WO2025111445A1 - Trop-2 radiopharmaceutical conjugate and uses thereof - Google Patents

Abstract

The present disclosure provides a composition comprising related to conjugates comprising a conjugate having a complex of: Trop2AB-L-chelator (Formula), wherein, L is a linker and Trop2AB is an antibody that binds to human Trop-2. Also provided herein is a method of treating a cancer with said composition.

Description

TROP-2 RADIOPHARMACEUTICAL CONJUGATE AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICACATIONS [0001] This application claims priority to U.S. Provisional Application No. 63/601,634, filed November 21, 2023, the disclosure of which is herein incorporated by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION [0002] Trop-2 expression has been reported for a variety of epithelial cancers, including breast, bladder, lung, colorectal and prostate cancers. It is estimated that over 430,000 men and women are diagnosed worldwide with bladder cancer. In addition, bladder cancer accounts for nearly 170,000 deaths worldwide annually. Urothelial cancer (UC) is the predominant histologic type in the United States and Europe. For over forty years, platinum-based chemotherapy was the standard of care for treating bladder cancer. However, recent advances in the genomic characterization of bladder cancer has led to investigations into the use of immune checkpoint inhibitors for the treatment of bladder cancer. In fact, from 2016 to 2019, the US Food and Drug Administration approved nine new therapies for the treatment of advanced urothelial carcinoma, seven of which involved immune checkpoint inhibitors (Patel, et al., Treatment of Muscle-Invasive and Advanced Bladder Cancer in 2020, CA Cancer J CLIN, 70:404-423, 2020). [0003] Despite these advances, there is still a need for the development of novel therapies for the treatment of cancers, such as Trop-2 expressing or tumor antigen positive cancers. [0004] For example, there is also a need for radiotherapeutic compounds that accumulate to a greater degree in tumors without unacceptable uptake in normal organs, as absorbed dose is a function of the integral of cumulative activity. though targeted radiotherapy has been practiced for some time using macrocyclic complexes of radionuclides, the macrocycles currently in use (e.g., DOTA) generally form complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium, radium, bismuth, and lead isotopes. There is thus a need for additional therapies for treating TROP-2 expression and the use of radiotherapeutic compounds for such specific cancers. SUMMARY OF THE INVENTION [0005] In some aspects disclosed herein is a conjugate having a complex of Trop2AB-L-chelator (Formula), wherein L is a linker and Trop2AB is an antibody that binds to human TROP-2. In some embodiments, the chelator is selected from table 1 provided herein. In some embodiments, the chelator is complexed or chelated to a radionuclide selected from the group consisting of: ¹¹C, ¹³N, ¹⁵O, ³²P, ³³P, ⁴⁷Sc, ⁵¹Cr, ⁵⁷Co, ⁵⁸Co, ⁵⁹Fe, ⁶²Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁷Ga, ⁷⁵Br, ⁷⁵Se, ⁷⁵Se, ⁷⁶Br, ⁷⁷As, ⁷⁷Br, ^80mBr, ⁸⁹Sr, ⁹⁰Y, ⁹⁵Ru, ⁹⁷Ru, ⁹⁹Mo, ^99mTc, ^103mRh, ¹⁰³Ru, ¹⁰⁵Rb, ¹⁰⁵Ru, ¹⁰⁷Hg, ¹⁰⁹Pd, ¹⁰⁹Pt, ¹¹¹Ag, ¹¹¹In, ^113mIn, ¹¹⁹Sb, ^121mTe, ^122mTe, ¹²⁵I, ^125mTe, ¹²⁶I, ¹³¹I, ¹³³I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵²Dy, ¹⁵³Sm, ¹⁶¹Ho, ¹⁶¹Tb, ¹⁶⁵Tm, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁶⁷Tm, ¹⁶⁸Tm, ¹⁶⁹Er, ¹⁶⁹Yb, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ^189mOs, ¹⁸⁹Re, ¹⁹²Ir, ¹⁹⁴Ir, ¹⁹⁷Pt, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁹⁹Au, ²⁰¹Tl, ²⁰³Hg, ²¹¹At, ²¹¹Bi, ²¹¹Pb, ²¹²Bi, ²¹²Pb, ²¹³Bi, ²¹⁵Po, ²¹⁷At, ²¹⁹Rn, ²²¹Fr, ²²³Ra, ²²⁵Ac, ²²⁷Th and ²⁵⁵Fm. In some embodiments, the radionuclide is ²²⁵Ac. In some embodiments, the chelator is DOTA, H2-MACROPA or PCTA. In some embodiments, the L is linked to Trop2AB and/or the chelator by NHS-ester or isothiocyanate linkage systems. In some embodiments, the conjugate is bound to a nucleophilic amino acid on the antibody. In some embodiments, NCS-DOTA, for example, or another can be used. In another embodiment, the NCS linker system can be used with another chelator, such as PCTA. In some embodiments, the amino acid is at least a lysine. In some embodiments, L comprises -N-C(=S)- or -C(=O)-. In some embodiments, L is: C₀-₂₀alkylene-C(=O)- or C₀-₂₀alkylene-(Cyc)_o-N-C(=S)-, wherein Cyc is a carbocyclic or heterocyclic ring, each of said moieties optionally substituted with one or more groups which do not interfere with binding to the antibody; and o is 0 or 1. In some embodiments, L is:

some embodiments,

. In some embodiments, the Trop2AB is a monoclonal antibody. [0006] In some aspects disclosed herein is a conjugate of Formula I wherein mAb is a TROP-2 antibody. [0007] In some aspects disclosed herein is a conjugate of Formula II wherein mAb is a TROP-2 antibody. [0008] In some aspects disclosed herein is a pharmaceutical composition comprising the conjugate of any one of the above aspects or embodiments, and a pharmaceutically acceptable carrier. [0009] In some aspects disclosed herein is a method of treating cancer in a subject in need thereof comprising administering the conjugate of any one of the above aspects or embodiments or the pharmaceutical composition of any of the above aspects or embodiments. In some embodiments, the cancer is selected from the group consisting of: epithelial cancers, bladder cancer, heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, cancer of the lymph nodes, colon cancer, small intestine, prostate cancer, brain cancer, cholangiocarcinoma, gallbladder carcinoma, cancer of the head and neck, bone cancer, Ewing’s sarcoma, skin cancer, kidney cancer, and cancer of the heart. In some embodiments, the subject is human. DETAILED DESCRIPTION [0010] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure. [0011] All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. [0012] Throughout the present specification, the terms “about” and/or “approximately” may be used in conjunction with numerical values and/or ranges. The term “about” is understood to mean those values near to a recited value. Furthermore, the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein. The terms “about” and “approximately” may be used interchangeably. [0013] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.). [0014] The term “a” or “an” refers to one or more of that entity; for example, “a cancer therapeutic” refers to one or more cancer therapeutics or at least one cancer therapeutic. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein. In addition, reference to “an inhibitor” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors. [0015] As used herein, the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present disclosure may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and/or reagents described in the claims. [0016] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation. [0017] The term “pharmaceutically acceptable salts” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. [0018] The term "treating" means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject. The term "treating" may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition. [0019] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof. [0020] As used herein, a “subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. [0021] “Mammal” includes humans and both domestic animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. [0022] All weight percentages (i.e., "% by weight" and "wt. %" and w/w) referenced herein, unless otherwise indicated, are measured relative to the total weight of the pharmaceutical composition. [0023] As used herein, "substantially" or "substantial" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of "substantially" is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of" other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents. In other words, a composition that is "substantially free of" an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof. [0024] As used herein, “complex” refers to a complex of the compound of the invention, e.g. Formula (I), complexed with a radionuclide or a metal ion, where at least one metal atom is chelated or sequestered. [0025] A “conjugate” refers to a chelating agent, complexed or not complexed to at least one metal atom, that is covalently attached to a biological carrier, such as an antibody, including antibody that binds to TROP-2. [0026] As used herein, the term “biological carrier” refers to any biological targeting vector, such as a protein, an antibody, an antibody fragment, a hormone, a peptide, a growth factor, an antigen, a hapten or any other carrier, which functions in this invention to recognize a specific biological target site. Antibody and antibody fragment refers to any polyclonal, monoclonal, chimeric, human, mammalian, single chains, dimeric and tetrameric antibody or antibody fragment. Such biological carrier, when attached to a functionalized complex, serves to carry the attached ion to specific targeted tissues. [0027] As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and/or one or more CDRs sufficient to confer specific binding to a particular target antigen). Thus, the term antibody includes, for example, and without limitation, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents that include antibody fragments, inclusive of synthetic, engineered, and modified forms thereof. The term antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies. In general, an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CHI, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the Abs may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. Naturally -produced antibodies are glycosylated, typically on the CH2 domain. Examples of antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, recombinantly produced antibodies, wholly synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chainantibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, Fab' fragments, F(ab’)2 fragments, Fd' fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), single chain or Tandem diabodies (TandAb®), Anticalins®, Nanobodies®, minibodies, BiTE®s, ankyrin repeat proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, TrimerX®, MicroProteins, m Fynomers®, Centyrins®, KALBITOR®s, and antigen-binding fragments of any of the above. [0028] As used herein, the term “Fc-silent antibody” refers to an antibody comprising one or more mutations in the Fc domain that reduce, prevent, or eliminate binding of the Fc region of the antibody to Fc receptors, such as FcyR or FcR, which may result in decreased antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity (CDC). Exemplary mutations that may reduce, prevent, or eliminate antibody binding to an Fc receptor include, but are not limited to, S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, L328R, P331S, and any combination thereof (Saunders, Conceptual Approaches to Modulate Antibody Effector Functions and Circulation Half-Life, Front. Immunol. , 2019, doi.org/10.3389/fimmu.2019.01296). In some embodiments, substitution