antibody is an engineered antibody fragment such as a single-chain fragment variable (scFv), fragment antigen-binding region (Fab). In certain embodiments, the antibody is a bi-specific, tri-specific, or multi-specific antibody which targets different epitopes of the target protein. In certain embodiments, the antibody is a bi-specific, tri-specific, or multi-specific antibody which targets two or more cell membrane proteins. Unlimited examples of targets for the binding moiety A, such as cell membrane proteins, can comprise epidermal growth factor (EGF), hepatocyte growth factor (FGF), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen (CEA), human epidermal growth factor receptor 3 (HER3), Delta-like ligand 3 (DLL3), fibroblast activation protein (FAP), PD-1 , PD-L1 , B7-H3,CD20, CD22, CD30, CD33, CD38, CD19 / CD3, B-cell maturation antigen (BCMA), CD3 / BCMA, CD19, CD52, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), receptor activator of nuclear factor kappa beta ligand (RANK-L), disialoganglioside (GD2), self-ligand receptor of the signaling lymphocytic activation molecule family member 7 (SLAMF7), platelet-derived growth factor receptor alpha (PDGFRA), tumor-associated calcium signal transducer 2 (TROP-2), folate receptor- a (FR-a), and mesenchymal-epithelial transition factor (MET). A person skilled in the art can use the methods disclosed herein to make conjugates of PSC with antibodies that are selective for targets other than EGFR, including those listed in Table 1.

[0071] Table 1 below lists certain antibodies below, along with the antigen that they target, and type of tumor in which the antigen may be overexpressed.Table 1

[0072] Furthermore, according to certain embodiments, in case where the binding moiety comprises an antibody, the conjugate can comprise one or more chelating moieties bound to the antibody, either directly or through a linker, on both heavy and light chains of the antibody, or on just one of the heavy and / or light chains.Linker

[0073] The linker may be any chemical group that serves to couple the binding moiety A to the lead specific chelating moiety. That is, according to certain embodiments, the moiety “L” in any of the Formulas herein may be either a bond that directly connects, or a linker that indirectly connects, the lead specific chelating moiety to the binding moiety A. For example, in certain embodiments, the linker can form a thiourea group that forms a thiourea linkage with primary amine moieties such as lysine residues present in a binding moiety A, for example as shown in Formulas 2a-2c above. For example, the linker can comprise the molecular structure shown in Formula 6below, where the asterisks (*) indicate points of attachment to the lead specific chelating moiety on one end, and the binding moiety A on the other end (e.g. via a thiourea linkage):Formula 6

[0074] Notably, in Formula 2a shown above, “L” comprises both the moiety shown in Formula 6 as well as an NH group connecting the moiety shown in Formula 6 to the chelating moiety.

[0075] In addition to a thiourea linkage, the linker may comprise a moiety that is capable of forming a bond with the binding moiety A via a different type of linkage, such as by amide bond, disulfide bond, or other connection.

[0076] In certain embodiments, the linker is a hydrophobic linker consisting of an aliphatic carbon chain that connects the chelating moiety to the binding moiety. In certain embodiments, L is a hydrophilic linker that includes heteroatom substitutions in the aliphatic chain that connects the chelating to the binding moiety. In certain embodiments, L is a mixture of hydrophilic and hydrophobic entities including piperidine insertions of amino acid insertions to lengthen the chain and modulate the pharmacodynamics properties of the composition. In certain embodiments, L is PEGn, wherein n is 1 -10 (PEG is polyethylene glycol). In certain embodiments, n is 2, 4 or 8 PEG subunits. In certain embodiments, n is 4. In certain embodiments, L is an aliphatic (ALP) linker of 2 or 4 carbons. In certain embodiments, L is a piperidine (PIP) based linker.Method of Manufacture of Radiolabeled Compound

[0077] Antibody-based compounds such as trastuzumab (Herceptin) via DOTA (31 ), c8C3 via TCMC (32), and peptides such as a-melanocyte-stimulating hormone (33), and low molecular weight PSMA ligands (34) have been labelled with203Pb using DOTA coordination chemistry. Also, the conditions required for labelling panitumumab with111In using diethylenetriamine-pentaacetic acid (DTPA) and / or89Zr using p- isothiocyanatobenzyl-desferrioxamine B included heating to 37°C, and depending on the chelating moiety administered, different reaction times of up to 4 h were required (35,36). Moreover, high temperatures (60-75°C) were reported for the radiolabeling of peptides with203Pb to achieve high incorporation efficiency with shorter incubation times (37,38).

