Radiolabeled metalloporphyrin conjugates and uses thereof

Abstract

Disclosed are compositions and methods for the treatment of disease (e.g., cancer) using conjugates comprising a protein-binding moiety (e.g., an antibody or an antigen-binding fragment thereof) and one or more radiolabeled metalloporphyrin complexes. Also disclosed are conjugates that further include one or more chemotherapeutic agents.

Description

[0001] Attorney Docket No.: 38451-0004WO1

[0002] RADIOLABELED METALLOPORPHYRIN CONJUGATES AND USES THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U. S. Application No. 63 / 740,515, filed on December 31, 2024. The contents of this application are hereby incorporated by reference in their entirety.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “38451-0004W01_SL_ST26. XML.” The XML file, created on December 9, 2025. is 11,662 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] FIELD OF THE DISCLOSURE

[0007] The present disclosure relates to compositions and methods for diagnosis and treatment of cancer using antibody-drug conjugates, wherein the drug includes one or more radiolabeled metalloporphyrin complexes and optionally one or more chemotherapeutic agents.

[0008] BACKGROUND

[0009] Antibody-drug conjugates (ADCs) are targeted therapies that leverage the specificity of monoclonal antibodies to deliver cytotoxic agents directly to cancer cells. By binding to antigens highly expressed on tumor cells but minimally present on normal tissues, ADCs provide a selective mechanism to reduce systemic toxicity while enhancing therapeutic efficacy. This approach has been particularly impactful in oncology, where precision targeting is critical to mitigating the often-debilitating side effects of traditional cancer treatments. ADCs are typically composed of three key components: a monoclonal antibody, a cytotoxic payload, and a chemical linker that covalently binds the two.

[0010] Recently, there has been an expanded interest among pharmaceutical companies in antibody drug conjugate therapies. ADC radioligand therapeutic drugs are among them. In the last decade, over a dozen new drugs have been approved in this field to treat multiple types of cancers. Unlike general radiation therapies, these drugs which deliver targeted radiation at the cellular level are becoming popular because the risk of collateral damage to healthy tissues is significantly reduced.Attorney Docket No.: 38451-0004WO1

[0011] The integration of ADCs with radiation and chemotherapy has emerged as a promising strategy to amplify their therapeutic effects. Radiation and chemotherapy involve systemic administration of cytotoxic agents that interfere with cell division, but its nonspecificity often leads to significant adverse effects. Radiation therapy uses ionizing radiation to kill cancer cells and shrink tumors by damaging the DNA, thereby stopping these cells from continuing to grow and divide. Currently, the most common way of exposing cancer patients to radiation is through external beam radiation therapy. External beam radiation delivers high-energy radiation not only to a tumor, but also to adjacent healthy tissues.

[0012] Targeted radionuclide therapy is a more focused treatment which like targeted chemotherapy uses a radioactive molecule (ligand) to deliver a focused radiation directly to cellular targets. Additionally, this type of systemically administered radiotherapeutic has the potential to eliminate not only a primary tumor, but also metastatic cells which have spread throughout the body and might not be detectable by diagnostic imaging.

[0013] Presently, radiation and chemotherapy include the traditional approach which is external radiation combined with chemotherapy. There remains a need to develop targeted cancer therapies that avoid off-target adverse events associated with traditional radiation and chemotherapy.

[0014] SUMMARY

[0015] Disclosed herein compositions and methods for targeted therapy, including targeted radionuclide therapy. In targeted radionuclide therapy, the biological effect is obtained by energy absorbed from emitted radiation. Radionuclides used for nuclear medicine imaging emit gamma rays, which penetrate deeply into the body and adversely affect healthy tissues. The radionuclides for targeted radionuclide therapy emit radiation with a short path length. There are three types of particulate radiation of consequence for targeted radionuclide therapy — beta particles, alpha particles, and Auger electrons which can irradiate tissue volumes with multicellular, cellular, and subcellular dimensions, respectively.

[0016] The disclosure provides a potential for customized therapies. Within each of these categories, there are multiple radionuclides with a variety of tissue ranges, half-lives, and chemistries. These properties offer an attractive array of possibilities to customize therapies for individual patients. Further development of this field is driven by the desire to move away from nonspecific toxic therapies commonly used in oncology and toward less toxic targeted treatments, which impact only targeted tissues.Attorney Docket No.: 38451-0004WO1

[0017] Unlike the combination therapy with an anti-cancer chemotherapeutic drug and radiation therapy as described above, the disclosure includes conjugating both an anti -cancer chemotherapeutic drug and a radioactive metalloporphyrin with the same antibody _(R*ECL-AI-M). Both radioactive and chemotherapeutic drug payloads are attached to the same carrier antibody through linkers (R*ECL-AI-M) creating a dual payload approach.