of any or all of positions 234, 235, 236 and/or 237 reduces affinity for Fey receptors, particularly FcyRI receptor (see, e.g., U.S. Pat. No. 6,624,821). In some embodiments, alanine is a preferred residue for substitution and L234A/L235A is a preferred dual mutation to reduce effector function. In some embodiments, other combinations of mutations with reduced effector functions include, but are not limited to, L234A/L235A/G237A, E233P/L234V/L235A/G236, A327G/A330S/P331S, K322A, L234A and L235A, L234F/L235E/P331S. Optionally, positions 234, 236 and/or 237 in human IgG2 are substituted with alanine and position 235 with glutamine, (see, e.g., U.S. Pat. No.5,624,821.) Two amino acid substitutions in the complement Clq binding site at EU index positions 330 and 331 reduce complement fixation (see Tao et al., J. Exp. Med. 178:661 (1993) and Canfield and Morrison, J. Exp. Med.173: 1483 (1991)). Substitution into human IgGl of IgG2 residues at positions 233-236 and IgG4 residues at positions 327, 330 and 331 greatly reduces ADCC and CDC (see, for example, Armour K L. et ah, 1999 Eur J Immunol.29(8):2613-24; and Shields R L. et ah, 2001. J Biol Chem. 276(9): 6591-604). N297A, N297Q, or N297G (Eu numbering) mutations reduce glycosylation and thereby effector functions. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIV. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, eliminate or prevent ADCC, ADCP, and/or CDC. In some embodiments, mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination thereof. In some embodiments, mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors include, but are not limited to, S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination thereof. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to Fc receptors and alternative strategies for reducing, preventing, or eliminating binding to Fc receptors are described in, e.g., Saunders, 2019, Tao, 1993, Canfield and Morrison, 1991, Armour, 1999, Shields, 2001, and U.S. No.6,624,821. [0029] As used herein, the terms “Fc-enabled antibody,” “Fc-enhanced antibody,” and “Fc- competent antibody” are used interchangeably and refer to an antibody comprising an FC domain that is capable of binding to Fc receptors, such as FcyR or FcR. These antibodies may further comprise one or more mutations to enhance or increase binding to Fc receptors, which may result in enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity (CDC). Exemplary mutations that may enhance ADCC include, but are not limited to, S298A, E333A, K334A, S239D, I332E, P2471, A339Q, and any combination thereof (van der Horst, et al., Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies, Cancers (Basel), 12(10):3041, 2020). Exemplary mutations that may enhance ADCP include, but are not limited to, F234L, R292P, Y300L, V305I, P396L, A330L, G236A, and any combination thereof (van der Horst, et al. , 2020). Exemplary mutations that may enhance CDC include, but are not limited to, E345G, E430G, K326W, E333S, S267E, H268E, S324T, and any combination thereof (van der Horst, et al. , 2020). In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to Fc receptors. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to FcyRIV. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and/or CDC. In some embodiments, one or more substitutions in the Fc region to enhance or enable binding to Fc receptors occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination thereof. In some embodiments, mutations in the Fc region to enhance or enable binding to Fc receptors include, but are not limited to, F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination thereof. In some embodiments, the Fc-enabled antibody comprises a modified IgGI domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering). Alternatively, glycoform perturbation can be used to enhance Fc-mediated therapeutic antibody function. The N-linked Fc glycosylations on IgGI antibodies are important for effector function. Sialylation, galactosylation, bisecting sugars, and fucosylation can all affect binding and activity of IgG molecules. Controlling the glycosylation patterns on therapeutic antibodies can be done a number of different ways. The type of cell producing the recombinant antibody and its culture conditions can affect glycosylation and activity of therapeutic antibodies. Furthermore, bioreactor conditions and downstream processing can also affect the glycan microheterogenity. Low or afucosylated antibodies have been shown to enhance Fc-mediating properties. Numerous ways to achieve this reduction of fucose levels by glycoengineering are well known in the art. One way is to manipulate the enzymes involved in the post-translational modification of antibodies. This can involve overexpression of glucosidases, such as P-l-4-N-acetylglucosaminyltransferase III, knocking out fucoslytransferases, or using cell lines that are naturally fucose-deficient or have been mutated to express low fucosylation levels. In addition, inhibitors of N-linked glucosidases, such as castanospermine, can also be used to obtain low fucose bearing IgG molecules. In some embodiments amino acid engineered variants can have more broadly enhanced affinity for multiple FcyR, whereas glycoform engineered antibody can generally have more specific affinity for enhanced FcyRIIIa binding. Glycoforms interact with proximal amino acids on the Fc portion and replacement of the amino acid that come in contact with Ig oligosaccharides can result in different glycoform structures. Additional mutations in the Fc region that enhance or enable binding to Fc receptors and alternative strategies for enhancing or enabling binding to Fc receptors are described in Saunders, 2019. [0030] Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and C1 alkyl (i.e., methyl). A C1-C6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non- limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0031] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C₁-C₁₂ alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted. [0032] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkenyl, an alkenyl comprising up to 10 carbon atoms is a C₂- C₁₀ alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C₂-C₆ alkenyl and an alkenyl comprising up to 5 carbon atoms is a C₂-C₅ alkenyl. A C₂-C₅ alkenyl includes C₅ alkenyls, C₄ alkenyls, C₃ alkenyls, and C₂ alkenyls. A C₂-C₆ alkenyl includes all moieties described above for C₂-C₅ alkenyls but also includes C6 alkenyls. A C2-C10 alkenyl includes all moieties described above for C₂-C₅ alkenyls and C₂-C₆ alkenyls, but also includes C₇, C₈, C₉ and C₁₀ alkenyls. Similarly, a C₂-C₁₂ alkenyl includes all the foregoing moieties, but also includes C₁₁ and C₁₂ alkenyls. Non-limiting examples of C₂-C₁₂ alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3- octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5- decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4- undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1- dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8- dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0033] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C₂-C₁₂ alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted. [0034] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkynyl, an alkynyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C₂-C₆ alkynyl and an alkynyl comprising up to 5 carbon atoms is a C₂-C₅ alkynyl. A C₂-C₅ alkynyl includes C₅ alkynyls, C₄ alkynyls, C₃ alkynyls, and C₂ alkynyls. A C₂-C₆ alkynyl includes all moieties described above for C₂-C₅ alkynyls but also includes C₆ alkynyls. A C₂-C₁₀ alkynyl includes all moieties described above for C₂-C₅ alkynyls and C₂-C₆ alkynyls, but also includes C₇, C₈, C₉ and C₁₀ alkynyls. Similarly, a C₂- C₁₂ alkynyl includes all the foregoing moieties, but also includes C₁₁ and C₁₂ alkynyls. Non- limiting examples of C₂-C₁₂ alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0035] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted. [0036] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted. [0037] “Aralkenyl” or “arylalkenyl” refers to a radical of the formula -Rb-Rc where Rb is an alkenylene o group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted. [0038] “Aralkynyl” or “arylalkynyl” refers to a radical of the formula -Rb-Rc where Rb is an alkynylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted. [0039] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted. [0040] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted. [0041] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted. [0042] “Ring” refers to a cyclic group which can be fully saturated, partially saturated, or fully unsaturated. A ring can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless stated otherwise specifically in the specification, a ring can be optionally substituted. [0043] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. [0044] For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NR gRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents. [0045] Human TROP-2 (Tacstd2, GA733-1 and EGP-1) (hereinafter also referred to as “hTROP- 2”) is a single transmembrane, type 1 cell membrane protein consisting of 323 amino acid residues and this protein has been known to be overexpressed in various types of epidermal cell carcinomas. The presence of a cell membrane protein associated with immunological resistance, which is commonly expressed in both human trophoblasts and cancer cells, had been long suggested. An antigen molecule recognized by mouse monoclonal antibodies (162-25.3, 162-46.2) reacting with the cell membrane protein of a human choriocarcinoma cell line BeWo was identified. This antigen molecule was considered as one of the molecules expressed in human trophoblasts, and was named as Trop-2. Thereafter, the same molecule was discovered by other researchers. That is to say, a tumor antigen recognized by a mouse monoclonal antibody GA733 which is obtained by immunization with stomach cancer cells SW948 was named as GA733-1 and an epithelial glycoprotein recognized by a mouse monoclonal antibody RS7-3G11 which is obtained by immunization with non-small cell lung cancer cells was named as an epithelial/carcinoma antigen, EGP-1. In 1995, the Trop-2 gene was cloned, and as a result, it was confirmed that these are the same molecules. Moreover, it was clarified that the molecule has a function to amplify intracellular calcium signals in cancer cells, and therefore, it is also referred to as a tumor-associated calcium signal transducer 2 (TACSTD2). [0046] Examples of anti-TROP-2 antibodies that can be used as the conjugate or methods provided herein include, but are not limited to, those described in WO2020016662 (Abmart), WO2020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech/Chiome), EP20110783675 (Chiome), W02015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), W02020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics/Gilead) , WO2011068845 (Immunomedics/Gilead) , US2016296633 (Immunomedics/Gilead), US2017021017 (Immunomedics/Gilead) , US2017209594 (Immunomedics/Gilead), US2017274093 (Immunomedics/Gilead) , US2018110772 (Immunomedics/Gilead), US2018185351 (Immunomedics/Gilead) , US2018271992 (Immunomedics/Gilead) , WO2018217227 (Immunomedics/Gilead) , _{US2019248917 (Immunomedics/Gilead) , CN111534585 (Immunomedics/Gilead) , US2021093730 (Immunomedics/Gilead), US2021069343 (Immunomedics/Gilead), US8435539 (Immunomedics/Gilead), US8435529 (Immunomedics/Gilead) , US9492566 (Immunomedics/Gilead), W02003074566 (Gilead), WO2020257648 (Gilead), US2013039861} (Gilead), WO2014163684 (Gilead), US9427464 (LivTech/Chiome), US10501555 (Abruzzo Theranostic/Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche), and WO2020094670 (SynAffix), each of which is incorporated by _{reference herein in its entirety. [0047] Anti-Trop-2 antibodies used herein can for example show high affinity and specific binding to TROP-2, which is highly express in a range of solid tumors, including breast cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, lung cancer, oral squamous cell carcinoma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, urinary bladder cancer, ovarian cancer, glioma, porta hepatis bile duct cancer, kidney cancer, colorectal cancer, T cell lymphoma, epithelial carcinoma, advanced epithelial carcinoma, and so on. [0048] The present invention specifically relates to conjugates comprising TROP-2 antibodies,} which include a radionuclide or metal ion. In a specific embodiment, the TROP-2 antibody is covalently linked or bonded to a chelator which comprises, such as by a complex, to the radionuclide or metal ion. In specific embodiment, the conjugate may include a linker (L) for _{covalently linking or binding the TROP-2 antibody to the chelator. In a specific embodiment, the conjugate is a structure as in Formula I: Trop2AB-L-chelator (Formula I), wherein, L is a linker} and Trop2AB is an antibody that binds to human Trop-2. _{[0049] In another embodiment, the chelator is one of the chelators in Table 1. [0050] TABLE 1:}