[0078] According to one embodiment, a process for a preparation of the conjugate comprises reacting a binding moiety A that is selective for a target other than EGFR, such as a monoclonal antibody, polyclonal antibody, antibody fragment, or synthetic protein, with a lead specific chelating moiety, such as for example via one or more linkers present on either or both of the binding moiety and / or lead specific chelating moiety, or via direct binding of the chelating moiety to the binding moiety. For example, the lead specific chelating moiety may be a derivatized chelator according to any of Formulas 3a-3c above, having an isothiocyanate group that is capable of reacting with lysine residues (or other primary amine-containing residues) in the binding moiety. According to one embodiment, the derivatized chelator of Formula 3a, where Ri is hydrogen, is reacted with an antibody, to prepare the conjugate. According to yet further embodiments, the binding moiety A (e.g. an antibody), can be combined with the lead specific chelating moiety to provide a conjugate having a ratio of binding moiety A to lead specific chelating moiety of 1 : 1 , 1 :2, 1 :2, 1 :4, 1 :5, 1 :6, 1 :7, and / or 1 :8, or in other words to provide multiple lead specific chelating moieties bound to the binding moiety A in the conjugate.

[0079] According to certain embodiments, the conjugate can be radiolabeled, such as with a lead radionuclide, to provide a radiotherapeutic and / or radiodiagnostic molecule (i.e., a radiopharmaceutical).

[0080] According to certain embodiments, the radiolabeling of the conjugate with lead, such as203Pb and / or212Pb, can occur at temperatures close to room temperature (25°C), and require a relatively short period of time to achieve desired levels of radiolabeling. According to one embodiment, the conjugate is combined with the lead radioisotope for radiolabeling at a temperature of no more than 60°C, no more than 55°C, no more than 50°C, no more than 45°C, no more than 40°C, no more than 35°C, no more than 30°C, no more than 25°C, and / or no more than 20°C. For example, the conjugate may be combined with the lead radioisotope for radiolabeling at a temperature that is in the range of from 20°C to 60°C, 20°C to 40°C, 20°C to 30°C, and / or about room temperature (25°C). According to one embodiment, the conjugate is combined with the lead radioisotope for radiolabeling for no more than 60 minutes, no more than 30 minutes, no more than 20 mins, no more than 15 mins, and / or no more than 10 mins, and at least 1 min, at least 3 mins, at least 4 mins, and / or at least 5 mins. Furthermore, according to certain embodiment, the conjugate is combined with the lead radioisotope for radiolabeling in aqueous solution having a pH in a range of from 4 to 6, and / or a pH of about 5.

[0081] For example, according to certain aspects of the present disclosure, radiolabeling of a PSC-antibody conjugate may be performed at a pH of 5.0 and about room temperature (25°C) for 5-10 minutes with [203Pb]Pb(OAc)2, and the incorporation efficiency can be determined using radio-TLC. Specifically, according to certain embodiments, an average of 4 to 5 Pb specific chelator (PSC) chelators can be attached to one antibody, with radiolabeling efficiency of at least 99%. According to certain embodiments, isolated radiochemical yield of203Pb-PSC conjugated antibody may be at least 40%, and the molar activity may be at least 1 .0 GBq / mg.

[0082] According to certain aspects of the present disclosure, the labeling process with the derivatized PSC chelator does not require any elevated temperatures, such as above 60°C, or even above 30°C and / or 25°C, and203Pb or212Pb incorporation can proceed with high efficiency (>99%) at short reaction times of 5-10 min at about room temperature (25°C).Diagnostic and Therapeutic Uses

[0083] Embodiments of the present disclosure further provide methods for imaging or diagnosing a cancer or tumor in a subject in need thereof, by administering a radiopharmaceutical comprising a radiolabeled conjugate described herein to the subject, and imaging tissue having the radiolabeled conjugate bound thereto. That is, when the radiolabeled conjugate is labeled with a lead radioisotope such as203Pb (Pb- 203) that is suitable for imaging purposes, the conjugate can be administered to a subject and will accumulate at target sites for which the binding moiety is selective. Imaging techniques such as SPECT imaging can be performed to view the accumulation of the radiolabeled conjugate at target sites, which may be indicative of a location of cancerous cells, such as cancerous cells overexpressing a target that is other than EGFR.

[0084] According to certain aspects,203Pb (Pb-203) may be suitable for imaging processes such as SPECT, to provide for imaging and diagnosing of the presence or extent of cancer and / or tumors in a subject.