[0018] Radioactive metalloporphyrins (R*M) as disclosed in this application are covalently- attached to a specific selected antibodies (Ab) through a linker (L). Once in circulation, these conjugated metalloporphyrins (R*ECL-AI-M) bind to specific antigens expressed by cancer cells. These interactions allow the conjugates to bind and enter cancer cells or other targets and kill them by delivering focused radioactive moieties at the cellular level.

[0019] When such (R*ECL-AI-M) conjugates are used in diagnostic imaging as radio tracers with lower intensity radionuclides, the location of cancer cells can be detected through imaging scans. There is no prior reported use of radioactive metalloporphyrins in targeted radiation therapy through antibody drug conjugates (ADC). Unlike other radioactive metal carriers presently used in targeted radiation therapy through ADC, these metalloporphyrins have special tumoricidal ability through a secondary mechanism. This secondary mechanism involves oxidative degradation in conjunction with radiation (like phototherapy) of DNA and other cellular constituents. The synergies between radiation and oxidative degradation as concurrent therapies could increase tumoricidal efficiency exponentially, while decreasing the need for higher levels of potentially toxic conventional agents.

[0020] As such, this disclosure includes the use of radioactive metalloporphyrins (R*ECL-AI-M) as combination radiation therapy together with ADC.

[0021] This disclosure leverages the fact that radioactive metalloporphyrins are better carriers for targeted radiotherapy and targeted dual therapy. It is well established in literature and laboratory experiments that metalloporphyrins have higher affinity for tumor cells than normal cells. This is because cancer cells express a higher number of receptors on their cell surfaces which can transport metalloporphyrins inside the cell. Once inside cancer cells, metalloporphyrins express toxicity by generating free radicals which can damage DNA and cause cell apoptosis. These metalloporphyrins can be easily chelated with radiometal nuclides of interest to create stable complexes. Based on previous studies, we expect the clearance from the body to be at the optimum level for these metalloporphyrin complexes, enabling them to function as medication delivery vehicles with less toxicity.

[0022] Theragnostic Applications: Metalloporphyrins can work as theragnostic agents because they can be complexed with low energy radionuclides for diagnostic purposes withAttorney Docket No.: 38451-0004WO1

[0023] limited cell damage. Conversely radionuclides with higher energy have a capacity to kill cancer cells for therapeutic purposes.

[0024] Versatility in tumor differentiation: Metalloporphyrins can also be complexed with various kinds of radiation emitters like Alpha, Beta and Auger electron particle emitters. These particles have distinctive characteristics in strength and penetrating distance, and they are useful for differentiating between types of cancer tissues. For example, Alpha particles have double the strength of beta particles, but they penetrate the tissue only half compared with beta particles.

[0025] Thus, in one instance, disclosed herein is an antibody-drug conjugate that includes an antibody or antigen-binding fragment thereof that specifically binds to an antigen, a linker and a radiolabeled metalloporphyrin complex. In another instance, disclosed herein is an antibody-drug conjugate that includes an antibody or antigen-binding fragment thereof that specifically binds to an antigen, a linker and a radiolabeled metallophthalocyanine complex.

[0026] In some instances, the metalloporphyrin complex has the following structure:

[0027]

[0028] Formula (I)

[0029] In another aspect, disclosed is an antibody -drug conjugate that includes the following structure:Attorney Docket No.: 38451-0004WO1

[0030]

[0031] where M is selected from Lu177, Ga68, Ac225. Cu64. Cu67. Pb212, Re188, Ra223. Th227, At211, Sm153, Y90, Tc99, Tb161, Co60, or Sr90. In this complex, Rl, R2, R3, R4, R5, R6, R7, and R8 are each selected from Me, CH2CH3, CH=CH2, (CH2)1-6COOH, (CH2)1-6OH, or (CH2)1-6NH2. X in the formula can be Cl or Br.

[0032] In some instances, the metalloporphyrin complex has the following structure:

[0033]

[0034] Formula (III)

[0035] In some instances, the radiolabeled metalloporphyrin complex comprises Formula (I), wherein:

[0036] M is selected from Lu177. Ga68. Ac225, Cu64, Cu67, Pb212, Re188. Ra223, Th227, At211, Sm153, Y90, Tc99, Tb161, Co60, or Sr90;

[0037] Rl is selected from H, Cl, Br, F, CH3, S03-, CN, S02R, CF3, orNO2;

[0038] R2 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, orNCHs.

[0039] R3 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, NHR, NR2, and NCH3

[0040] R4 is selected from H, Cl, Br, CN, [N(R}1]’, COOR', OCONR’2, CON-R', CONR'2, CH=NR', SO2NR'2, SO2R, CF3, or NO2; andAttorney Docket No.: 38451-0004WO1

[0041] X is selected from the group consisting of H, OH, Cl, Br, CN, [N(R} 1]', COOR', -OCONR'2, -OMOM, CON-R', CONR'2, CH=NR'. SO2NR'2, SO2R. CF3, SH, andNO2.