[0051] In a specific embodiment, the chelator is DOTA, H2-MACROPA or PCTA. [0052] In another embodiment, the conjugate may include a chelator that is complexed and/or chelated to a radionuclide or metal atom. In another embodiment, the radionuclide is selected from the group consisting of:

^189mOs, ¹⁸⁹Re, ¹⁹²Ir, ¹⁹⁴Ir, ¹⁹⁷Pt, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁹⁹Au, ²⁰¹Tl, ²⁰³Hg, ²¹¹At, ²¹¹Bi, ²¹¹Pb, ²¹²Bi, ²¹²Pb, 2¹³Bi, ²¹⁵Po, ²¹⁷At, ²¹⁹Rn, ²²¹Fr, ²²³Ra, ²²⁵Ac, ²²⁷Th and ²⁵⁵Fm. [0053] In another specific embodiment, the radionuclide is ²²⁵Ac. In another embodiment, the chelator may complex and/or chelate to the ²²⁵Ac either by the use of 3 arms or 4 arms of the chelator. In another embodiment, the radionuclide is ²²⁵Ac and the chelator is DOTA, H2- MACROPA or PCTA. In nother specific embodiment, the chelator is DOTA, which may use 3 arms or 4 arms of DOTA to complex to the radionuclide, such as ²²⁵Ac. [0054] In one embodiment, the linker L is used to link the chelator and antibody with methods known in the art, including for example the use of NHS-ester or isothiocyanate linkage systems. In a specific embodiment, the linker conjugate binds to any amino acid of the antibody. In a specific embodiment, the conjugate is bound to a nucleophilic amino acid on the antibody. In a specific embodiment, the amino acid is at least a lysine. [0055] In one embodiment, the linker L comprises -N-C(=S)- or -C(=O)-. In another specific embodiment, L is: C₀-₂₀alkylene-C(=O)- or C₀-₂₀alkylene-(Cyc)_o-N-C(=S)-, wherein Cyc is a carbocyclic or heterocyclic ring, each of said moieties optionally substituted with one or more groups which do not interfere with binding to the antibody; and o is 0 or 1. In another embodiment, L is:

or . [0056] In a specific embodiment, L is:

[0057] In embodiments, the conjugate is of Formula I

_{wherein mAb is a Trop2 antibody and L is a linker e.g., as disclosed herein. [0058] In another specific embodiment, the conjugate is of Formula II}

wherein mAb is a Trop2 antibody. In another specific embodiment the Trop2AB is a monoclonal antibody. In another specific embodiment, the conjugate may be included in a pharmaceutical composition additionally comprising a pharmaceutically acceptable carrier. Therapeutic Use _{[0059] The present compounds find use in any number of methods. For example, in embodiments,} the conjugates of the present disclosure are useful in methods for treating cancer. _{[0060] In embodiments, the present disclosure relates to a method for using the conjugates of Formula (I) or (II) salts thereof and compositions thereof, to treat a proliferative disorders. In} embodiments, compounds of the present disclosure can be utilized to inhibit, block, reduce, _{decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. In embodiments,} the condition or disease associated with cell proliferation is cancer. [0061] In embodiments of the methods disclosed herein, the cancer is a haematological malignancy or a solid tumor. In embodiments, the cancer is selected from the group consisting of: heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, cancer of the lymph nodes, colon cancer, small intestine, prostate cancer, brain cancer, cholangiocarcinoma, gallbladder carcinoma, cancer of the head and neck, bone cancer, Ewing’s sarcoma, skin cancer, kidney cancer, and cancer of the heart. In embodiments, the cancer is leukemia, lymphoma, head and neck cancer, brain cancer, cancer of the thorax, lung cancer, gastrointestinal cancer, colon cancer, endocrine cancer, mammary and other gynecological cancer, urological cancer, renal cancer, bladder cancer prostate cancer, and skin cancer. In embodiments, the cancer is glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, lung cancer, e.g., non-small cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, rmyelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, prostate cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient. In embodiments, the cancer is glioma, glioblastoma, acute myelogenous leukemia (AML), melanoma, cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL). In one embodiment, the cancers are epithelial cancers, including breast, bladder, lung, colorectal and prostate cancers. In another embodiment, the cancers are TROP-2 expressing cancers. [0062] Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention. Examples Example 1: Conjugation of DOTA with Ac-225 to anti-TROP-2 mAb [0063] The preparation of the ²²⁵Ac complexes to anti-TROP-2 antibodies is known in the art. First, a 2-step labeling method to prepare mCi amounts of Ac-225 labeled DOTA-NCS species at pH 4.5-5 in acetate buffer at 55-60° C. for 30 min. in high yield is performed. Second, the [Ac- 225]DOTA-NCS is mixed with anti-TROP-2 antibody in carbonate buffer at pH 8.5-9 at 37° C. for 30 min. The final product is purified by size exclusion chromatography using a 10 mL BioRad 10DG column and 1% HSA. Typical reaction yields are 10%±5%. Constructs thus prepared are assayed using established ITLC methods that quantify labeled antibody, free [Ac-225]chelate and unbound Ac-225 and cell-based immunoreactivity assays. Example 2: Conjugation of PCTA with Ac-225 to anti-TROP-2 mAb [0064] Anti-TROP-2 mAb is prepared at a concentration of 10 mg/mL in 0.05 M HEPES buffer, pH 7.5. The chelator, p-NCS-Bn-PCTA is dissolved in metal-free water at a concentration of 10 _{mg/mL. The mAb (10 mg) and PCTA (0.1-0.4 mg) are mixed, and pH adjusted to 8.8 0.3 using} sodium bicarbonate solution. The mixture is allowed to incubate at 37^oC for 2 hours. Subsequently, PCTA-TROP-2 mAb is separated from unreacted PCTA using PD-10 gel filtration column. The fractions containing the conjugated protein are pooled and washed several times (20 mL x 2 times) with HEPES buffer using centrifugal membrane concentrator (50 K molecular cut-off). The protein concentration is adjusted to 5-10 mg/mL and then stored at 2-8 ^oC. [0065] ²²⁵Ac is dissolved in 0.2 M hydrochloric acid prior to use. ²²⁵Ac activity is measured in radioisotope calibrator (Capintec, Inc), previously calibrated with Ac-225 from ORNL. The parent ²²⁵Ac is measured when it was in secular equilibrium with its daughters (at least 6 hours and typically the next day after sample collection). [0066] ²²⁵Ac activity in HCl solution is first mixed with tetramethyl ammonium acetate buffer, pH 5.5 and L-ascorbic acid solution to bring the pH of ²²⁵Ac solution to 5.5-6.0. To this solution, PCTA-TROP-2 mAb is added. The mixture is gently mixed and incubated at 37^oC for 5-30 min. At the end of incubation, DTPA solution (0.05 mL) is added to stop the labeling reaction. [0067] The labeling efficiency (LE) is determined using ITLC (SG) and 10 mM EDTA solution. ITLC chromatograms are scanned for radioactivity distribution only after the parent-daughter equilibrium is reached. [0068] ²²⁵Ac activity is identified bound to the PCTA-TROP-2 mAb. mAb is then purified from any unreactive Ac-225 using PD-10 gel filtration column using physiological saline solution containing 2% human serum albumin. The purified product (4-5 mL) is sterilized using 0.2μ membrane sterilizing filter. The radiochemical purity (RCP) is >95%. Example 3: Conjugate Binding to Trop-2 Analysis [0069] For analysis of binding of conjugated mAb to TROP-2, a GatorPrime instrument is used streptavidin-biotin chemistry at 25° C. in HBS-P+ buffer (10 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.4). A dilution series of His-tagged Trop-2 (AcroBiosystems, TR2-H5223) was prepared in this buffer with a top peptide concentration at 100 nM and 6 further 3-fold dilutions. The BLI analysis is run at 30° C. with a 120 second association and 120 second dissociation. All data was analyzed using GatorLaunch software. Data was fitted using a Langmuir 