[0085] Furthermore, according to certain embodiments, a method of treatment of cancer can be provided in a subject in need thereof, by administering a radiopharmaceutical comprising a radiolabeled conjugate described herein to the subject, in therapeutically effective amounts that are sufficient to treat the subject. That is, when the radiolabeled conjugate is labeled with a lead radioisotope such as212Pb (Pb-212) that is suitable for treatment purposes, the conjugate can be administered to a subject and will accumulate at target sites for which the binding moiety is selective, and which may be indicative of a location of cancerous cells, such as cancerous cells overexpressing a target that is other than EGFR. The radiation emitted by the radiolabeled conjugate bound to the target site may provide a cell killing effect that is selective for the target cells, thereby providing treatment. In some embodiments, the cancer is selected from the group consisting of B-cell non-Hodgkin lymphomas (NHL), chronic lymphocytic leukemia (CLL), NHL, acute lymphoblastic leukemia (ALL), hairy cell leukemia, anaplastic large cell lymphoma (ALCL), Hodgkin lymphoma, acute myeloid leukemia, multiple myeloma, relapsed multiple myeloma, diffuse large B-celllymphoma, breast cancer, gastric cancer, urothelial carcinoma, non-small cell lung cancer (NSCLC), markel cell carcinoma, colorectal cancer, lung cancer, glioblastoma, hepatocellular carcinoma, melanoma, stomach cancer, colon cancer, liver cancer, myeloma, cutaneous squamous cell carcinoma (cSCC), endometrial cancer, secondary bone cancer, neuroblastoma, relapsed neuroblastoma in bone or bone marrow, soft tissue sarcoma, triple negative breast cancer, head and neck squamous cell carcinoma, and ovarian cancer.

[0086] Aspects of the present disclosure further provide203 / 212Pb-PSC-antibody as ideal radiotheranostics for combined SPECT imaging and targeted alpha therapy of cancers that overexpress certain targets, and which may be other than EGFR- overexpressing cancers.203 / 212Pb radiotheranostics represent an attractive alternative to currently used225Ac-based radiotheranostics for targeted alpha therapy. The availability of212Pb through the emerging224Ra / 212Pb generator technology and the ideal radionuclide matching pair characteristics of radiometals203Pb and212Pb ensure identical coordination chemistry and identical biodistributions profiles of203 / 212pb radiotheranostics. This represents a significant advantage to currently used225Ac-based radiotheranostics for targeted alpha therapy relying on chemically different imaging surrogates, such as133La and134Ce (42).

[0087] The following examples are provided to further illustrate the methods of the present disclosure. These examples are illustrative only and are not intended to limit the scope of the disclosure in any way.Formulations

[0088] The radiolabeled conjugates / radiopharmaceutical compounds described herein can be administered in a radiopharmaceutical formulation suitable for delivery to a subject, such as for example via intravenous administration, and may be in form of an aqueous solution (e.g. saline solution) containing the radiolabeled conjugate in a concentration sufficient for one or more of diagnostic and therapeutic purposes, as well as optional stabilizers and / or oxidants, buffers, etc. According to one embodiment, asuitable dosage of the radiolabeled conjugate, such as for example the radiolabeled conjugate according to any of Formulas 2a-1 , 2b-1 or 2c-1 above being used for diagnostic or medical imaging purposes, where the binding moiety is an antibody, and the lead radionuclide is203Pb (Pb-203), may be from 5-1000 MBq, preferably from 100- 500 mBq, such as from 50-500 MBq, preferably between 100-400 MBq, and more preferably between 200-300 MBq. According to one embodiment, a suitable dosage of the radiolabeled conjugate, such as for example the radiolabeled conjugate according to any of Formulas 2a-1 , 2b-1 or 2c-1 above being used for therapeutic treatment purposes, where the binding moiety is an antibody, and the lead radionuclide is2212Pb (Pb-212), may be from 5-1000 MBq, such as from 18-555 MBq, preferably between 37- 370, and more preferably between 74-185 MBq, such as between 74-278 MBq. The radiolabeled conjugate may be prepared in phosphate-buffered saline (PBS) with or without stabilizers including any one or more of ascorbic acid, sodium acetate, gentisic acid, a chelator (e.g. DTPA (diethylenetriaminepentaacetic acid) or DSMA (dimercaptosuccinic acid)), and ethanol, at concentrations that are suitable for human or animal use.EXAMPLESExample 1 Production of203Pb