[0042] In some instances, the radiolabeled metalloporphyrin complex comprises Formula (I) or Formula (III), wherein:

[0043] M is selected from Lu177, Ga68, Ac225, Cu64, Cu67, Pb212, Re188, Ra223, Th227, At211. Sm153, Y90. Tc99, Tb161, Co60, or Sr90;

[0044] R1 is selected from H, Cl, Br, F, CH3, SO3-, CN, S02R, CF3, orNO2;

[0045] R2 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, or NCH3;

[0046] R3 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, NHR, NR2, and NCH3;

[0047] R4 is selected from H, Cl, Br, CN, [N(R}1]’, COOR', OCONR’2, CON-R', CONR'2, CH=NR’, SO2NR’2, SO2R, CF3, or NO2; and

[0048] X is selected from the group consisting of H, OH, Cl, Br, CN, [N(R} 1]'.

[0049] COOR', -OCONR'2, -OMOM. CON-R'. CONR'2. CH=NR'. SO2NR'2, SO2R. CF3, SH, and NO2.

[0050] Additionally, the complex can be synthetic.

[0051] In some instances, the radiolabeled metallophthalocyanine complex comprises a radioactive metal and phthalocyanines.

[0052] In some instances, the radiolabeled metalloporphyrin complex includes one of the following structures:

[0053] Formula (IV); or

[0054]

[0055] Attorney Docket No.: 38451-0004WO1

[0056]

[0057] In some instances, the antibody or antigen -binding fragment thereof can include Fab fragments, F(ab')2 fragments, scFv, scAb, or dAb. In some instances, the antibody-drug conjugate has a drug-to-radiolabeled metalloporphyrin complex ratio (DAR) of 1, 2, 4, or 8. In some instances, the antigen binding fragment thereof is selected from the group consisting of a Fab fragment, a F(ab')2 fragment, a scFv, a scAb, and a dAb.

[0058] In some instances, the antibody or antigen-binding fragment thereof is selected from gemtuzumab, brentuximab, inotuzumab, moxatemomab, polatezumomab, lonastuximab, polantamab, ado-trastuzumab, enfortumab, sacituzumab, fam-trastuzumab, cetuximab, disitamab, tisotumab, datopotamab, mirvetuximab, tusamitomab, or a urea-linked lysineglutamic acid.

[0059] In some instances, the antibody or antigen-binding fragment thereof is selected from an antibody of Table 1.

[0060] In some instances, the antibody-drug conjugate has a drug-to-antibody ratio (DAR) of 1, 2, 4, or 8, wherein the drug is any one, two, or all three of the radiolabeled metalloporphyrin complex, the radiolabeled metallophthalocyanine complex, or theAttorney Docket No.: 38451-0004WO1

[0061] chemotherapeutic agent. In some instances, the antibody or antigen-binding fragment thereof is selected from a small molecule antibody. In some instances, the antibody or antigenbinding fragment thereof is selected from a peptide or a cyclic peptide antibody.

[0062] In some instances, the antibody or antigen-binding fragment thereof is selected from gemtumab, moxetumamab, trastuzumab, or cetuximab.

[0063] In some instances, the antibody or antigen-binding fragment thereof comprises the following sequences:

[0064] DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQ GS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVKRTVAAPS VF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1); and EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGG TDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 2).

[0065] In some instances, the antibody or antigen-binding fragment thereof comprises the folio wing sequences:

[0066] MEVQLVESGGGLVKPGGSLKLSCAASGFAFSIYDMSWVRQTPEKCLEWVAYISSGGG TTYYPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHSGYGTHWGVLFAY WGQGTLVSAKASGGPEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQ RLVALYIAARLSWNQVDQVIRALASPGSGGDLGEAIREQPEQARLALTLAAAESERFV RQGTGNDEAGAANGPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERL LQAHRQLEERGYVFVGYHGTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAY GYAQDQEPDARGRIRNGALLRVYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPL RLDAITGPEEEGGRLETILGWPLAERTWIPSAIPTDPRNVGGDLDPSSIPDKEQAISALP DYASQPGKPPREDLK (SEQ ID NO: 3);

[0067] andAttorney Docket No.: 38451-0004WO1

[0068] MDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSG VP SRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPWTFGCGTKLEIK (SEQ ID NO: 4); and PEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYLAARLSWN QVDQVIRNALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAA NGPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERLLQAHRQLEERGYV FVGYHGTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAYGYAQDQEPDARG RIRNGALLRVYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPLRLDAITGP EEEGG RLETILGWPLAERTVVIPSAIPTDPRNVGGDLDPSSIPDKEQAISALPDYASQPGKPPRE DLK (SEQ ID NO: 5).