1:1 binding model. Kd values of the mAb conjugates from Example 1 and Example 2 are obtained, demonstrating that the ²²⁵Ac PCTA-TROP-2 mAb and ²²⁵Ac DOTA-TROP-2 mAb retain activity and binding to Trop-2 peptide. Example 4: Conjugate Binding to TROP-2 Expressing Cells [0070] Conjugate binding to TROP-2 expressing cells is performed with A431 cells using biotinylated antibody and streptavidin system. EC₅₀ values of ²²⁵Ac PCTA-TROP-2 mAb and ²²⁵Ac DOTA-TROP-2 mAb are separately obtained using a SYTOX viability die assay as follows: (1) Wash A431 cells with PBS once; (2) Incubate cells with 5 ml of Accutase at 37 degrees for 2- 5 minutes. Gently rock the flask until the layer of cells pilling off; (3) Add 15 ml of PBS into flask and transferred to a 50 ml conical tube; (4) Spin down 1600 rpm 3 minutes; (5) Resuspend in 2 ml of PBS, and counted cells; (6) Adjust cell density to 2e6 cells/ml with PBS and then added 100 uL/well to the plate and mix well; (7) Spin down 1600 rpm 3 minutes; (8) Add 100 uL of ²²⁵Ac PCTA-TROP-2 mAb or ²²⁵Ac DOTA-TROP-2 mAb /well respectively. Prepare serial dilute of each conjugate in PBS, 1 uM to 0.01 nM, 1:3 dilution, 10 point curve; (9) Incubate for 50 minutes total; (10) Wash wells with 150 uL PBS and spun down 1600 rpm 3 min and dumped; (11) Add SA-A647, 1:1000 dilution in FACS buffer, 100 ul/well to respective wells; (12) Incubated for 50 min on ice; (13) Wash with 200 uL PBS spun 1600 rpm 3 min dump SA-A647; (14) Resuspended in 100 uL SYTOX, 1:1000 dilution in FACS buffer and obtain EC₅₀ values The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. Example 5: In vivo efficacy study [0071] In vivo efficacy studies of the mAB conjugates from Example 1 and Example 2 herein are performed. NCI-N87, human gastric carcinoma model cell line is maintained in vitro and the cells in an exponential growth phase are harvested and counted for tumor inoculation. [0072] CB.17 SCID mice (female) of 8-12 weeks old at the start date, receive a subcutaneous injection in the flank region with 1 x 10⁷ tumor cells in 0.1 ml of PBS mixed with Matrigel for tumor development. When tumors reached an average size of 150-200 mm3, randomization was performed into 3 groups of 8 mice for treatment. Each mAB conjugate is administered via intravenous injection. Treatment is initiated on the same day of randomization. [0073] After tumor cells inoculation, the animals are checked daily for morbidity and mortality. At the time of routine monitoring, the animals are checked for any adverse effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss, eye/hair matting and any other abnormal effects. Tumor volumes are measured every 3-4 days in two dimensions using an caliper, and the volume data are expressed in mm3 using the formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements will be conducted in a Laminar Flow Cabinet. The endpoint of the experiment is a tumor volume of 800 mm³, body weight loss over 20% or 45 days, whichever comes first. [0074] Data for efficacy study is collected showing that the administration of each mAB conjugate from Example 1 or Example 2 leads to tumor regression. The tumor regression is almost equal to Trodelvy. Example 6: In vivo efficacy study [0075] Colo-205, colon cancer xenograft model cell line is maintained in vitro using RPMI-1640 medium supplemented with 10% FBS in humidified cell culture incubator at 37°C with standard 5% CO₂ specs. The cells in an exponential growth phase are harvested and counted for tumor inoculation. [0076] BALB/c nude mice (female) of 7-9 weeks old receive a subcutaneous injection in the right front flank region with 5 x 106 tumor cells in 0.1 ml of PBS mixed with Matrigel (1 :1) for tumor development. When tumors reach an average size of 100-200 mm³, randomization was performed into 5 groups of 8 mice and treatment began. Randomization will be performed based on “Matched distribution” method (Study Director™ software, version 3.1.399.19). The date of randomization will be denoted as day 0. [0077] Electronic caliper measurement are performed 2 times a week. Daily observations for clinical signs, food and water consumption, behavioral changes, animals are weighed 2 times per week. The endpoint of the experiment is a tumor volume of 3,000 mm³, body weight loss over 20% or 77 days, whichever comes first. [0078] Randomization: The randomization is performed when the mean tumor size reached approximately 143 mm3. Totally 40 mice were enrolled in a NCI-H446 cell line model study and randomly allocated to 5 groups, with 8 mice per group. Randomization will be performed based on “Matched distribution” method (Study Director™ software, version 3.1 .399.19). The date of randomization will be denoted as day 0. Due to the cachectic nature of the tumor model, all animals received supplemental gel from the day of randomization. [0079] mAB conjugate administration: Each mAB conjugate from Example 1 and Example 2 is separately injected via intravenous injection through tail vein with a dosing volume of 10 mL/kg. Treatment is initiated on the same day of randomization. Dosing is conducted in a Laminar Flow Cabinet. [0080] Observation and data collection: After tumor cells inoculation, the animals are checked daily for morbidity and mortality. At the time of routine monitoring, the animals are checked for any adverse effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss, eye/hair matting and any other abnormal effects. Tumor volumes are measured every 3-4 days in two dimensions using an caliper, and the volume data are expressed in mm3 using the formula: V = (L x Wx W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements will be conducted in a Laminar Flow Cabinet. [0081] Tumor volume over time and mice body weight in the efficacy study and the corresponding Kaplan-Meier plot with the test items above are determined. Data for efficacy study is collected showing that the administration of each mAB conjugate from Example 1 or Example 2 leads to tumor regression.