[0089] 203Pb was produced using a recently published procedure (12). Briefly,205TI metal (99.9% isotopic enrichment) targets were irradiated at 23.3 MeV on a TR-24 cyclotron at currents up to 60 pA to produce203Pb via the205TI(p,3n)203Pb nuclear reaction. Following a cool-down period of >12 hours, targets were removed and irradiated205TI dissolved in 4 M HNOs. A NEPTIS Mosaic-LC synthesis unit performed automated separation using Eichrom Pb resin, and203Pb was eluted using 8 M HCI or 1 M NH4OAC. Purified203Pb yields of up to 12 GBq were attained (15.8 GBq at EOB). The [203Pb]PbCl2 and [203Pb]Pb(OAc)2 products contained no detectable radionuclidic impurities besides201Pb (<0.1 %), and <0.4 ppm stable Pb.205TI metal was recovered with a 92% batch yield.Example 2Preparation of203Pb-PSC-antibody radioimmunoconjugateGeneral

[0090] The following is an example of a protocol for preparing a radiolabeled conjugate of the lead specific chelator with a predetermined antibody. Other methods can also be used, as would be understood by those of ordinary skill in the art, and radiolabeling with212Pb can also be performed as an alternative to203Pb.

[0091] All glassware can be rinsed with ultra-pure HCI (Fisherbrand, A508-P500). Trace metal-based ultra-pure chemicals for buffer preparations can be purchased from Sigma Aldrich. All buffer solutions were treated with biotechnology-grade Chelex 100 (Bio-Rad, 143-2832).PSC functionalization of antibody and radiolabeling with [203Pb]Pb(OAc)2

[0092] 2,2'-(4-(2-amino-2-oxoethyl)-10-(2-((4-isothiocyanatobenzyl)amino)-2- oxoethyl)-1 ,4,7,10-tetra-azacyclododecane-1 ,7-diyl) diacetic acid (PSC-NCS) chelator (e.g. 200 pg) can be dissolved in, e.g., 50 pL of 0.1 M NaHCC (pH = 8.0) and added to a select antibody, such as an antibody that is not selective for EGFR. The pH can be adjusted, for example, to 8.0, and left on a thermoshaker set at 800 rpm and 30 °C for 2.5 hours.

[0093] The samples can be purified via size exclusion chromatography (Bio-Rad 10DG desalting column, USA), which can be pre-equilibrated and eluted with, for example, 0.025 M NaOAc buffer (pH=5.5). The antibody concentration of each fraction can be measured using nanodrop (Thermo Scientific, NanoDrop OneC), and the fraction with the highest concentration can be submitted for matrix-assisted laser desorption / ionization (MALDI) to assess the number of PCS chelators per antibody.[203Pb]Pb(OAc)2 (150-200 MBq) can be added to PSC-antibody, and the reaction can be kept at room temperature for 5-10 minutes at pH=5.

[0094] Radio-thin layer chromatography (radio-TLC) analysis (AR-2000, Eckert and Ziegler) can be used to determine203Pb incorporation efficiency by spotting samples on silica plates and using 20 mM EDTA and 0.2 M NaOAc as the mobile phase.203Pb-PSC-antibody can be purified on an Econo-Pac 10DG desalting column pre-equilibrated with, e.g., 0.25 M sodium acetate, pH 5.5 used as the eluant.

[0095] Elution fractions (300 pL) can be collected from the column, and the radioactivity can be measured using an Atomlab 400 dose calibrator (Biodex, Shirley, NY, USA). Laemmli buffer (Bio-Rad, USA) can be added to203Pb-PSC-antibody, and the samples (15 pL) can be incubated at 95 °C for 5 minutes. Then, the samples can be loaded on SDS-PAGE (Bio-Rad, Mini-PROTEAN® TGXTMPrecast Protein Gels) and ran at 120 V. The gel can be imprinted on film and evaluated by autoradiography on a BAS-5000 phosphor imager (Fujifilm).

[0096] According to certain embodiments, the functionalization can generally involve conjugating antibodies (e.g. monoclonal antibodies) with PSC chelator by modifying lysine amino acids on the antibodies with the 2,2’-(4-(2-amino-2-oxoethyl)-10- (2-((4-isothiocyanatobenzyl)amino)-2-oxoethyl)-1 ,4,7,10-tetra-azacyclododecane-1 ,7- diyl) diacetic acid (PSC-NCS) chelator. Alternative bioconjugation strategies for modifying antibodies to conjugate to PSC chelator may include, but are not limited to: s- amine lysine side chain modification through NCS or N-hydroxysuccinimide ester on the chelator; reduction of a cysteine thiol group, or through an engineered cysteine, and formation of a thioether bond with maleim ide-functionalized linkers; oxidation of antibody glycosylation sites and reaction with hydrazide-functionalized linkers; introduction of non-natural amino acids for conjugation; and introduction of engineered tags to the antibody for covalent modification (e.g. sortase, split-proteins, coiled-coils, spy-tag / spy-catcher).Example 3Conjugation of PSC chelator to trastuzumab, sacituzumab and M5A antibodies