[0069] In some instances, the antibody or antigen-binding fragment thereof comprises the following sequences:

[0070] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGV PS RFSGSRSGTDFTLT1SSLQPEDFATYYCQQHYTTPPTFGQGTKVE1KRTVAAPSVF1FPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 6);

[0071] and EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGY TRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 7).

[0072] In some instances, the antibody or antigen-binding fragment thereof comprises the following sequences:

[0073] QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTL VTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPAttorney Docket No.: 38451-0004WO1

[0074] CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 8);

[0075] and DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9).

[0076] The linker used in the conjugate can be cleavable or non-cleavable. The linker covalently conjugates the antibody or antigen-binding fragment thereof to the radiolabeled metalloporphyrin complex or the chemotherapeutic agent. Examples of linkers include a maleimidocaproyl (me) linker, a maleimidomethyl cyclohexyl-1-carboxylate linker, a selfstabilizing malemide linker, a mcc hydrazide linker, an mc-val-ala linker, an mc-val-cit-pabc linker, an SPDB linker, a sulfo-SPDB linker, or an AcBut linker. In some instances, the structures of these linkers are defined by Formulas (VII) through (XV):

[0077] Formula (VII); or

[0078] Formula (VIII); or

[0079]

[0080] Formula (IX); orAttorney Docket No.: 38451-0004WO1

[0081] o

[0082] Formula (X); or

[0083] Formula (XI); or

[0084]

[0085] Formula (XII); or

[0086] o

[0087] HOA^^SH

[0088] Formula (XIII); or

[0089] Formula (XIV); or

[0090]

[0091] Formula (XV).

[0092] In some instances, the one or more linkers are not identical to each other.Attorney Docket No.: 38451-0004WO1

[0093] The conjugate can also include structural arrangements from N-terminus to C-terminus. These arrangements can involve various sequences of components, including linkers, peptides, and therapeutic agents. For example, in some instances, the antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows: (the radiolabeled metalloporphyrin complex)-(a linker)-(antibody or antigen-binding fragment thereof); or (antibody or antigen-binding fragment thereof)-(a linker)-(the radiolabeled metalloporphyrin complex).

[0094] The chemotherapeutic agent in the conjugate can be selected from a variety of drugs. Examples include daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, mitoxantrone, valrubicin, bleomycin, dactinomycin, mitomycin-c, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine, vincristine liposomal, vinorelbine. etoposide, irinotecan, irinotecan liposomal, mitoxantrone, teniposide, or topotecan.

[0095] In some instances, the antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows:

[0096] (the chemotherapeutic agent)-(a linker)-(the radiolabeled metalloporphyrin complex)-(a linker)-(antibody or antigen- binding fragment thereof);

[0097] (the radiolabeled metalloporphyrin complex)-(a linker)-(the chemotherapeutic agent)-(a linker)-(antibody or antigen-binding fragment thereof);

[0098] (antibody or antigen-binding fragment thereof)-(a linker)-(the radiolabeled metalloporphyrin complex)-(a linker)-(the chemotherapeutic agent); or

[0099] (antibody or antigen-binding fragment thereof)-(a linker)-(the chemotherapeutic agent)-(a linker)-(the radiolabeled metalloporphyrin complex). In some instances, the antibody-drug conjugate further comprises one or more linking peptides (LPs). In some instances, the one or more linking peptides comprise a first linking peptide (LP1) and a second linking peptide (LP2), wherein the antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows:

[0100] (the radiolabeled metalloporphyrin complex)-LPl-(a linker)-LP2-(antibody or antigen-binding fragment thereof); or

[0101] (antibody or antigen-binding fragment thereof)-(LP2)-(a linker)-(LPl)-(the radiolabeled metalloporphyrin complex).

[0102] In some instances, the one or more linking peptides comprise a first linking peptide (LP1) and a second linking peptide (LP2), wherein the antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows:Attorney Docket No.: 38451-0004WO1

[0103] (a chemotherapeutic agent)-(a first linker of the one or more linkers)-(the radiolabeled metalloporphyrin complex)-LP1-(a second linker of the one or more linkers )-LP2-(the antibody or antigen-binding fragment thereof); or

[0104] (the antibody or antigen-binding fragment thereof)-(LP2)-(a linker of one or more linkers )-(LP1)-(the radiolabeled metalloporphyrin complex)-(a first linker of the one or more linkers)-(a chemotherapeutic agent).

[0105] In some instances, each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length.