Claims

What is Claimed is: 1. A conjugate having a complex of: Trop2AB-L-chelator (Formula), wherein, L is a linker and Trop2AB is an antibody that binds to human Trop-2. 2. The conjugate of claim 1, wherein the chelator is selected from:

PCTA, 3,6,9,15-tetraazabicyclo[9.3.1]- pentadeca-1(15),11,13-triene-3,6,9,- triacetic acid or H2-MACROPA (N,N’-bis[(6-carboxy-2- pyridil)methyl]-4,13-diaza-18-crown-6)

3. The conjugate of claim 1 or 2, wherein the chelator is complexed to a radionuclide selected from the group consisting of: 4.

5. The conjugate of any one of claims 1-4, wherein the chelator is DOTA, H2-MACROPA or PCTA. 6. The conjugate of any one of claims 1-5, wherein the L is linked to Trop2AB and/or the chelator by NCS, NHS-ester or isothiocyanate linkage systems. 7. The conjugate of any one of claims 1-6, wherein the conjugate is bound to a nucleophilic amino acid on the antibody. 8. The conjugate of claim 7, wherein the amino acid is at least a lysine. 9. The conjugate of any one of claims 1-8, wherein L comprises -N-C(=S)- or -C(=O)-. 10. The conjugate of any one of claims 1-9, wherein L is: C0-20alkylene-C(=O)- or C0-20alkylene- (Cyc)o-N-C(=S)-, wherein Cyc is a carbocyclic or heterocyclic ring, each of said moieties optionally substituted with one or more groups which do not interfere with binding to the antibody; and o is 0 or 1.

₁1. The conjugate of claim 10, wherein L is:

or . 12. The conjugate of claim 11, wherein L is

13. The conjugate of any one of claims 1-12, wherein the Trop2AB is a monoclonal antibody. 14. The conjugate of any one of claims 1-13, wherein the complex comprises Formula I

wherein mAb is a Trop2 antibody and L is a linker. 15. The conjugate of any one of claims 1-13, wherein the complex comprises Formula II

wherein mAb is a Trop2 antibody.

16. A pharmaceutical composition comprising the conjugate of any one of claims 1-15, and a pharmaceutically acceptable carrier. 17. A method of treating cancer in a subject in need thereof comprising administering the conjugate of any one of claims 1-15 or the pharmaceutical composition of claim 16. 18. The method of claim 17, wherein the cancer is selected from the group consisting of: epithelial cancers, bladder cancer, heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, cancer of the lymph nodes, colon cancer, small intestine, prostate cancer, brain cancer, cholangiocarcinoma, gallbladder carcinoma, cancer of the head and neck, bone cancer, Ewing’s sarcoma, skin cancer, kidney cancer, and cancer of the heart. 19. The method of claim 18, wherein the subject is human.