[0097] Antibodies were incubated with a 10-30 fold molar excess of PSC-NCS in 0.1 M sodium bicarbonate buffer (pH 8) for 90-150 min at 37°C (300-500 rpm). The products were purified by size exclusion chromatography. Quantitative time of flight (qTOF) liquid chromatography tandem mass spectrometry (LC-MS / MS; Waters Xevo G2 QTOF coupled with a Waters Acquity UPLC) were performed on PSC-trastuzumab, PSC-sacituzumab and PSC-M5A conjugation products to determine the average number of PSC conjugates per antibody. Chromatograms are presented in FIGS. 1A- 1C and deconvoluted mass spectra in FIGS. 2A-2C. LC-MS / MS analysis revealed an average degree of conjugation of 7-12 chelators / antibody.Example 4Radiolabeling of PSC-conjugated monoclonal antibodies with Pb-203

[0098] PSC-conjugated antibodies were radiolabeled with Pb-203 at 5-100 pCi / nmol. [203Pb]Pb(OAc)2 (1-33 pCi) was incubated with 50 pg PSC-conjugated antibody in sodium acetate buffer at pH5 and 1 mg / mL sodium ascorbate for 10-60 min at 42°C. The radiochemical purity of [203Pb]Pb-PSC-antibodies was assessed by instant thin-layer silica gel chromatography (ITLC-SG) developed in sodium citrate buffer pH 5. Activity at the origin (Rf=0-5, [203Pb]Pb-PSC-antibodies) and at the solvent front (Rf=5- 10, [203Pb]Pb(OAc)2) was then analyzed via a Packard COBRA II automatic gamma counter to determine the radiochemical purity (RCP) determined as the ratio of counts for Rf=0-5 relative to the total counts for the ITLC-SG paper. The RCP of [203Pb]Pb- PSC-antibodies after 10 min incubation was >90% for all PSC-conjugated antibodies at <100 pCi / nmol, and RCP >98% after a 60 min incubation (Table 2).Table 2Radiochemical purity of monoclonal antibodies conjugated with lead-specific chelator (PSC) and radiolabeled with [203Pb]Pb(OAc)2[2°3Pb]Pb-PSC- [203Pb]Pb-PSC-[2°3Pb]Pb-PSC-M5A Trastuzumab Sacituzumab10 min 30 min 60 min 10 min 30 min 60 min 10 min 30 min 60 min5 pCi / nmol 97% 98% 99% 97% 98% 99% 93% 96% 98% 0 pCi / nmol 99% 99% >99% 99% >99% >99% 97% 98% 99%00 pCi / nmol >99% >99% >99% >99% >99% >99% 99% >99% >99%Example 5Cell binding of [203Pb]Pb-PSC-antibodies