[0106] The conjugate can be formulated as a pharmaceutical composition with a carrier. Methods of synthesizing the conjugate include providing the antibody or fragment, the linker, and the radiolabeled metalloporphyrin complex, and optionally the chemotherapeutic agent. These components are then synthesized into the conjugate.

[0107] The antibody-drug conjugate can be used in methods for treating, preventing, or delaying cancer progression. The conjugate can alleviate symptoms and inhibit cancer cell growth. It can also be used to treat specific cancers such as breast cancer, lung cancer, nonsmall cell lung cancer, stomach cancer, prostate cancer, ovarian cancer, colorectal cancer, colon cancer, esophageal cancer, tracheal cancer, gastric cancer, bladder cancer, uterine cancer, rectal cancer or cancer of the small intestine, pancreatic cancer, head and neck cancer, thyroid cancer, endometrial cancer, epithelial cancer, or metastases associated therewith. In some instances, the cancer is a solid tumor cancer. In some instances, the cancer is advanced or metastatic cancer.

[0108] In some instances, the subject is human.

[0109] The conjugate can be administered by continuous infusion, intramuscularly, subcutaneously, parenterally, intra-articularly, intrasynovially. intrathecally. orally, topically, intratumorally, peritumorally, intralesionally, or via perilesionally, or via inhalation. In some instances, administering is intravenous administration.

[0110] Additionally, it can be used for diagnostic purposes by administering and imaging the conjugate in the subject. After diagnosis, the ADC can be administered to the subject.

[0111] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or item of information was specifically and individually indicated to be incorporated by reference. To the extent publications, patents, patent applications, and items of information incorporated by reference contradict the disclosure contained in theAttorney Docket No.: 38451-0004WO1

[0112] specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0113] Where values are described in terms of ranges, it should be understood that the description includes the disclosure of all possible sub-ranges within such ranges, as well as specific numerical values that fall within such ranges irrespective of whether a specific numerical value or specific sub-range is expressly stated.

[0114] The term “each,” when used in reference to a collection of items, is intended to identify an individual item in the collection but does not necessarily refer to every item in the collection, unless expressly stated otherwise, or unless the context of the usage clearly indicates otherwise.

[0115] Various embodiments of the features of this disclosure are described herein. However, it should be understood that such embodiments are provided merely by way of example, and numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the scope of this disclosure. It should also be understood that various alternatives to the specific embodiments described herein are also within the scope of this disclosure.

[0116] DESCRIPTION OF DRAWINGS

[0117] The following drawings illustrate certain embodiments of the features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner. Like reference symbols in the drawings indicate like elements.

[0118] FIG. 1 is a schematic of an antibody-drug conjugate of the disclosure.

[0119] FIG. 2 is a schematic of an antibody-drug conjugate comprising a dual payload. FIG.3 shows a schematic of an antibody-drug conjugate comprising a Lu-177 radioactive metal incorporated into a synthetic porphyrin, a non-cleavable linker, and an antibody.

[0120] FIGs. 4A-4D show a schematic of radioligand linker antibody conjugate synthesis.

[0121] FIGs. 4A-4D are a continuous flow chart (i.e., the image in FIG.4A leads to FIG.4B and so on.). The arrows leading from FIG. 4A to FIG. 4B (and so on) are redundant in the flow chart images. For instance, The arrow at the bottom of FIG. 4A is the same as the arrow at the top of FIG. 4B.Attorney Docket No.: 38451-0004WO1

[0122] DETAILED DESCRIPTION

[0123] A. Introduction

[0124] Antibody-Drug Conjugates (ADCs) are an innovative class of targeted cancer therapies that combine the specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. This dual-action approach aims to deliver highly potent drugs directly to tumor cells while sparing healthy tissues, thereby enhancing therapeutic efficacy and reducing systemic toxicity.

[0125] Disclosed herein are compositions and methods for ADCs. In some instances, the ADCs include a single type of drug payload (e.g., a radiolabeled metalloporphyrin complex or a radiolabeled metallophthalocyanine complex). In other instances, the ADCs include a dual-payload structure. Uses of any of these ADCs include diagnostic and therapeutic applications. In some instances, a subject having cancer is diagnosed or treated.

[0126] In some instances, an ADC is disclosed, comprising an antibody or antigen-binding fragment thereof that specifically binds to a designated antigen, ensuring targeted delivery. The ADC incorporates a linker that connects the targeting component to a therapeutic payload, designed for stability in circulation and efficient release within the target cell environment. The therapeutic payload in this invention is a radiolabeled metalloporphyrin complex or a radiolabeled metallophthalocyanine complex, offering unique capabilities for imaging, therapy, or both, depending on the radioisotope used. This ADC combines the precision of antibody targeting with the versatile functionalities of radiolabeled metalloporphyrin or metallophthalocyanine complexes, enabling effective therapeutic and diagnostic applications.