[0099] Binding specificity was evaluated in cell binding assays. Approximately 2x106U87MG-ErbB2 (HER2high, TROP2|OW, CEACAM5neg), A431 (TROP2high, HER2|OW, CEACAM5|OW) and LS174T (CEACAM5high, TROP2|OW, HER2|OW) cells were first incubated with 1 % bovine serum albumin (BSA) in phosphate buffered saline (PBS) for 30 minutes to block nonspecific binding prior to addition of 20 nM of [203Pb]Pb-PSC- trastuzumab, of [203Pb]Pb-PSC-sacituzumab or of [203Pb]Pb-PSC-M5A. Cells were incubated with PSC-antibody conjugates for 2 hours at 2-8°C in the presence of 0.7% BSA. The supernatant containing unbound conjugate was removed and cells washed with PBS. The radioactivity bound to cells was measured in a Packard COBRA II automatic gamma counter. The activity bound to cells relative to the total activity added (percentage incubated activity, %IA) was compared for the PSC-antibody conjugates in cells expressing high and low levels of the target (FIGS. 3A-3C). [203Pb]Pb-PSC-M5A exhibited specific binding to CEACAM5-overexpressing LS174T cells, with 4.6 to 7.5- fold higher binding compared to cells with low to negligible CEAMCAM5 expression. High specific binding of [203Pb]Pb-PSC-sacituzumab to A431 cells with high TROP2 expression was observed (21 -26 fold higher than binding to U87MG-ErbB2 and LS174T cells). [203Pb]Pb-PSC-trastuzumab also exhibited high specific binding to U87MG-ErbB2transfected to express high levels of HER2 (52-73 fold higher than binding to U87MG- ErbB2 and LS174T cells).Example 6Binding kinetics and affinity of [203Pb]Pb-PSC-antibodies[000100] Surface plasmon resonance (SPR) assays were performed on a Cytiva Biacore 1 S+ to characterize the effect of PSC conjugation to monoclonal antibodies. Native sacituzumab antibody or PSC-sacituzumab were immobilized on a Series S CM4 chip using lysine conjugation, ligands (5 pg / mL, 10 mM sodium acetate buffer pH 5) were immobilized following surface activation with 1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 75 mg / mL) and N-hydroxysuccinimide (NHS, 11.5 mg / mL) mixed at a 50:50 ratio to achieve approximately 140 response units (Rll), and followed by deactivation with 1 M ethanolamine hydrochloride-NaOH (pH 8.5). Human TROP2 protein was prepared at 0.01 -20 nM in HBS-P+ running buffer (0.01 M HEPES pH 7.4, 0.15 M NaCI, 0.005% v / v Surfactant P20) and run with an association phase of 800 s at 30 pL / min and dissociation phase of 10-60 min on flow cells conjugated with native and PSC-conjugated antibodies using multicycle kinetics. Interaction of human TROP2 protein with native and PSC-conjugated antibodies was analyzed using 1 :1 binding using Biacore Insight Evaluation Software (FIGS. 4A-4B). Both sacituzumab and sacituzumab-PSC were characterized with a rapid association (ka= 7.6 x 104M'1s'1and 7.3 x 104M-1s ’1, respectively) and slow dissociation in all assays (kd = 1.6 x 10-5s-1and 0.97 x 10'5s-1, respectively) and equilibrium dissociation constants (KD) of 0.21 and 0.13 nM, respectively.Example 7Biodistribution of [203Pb]Pb-PSC-M5A in human cancer xenografts[000101] To evaluate tumor and non-target organ uptake of [203Pb]Pb-PSC-M5A, female athymic nude mice were implanted with approximately 2x106LS174T cells. Following tumor establishment, approximately 0.3 MBq of [203Pb]Pb-PSC-M5A (50 pg, 150 pL in 0.9% NaCI) was administered intravenously (i.v.; tail vein). Tumor-bearing mice were euthanized at 5 days post-injection (p.i.) of [203Pb]Pb-PSC-M5A and the tumor, blood, and relevant tissues were isolated, weighed and the radioactivity measured by a Packard COBRA II automatic gamma counter. 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Claims

WHAT IS CLAIMED IS:1 . A conjugate having the formula A-(L-C)n, whereinA is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein that is selective for a target that is other than epidermal growth factor receptor (EGFR),L is a bond or a linker,C is a lead specific chelating moiety according to Formula 5a,Formula 5a each Ri is independently hydrogen or an alkyl group,R2 is -ORi, -NFh or a bond connecting the lead specific chelating moiety, C, to the linker, L,R4 and Rs are independently hydrogen or a bond connecting the lead specific chelating moiety to the linker, L, provided (i) at least one of R4 and Rs is hydrogen, and (ii) each of R4 and Rs is hydrogen when R2 is a bond connecting the lead specific chelating moiety, C, to the linker, L, and n is at least 1 .

2. The conjugate of claim 1 wherein the conjugate further comprises a lead isotope, xPb, chelated by the lead specific chelating moiety, C.The conjugate of claim 1 wherein the conjugate corresponds to Formula 1a,Formula 1b or Formula 1c:Formula 1bwhereinA is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein that is selective for a target that is other than epidermal growth factor receptor (EGFR),L is a bond or a linker,R3 is -ORi or -NH2, wherein Ri is an alkyl group, and n is at least 1 .

4. The conjugate of claim 3 wherein the conjugate corresponds to Formula 1 a, 1 b or 1c and the conjugate further comprises a lead isotope,xPb, chelated by the lead specific chelating moiety, C.

5. The conjugate of claim 3 wherein the conjugate corresponds to Formula 1 a and the conjugate further comprises a lead isotope,xPb, chelated by the lead specific chelating moiety, C, corresponding to Formula 1a-1 :Formula 1 a-16. The conjugate of claim 1 , corresponding to Formula 2a:whereinA and n are as defined in claim 1 , Ri is hydrogen, andZ is -NH- and is the residue of a primary amine moiety comprised by A.