[0127] In some instances, an ADC is provided, comprising an antibody or antigen-binding fragment thereof that specifically binds to a target antigen, ensuring precise targeting of diseased cells. The ADC includes one or more linkers, designed to stably attach therapeutic components and release them efficiently upon reaching the target site. The conjugate incorporates a radiolabeled metalloporphyrin complex or a radiolabeled metallophthalocyanine complex, enabling therapeutic or diagnostic functionalities through radiolabeling.

[0128] Additionally, the ADC contains a chemotherapeutic agent, delivering a potent cytotoxic effect to targeted cells. This innovative combination of targeting specificity, radiolabeling capability, and chemotherapeutic action offers a versatile platform for enhanced therapeutic and diagnostic applications.

[0129] Additional details on the disclosed methods are provided.Attorney Docket No.: 38451-0004WO1

[0130] B. Antibody Drug Conjugates

[0131] 1. Antibodies and Antigen-Binding Fragments Thereof A component of the ADC includes an antibody or antigen-binding fragment thereof. Antibodies, or immunoglobulins (Ig), are Y-shaped glycoproteins produced by B cells in response to the presence of antigens. They play a central role in the immune system by specifically recognizing and neutralizing pathogens, such as bacteria, viruses, and toxins. Antibodies are composed of two identical heavy chains and two identical light chains linked by disulfide bonds, forming a symmetrical structure. Each antibody is divided into two main functional regions: the Fab (fragment antigen-binding) region and the Fc (fragment crystallizable) region.

[0132] The Fab region is responsible for antigen recognition and binding. It contains the variable domains of both the heavy (VH) and light (VL) chains. These domains feature hypervariable loops, known as complementarity-determining regions (CDRs), which directly interact with the antigen. The CDRs are embedded within a more conserved framework region that maintains the overall structural integrity. The diversity in CDR sequences allows antibodies to recognize a virtually unlimited array of antigens with high specificity and affinity.

[0133] The Fc region mediates effector functions, such as complement activation and engagement with Fc receptors on immune cells. This region is relatively constant and determines the antibody’s isotype (e.g., IgG, IgA, IgM) and its associated functional properties. The hinge region between the Fab and Fc segments imparts flexibility, enabling the antibody to adapt its conformation to optimally engage with antigens of varying spatial arrangements.

[0134] Antigen-binding fragments (Fab fragments) are portions of antibodies that contain the complete antigen-recognition machinery but lack the Fc region. They consist of one light chain and the corresponding portion of the heavy chain, encompassing the VH and VL domains along with their respective constant domains (CHI and CL). Fab fragments retain the antigen-binding specificity of the parent antibody and are commonly used in applications where Fc-mediated effector functions are unnecessary or undesirable, such as in diagnostic assays or therapeutic delivery systems.

[0135] In addition to Fab fragments, other antibody-derived fragments have been developed for specialized applications. These include single-chain variable fragments (scFvs), which link the VH and VL domains via a flexible peptide, and antigen-binding fragments (F(ab')2), which are composed of two Fab fragments connected by a portion of the hinge region. TheseAttorney Docket No.: 38451-0004WO1

[0136] fragments offer advantages such as reduced immunogenicity smaller size for improved tissue penetration, and the ability to construct multispecific or bispecific antibody formats.

[0137] The ADC features an antigen-binding fragment selected from Fab fragments, F(ab')2 fragments, single-chain variable fragments (scFv), single-chain antibodies (scAb), domain antibodies (dAb), or other antibody fragments. These smaller fragments retain the high specificity of full-length antibodies but provide advantages such as reduced size for better tumor penetration and the ability to create multispecific ADCs. Their versatility enables the design of ADCs that can target a broad range of antigens and adapt to unique therapeutic or diagnostic needs, expanding the utility of antibody-based therapies.

[0138] The ADC is further refined by incorporating a specific drug-to-antibody ratio (DAR) of 1, 2, 4, or 8, which determines the number of drug molecules attached to each antibody molecule. This precise DAR allows for the customization of therapeutic potency and pharmacokinetics. The conjugated drugs can include any one, two, or all three of the follow ing: a radiolabeled metalloporphyrin complex, a radiolabeled metallophthalocyanine complex, and a chemotherapeutic agent. This flexibility in drug combination enables the ADC to be tailored for specific therapeutic needs, providing a balanced approach to efficacy and safety by optimizing the payload distribution on the antibody scaffold.

[0139] The ADC utilizes an antibody or antigen-binding fragment thereof derived from a small-molecule antibody. Small-molecule antibodies are characterized by their reduced size, allowing improved tissue penetration and faster clearance rates, which are particularly advantageous in targeting solid tumors or deeply embedded antigenic sites. This design enhances the ADC’s ability to access challenging targets while maintaining specificity and reducing potential off-target effects. The use of small-molecule antibodies opens new possibilities for developing highly effective and versatile ADCs.