7. The conjugate of claim 6 wherein the conjugate further comprises a lead isotope, xPb, chelated by the lead specific chelating moiety, C, corresponding to Formula 2a-1Formula 2a-1 whereinA and n are as defined in claim 1 and xPb is an isotope of lead.

8. The conjugate of claim 1 , corresponding to Formula 2b:whereinA and n are as defined in claim 1 , andZ is -NH- and is the residue of a primary amine moiety comprised by A.

9. The conjugate of claim 8 wherein the conjugate further comprises a lead isotope, xPb, chelated by the lead specific chelating moiety, C, corresponding to Formula 2b-1whereinA and n are as defined in claim 1 and xPb is an isotope of lead.

10. The conjugate of claim 1 , corresponding to Formula 2c:A and n are as defined in claim 1 , andZ is -NH- and is the residue of a primary amine moiety comprised by A.11 . The conjugate of claim 10 wherein the conjugate further comprises a lead isotope,xPb, chelated by the lead specific chelating moiety, C, corresponding to Formula 2c-1Formula 2c-1 whereinA and n are as defined in claim 1 and xPb is an isotope of lead.

12. A process for the preparation of a compound suitable for radiolabeling comprising reacting a binding moiety A that is selective for a target that is other than epidermal growth factor receptor (EGFR), and that is any of a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein, and comprises a lysine residue, with a lead specific chelating moiety C corresponding to any of Formulas 3a, 3b and 3cwhereinRi is hydrogen.

13. A method of radiolabeling a conjugate corresponding to any of Formula 1a,Formula 1 b or Formula 1 cFormula 1bwhereinA is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein selective for a target that is other than epidermal growth factor receptor (EGFR),L is a bond or linker,R3 is -OR1 or -NH2, wherein R1 is an alkyl group, and n is at least 1 , the method comprising: combining the conjugate with a lead radioisotope in aqueous solution at a temperature of no more than 60°C.

14. The method according to claim 13, wherein the conjugate comprises any of Formula 2a, Formula 2b, or Formula 2c:Formula 2c n whereinA is a binding moiety comprising a monoclonal antibody, a polyclonal antibody, an antibody fragment or a synthetic protein selective for epidermal growth factor receptor (EGFR), n is at least 1 ,Ri is hydrogen, andZ is -NH- and is the residue of a primary amine moiety comprised by A.

15. A method of imaging or diagnosing a subject suffering from a cancer associated with overexpression of a target that is other than epidermal growth factor receptor (EGFR), the method comprising administering the conjugate of any preceding claim, as radiolabeled with a lead radioisotope203Pb, to the subject, and imaging tissue having the radiolabeled conjugate compound bound thereto.

16. A method of treating a subject suffering from a cancer associated with overexpression of a target that is other than epidermal growth factor receptor (EGFR),the method comprising administering the conjugate of any preceding claim, as radiolabeled with a lead radioisotope212Pb, to the subject, in a dosage sufficient to kill tumor cells.

17. A method of diagnosing and treating a subject suffering from a cancer associated with overexpression of a target that is other than EGFR, the method comprising: diagnosing the subject by administering the conjugate of any preceding claim to the subject, as radiolabeled with a lead radioisotope where203Pb, and imaging tissue having the radiolabeled conjugate compound bound thereto to diagnose the subject as being afflicted with the cancer, and treating the subject diagnosed as being afflicted by the cancer, by administering the conjugate of any preceding claim to the subject, as radiolabeled with a lead radioisotope212Pb, in a dosage sufficient to kill cancer cells.

18. The use of the conjugate according to any preceding claim for medical imaging and / or diagnosis of a subject suffering from cancer, as radiolabeled with203Pb.

19. The use of the conjugate according to any preceding claim for treatment of a subject suffering from cancer, as radiolabeled with212Pb.

20. An aqueous formulation comprising the conjugate of any preceding claim and as radiolabeled with a lead radioisotope, wherein the formulation comprises a buffer and optionally further comprises any one or more of ascorbic acid, sodium acetate, gentisic acid, DTPA, DSMA, and ethanol.21 . The aqueous formulation according to claim 20, wherein the lead radioisotope is203Pb (Pb-203), and is provided in the formulation in an amount sufficient to provide a dosage of 5-1000 MBq, and / or 100-500 MBq.

22. The aqueous formulation according to claim 20, wherein the lead radioisotope is212Pb (Pb-212), and is provided in the formulation in an amount sufficient to provide a dosage of 5-1000 MBq, 37-370 MBq, and / or 74- 278 MBq.