[0140] In another embodiment, the ADC incorporates an antibody or antigen-binding fragment thereof selected from peptide or cyclic peptide antibodies. These peptides provide a high degree of structural stability and often demonstrate strong binding affinity to their target antigens. Additionally, cyclic peptides, due to their constrained conformations, exhibit enhanced resistance to proteolytic degradation and improved binding selectivity. This choice of targeting moiety offers the potential for creating robust ADCs with greater stability and longevity in systemic circulation, enhancing therapeutic outcomes.

[0141] The antibody or antigen-binding fragment thereof of the ADC is selected from clinically validated antibodies, including gemtuzumab, moxetumomab, trastuzumab, and cetuximab. These antibodies are well-known for their high specificity and proven therapeuticAttorney Docket No.: 38451-0004WO1

[0142] efficacy against a variety of diseases. By incorporating these established antibodies into the ADC platform, the invention builds upon existing therapeutic successes, ensuring a reliable foundation for targeted drug delivery. This choice enhances the clinical translatability of the ADC, enabling rapid development and potential use in a wide range of indications.

[0143] In some instances, the antibody or antigen-binding fragment thereof is gemtumab. In some instances, the antibody or antigen-binding fragment therefore includes the following sequences:

[0144] DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQ GS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVKRTVAAPS VF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1); and EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGG TDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 2). In some instances, the antibody or antigen-binding fragment thereof is moxetumamab. In some instances, the antibody or antigen-binding fragment therefore includes the following sequences:

[0145] VH-P38 subunit:

[0146] MEVQLVESGGGLVKPGGSLKLSCAASGFAFSIYDMSWVRQTPEKCLEWVAYISSGGG TTYYPDTVKGRFTISRDNAKNTLYLQMS SLKSEDTAMYYC ARHS GYGTHWGVLFAY WGQGTLVSAKASGGPEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQ RLVALYIAARLSWNQVDQVIRALASPGSGGDLGEAIREQPEQARLALTLAAAESERFV RQGTGNDEAGAANGPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERL LQAHRQLEERGYVFVGYHGTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAY GYAQDQEPDARGRIRNGALLRVYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPLAttorney Docket No.: 38451-0004WO1

[0147] RLDAITGPEEEGGRLETILGWPLAERTWIPSAIPTDPRNVGGDLDPSSIPDKEQAISALP DYASQPGKPPREDLK (SEQ ID NO: 3);

[0148] VL subunit MDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSG VP SRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPWTFGCGTKLEIK (SEQ ID NO: 4); and

[0149] PE-38 of Moxetumomab PEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYLAARLSWN QVDQVIRNALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAA NGPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERLLQAHRQLEERGYV FVGYHGTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAYGYAQDQEPDARG RIRNGALLRVYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPLRLDAITGP EEEGG RLETILGWPLAERTVVIPSAIPTDPRNVGGDLDPSSIPDKEQAISALPDYASQPGKPPRE DLK(SEQ ID NO: 5).

[0150] In some instances, the antibody or antigen-binding fragment thereof is trastuzumab. In some instances, the antibody or antigen-binding fragment therefore includes the following sequences:

[0151] Anti-HER2 Light chain (1 and 2) DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGV PS RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 6); and Anti-HER2 Heavy chain ( 1 and 2) EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGY TRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGEYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 7).Attorney Docket No.: 38451-0004WO1

[0152] In some instances, the antibody or antigen-binding fragment thereof is cetuximab. In some instances, the antibody or antigen-binding fragment therefore includes the following sequences:

[0153] Cetuximab heavy chain QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTL VTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 8); and

[0154] Cetuximab light chain DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS RFSGSGSGTDFTLS1NSVESED1ADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVF1FP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9).

[0155] In some instances, the antibody or antigen-fragment thereof is selected from any one of the antibodies in Table 1. In some instances, the route of administration, target, and indication is provided for each antibody below.