23. The conjugate according to any of claims 1 -2, wherein the lead isotope is selected from the group consisting of Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb- 201 , Pb-202, Pb-203, Pb-205, Pb-209, Pb-210, Pb- 211 , Pb-212, Pb-213, Pb-214, Pb- 215, and Pb-216.

24. The conjugate according to any of claims 1 -2, wherein the lead radioisotope is203Pb (Pb-203) or212Pb (Pb-212).

25. The conjugate and / or method according to any preceding claim, wherein the binding moiety A is an antibody selective for any one selected from the group consisting of: CD20, CD22, CD30, CD33, CD38, CD19 / CD3, B-cell maturation antigen (BCMA), CD3 / BCMA, CD19, CD52, human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen (CEA), PD-L1 , vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), PD-1 , receptor activator of nuclear factor kappa beta ligand (RANK-L), disialoganglioside (GD2), self-ligand receptor of the signaling lymphocytic activation molecule family member 7 (SLAMF7), platelet-derived growth factor receptor alpha (PDGFRA), tumor-associated calcium signal transducer 2 (TROP- 2), folate receptor- a (FR-a), or combinations thereof.

26. The conjugate and / or method according to any preceding claim, wherein the binding moiety A is selected from the group consisting of rituximab, ibritumomab, tiuxetan, tositumomab, ofatumumab, oblinutuzumab (glycoengineered), inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, gemtuzumab ozogamicin, daratumumab, isatuximab, blinatumomab, teclistamab, belantamabmafodotin, tafasitamab, loncastuximabtesirine, alemtuzumab, trastuzumab, M5A, ado- trastuzumabemtansine, pertuzumab, atezolizumab, avelumab, durvalumab, bevacizumab, ramucirumab, ipilimumab, tremelimumab, pembrolizumab, nivolumab,cemiplimab, dostarlimab, denosumab, dinutuximab, naxitamab, elotuzumab, olaratumab, sacituzumab govitecan, and mirvetuximabsoravtansine-gynx.

27. The conjugate and / or method according to any preceding claim wherein n at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, and / or at least 10.

28. The conjugate and / or method according to any preceding claim, wherein the binding moiety A is an antibody, and wherein the binding moiety A is bound to leadspecific chelating moieties on both the light and heavy chains.

29. The method of radiolabeling according to claim 13 or 14, wherein the conjugate is combined with the lead radioisotope at a temperature of no more than 60°C, no more than 50°C, no more than 45°C, no more than 40°C, no more than 35°C, no more than 30°C, and / or no more than 25°C.

30. The method of radiolabeling according to any of claims 13-14 and 29, wherein the conjugate is combined with the lead radioisotope at a temperature that is in the range of from 20°C to 60°C, 20°C to 40°C, 20°C to 30°C, and / or about 25°C.31 . The method of radiolabeling according to any of claims 13-14 and 29-30, wherein the conjugate is combined with the lead radioisotope for no more than 60 minutes, no more than 30 mins, and / or no more than 15 mins, and at least 1 min, at least 3 mins, at least 4 mins, and / or at least 5 mins.

32. The method of radiolabeling according to any of claims 13-14 and 29-31 , wherein the conjugate is combined with the lead radioisotope in aqueous solution having a pH in a range of from 4 to 6, and / or a pH of about 5.

33. The method of imaging or diagnosing the cancer according to claim 15, wherein the tissue is imaged via single-photon emission computed tomography (SPECT) imaging, optionally in combination with computed tomography (CT) imaging.

34. The method according to any of claims 15-17 and 33, wherein the cancer that is associated with overexpression of a target that is other than EGFR is any of B-cell nonHodgkin lymphomas (NHL), chronic lymphocytic leukemia (CLL), NHL, acute lymphoblastic leukemia (ALL), hairy cell leukemia, anaplastic large cell lymphoma (ALCL), Hodgkin lymphoma, acute myeloid leukemia, multiple myeloma, relapsed multiple myeloma, diffuse large B-cell lymphoma, breast cancer, gastric cancer, urothelial carcinoma, non-small cell lung cancer (NSCLC), markel cell carcinoma, colorectal cancer, lung cancer, glioblastoma, hepatocellular carcinoma, melanoma, stomach cancer, colon cancer, liver cancer, myeloma, cutaneous squamous cell carcinoma (cSCC), endometrial cancer, secondary bone cancer, neuroblastoma, relapsed neuroblastoma in bone or bone marrow, soft tissue sarcoma, triple negative breast cancer, head and neck squamous cell carcinoma, and ovarian cancer.

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