[0156] Table 1. Antibodies for ADCs of the Disclosure

[0157] Drug Bank

[0158] Accession

[0159] Number

[0160] (with

[0161] Brand sequences; Type of

[0162] Antibody Route Target Indication(s) Name each of Antibody

[0163] which is

[0164] incorporated

[0165] by

[0166] reference)

[0167] Percutaneous chimeric GPIIb / I

[0168] abciximab ReoPro DB00054 intravenous coronary Fab Ila

[0169] intervention

[0170]

[0171] Attorney Docket No.: 38451-0004WO1

[0172] fully

[0173] adalimumab Humira DB00051 subcutaneous TNF Rheumatoid arthritis human

[0174] fully

[0175] adalimumab- Cyltezo DB00051 subcutaneous human, TNF Rheumatoid arthritis adbm

[0176] biosimilar

[0177] fully

[0178] adalimumab- Juvenile idiopathic Cyltezo DB00051 subcutaneous human, TNF

[0179] adbm arthritis biosimilar

[0180] fully

[0181] adalimumab- Cyltezo DB00051 subcutaneous human, TNF Psoriatic arthritis adbm

[0182] biosimilar

[0183] fully

[0184] adalimumab- Ankylosing Cyltezo DB00051 subcutaneous human, TNF

[0185] adbm spondylitis biosimilar

[0186] fully

[0187] adalimumab- Cyltezo DB00051 subcutaneous human, TNF Crohn's disease adbm

[0188] biosimilar

[0189] fully

[0190] adalimumab- Cyltezo DB00051 subcutaneous human, TNF Ulcerative colitis adbm

[0191] biosimilar

[0192] fully

[0193] adalimumab- Cyltezo DB00051 subcutaneous human, TNF Plaque psoriasis adbm

[0194] biosimilar

[0195] fully

[0196] adalimumab- Amjevita DB00051 subcutaneous human, TNF Rheumatoid arthritis atto

[0197] biosimilar

[0198] fully

[0199] adalimumab- Juvenile idiopathic Amjevita DB00051 subcutaneous human, TNF

[0200] atto arthritis biosimilar

[0201] fully

[0202] adalimumab- Amjevita DB00051 subcutaneous human, TNF Psoriatic arthritis atto

[0203] biosimilar

[0204] fully

[0205] adalimumab- Ankylosing Amjevita DB00051 subcutaneous human, TNF

[0206] atto spondylitis biosimilar

[0207] fully

[0208] adalimumab- Amjevita DB00051 subcutaneous human, TNF Crohn's disease atto

[0209] biosimilar

[0210] adalimumab- fully

[0211] Amjevita DB00051 subcutaneous TNF Ulcerative colitis atto human,

[0212]

[0213] Attorney Docket No.: 38451-0004WO1

[0214] biosimilar

[0215] fully

[0216] adalimumab- Amjevita DB00051 subcutaneous human, TNF Plaque psoriasis atto

[0217] biosimilar

[0218] humanized,

[0219] ado- Metastatic breast trastuzumab Kadcyla DB05773 intravenous antibodyHER2

[0220] cancer em tansine drug

[0221] conjugate

[0222] Campath

[0223] B-cell chronic alemtuzumab DB00087 intravenous humanized CD52 lymphocytic Lemtrad

[0224] leukemia a

[0225] Heterozygous famili fully al alirocumab Praluent DB09302 subcutaneous PCSK9

[0226] human hypercholesterolemi a fully Refractory hypercho alirocumab Praluent DB09302 subcutaneous PCSK9

[0227] human lesterolemia Tecentri Urothelial atezolizumab DB11595 intravenous humanized PD-L1

[0228] q carcinoma Tecentri Urothelial atezolizumab DB11595 intravenous humanized PD-L1

[0229] q carcinoma Metastatic nonTecentri

[0230] atezolizumab DB11595 intravenous humanized PD-L1 small cell lung q

[0231] cancer Bavenci fully Metastatic Merkel avelumab DB 11945 intravenous PD-L1

[0232] o human cell carcinoma Prophylaxis of acute organ basiliximab Simulect DB00074 intravenous chimeric IL2RA

[0233] rejection in renal transplant fully Systemic lupus belimumab Benlysta DB08879 intravenous BLyS

[0234] human erythematosus interleu

[0235] kin-5 Severe asthma, benralizumab Fasenra DB 12023 subcutaneous humanized recepto eosinophilic r alpha phenotype subunit

[0236]

[0237] Attorney Docket No.: 38451-0004WO1

[0238] Metastatic colorecta bevacizumab Avastin DB00112 intravenous humanized VEGF

[0239] 1 cancer humanized,

[0240] bevacizumab- Metastatic colorecta Mvasi DB00112 intravenous VEGF

[0241] awwb 1 cancer biosimilar

[0242] Non- humanized,

[0243] bevacizumab- squamous Non- Mvasi DB00112 intravenous VEGF

[0244] awwb small-cell lung biosimilar

[0245] carcinoma humanized,

[0246] bevacizumab- Mvasi DB00112 intravenous VEGF Glioblastoma a\w\b

[0247] biosimilar

[0248] humanized,

[0249] bevacizumab- Metastatic renal cell Mvasi DB00112 intravenous VEGF

[0250] awwb carcinoma biosimilar

[0251] humanized,

[0252] bevacizumab- Mvasi DB00112 intravenous VEGF Cervical cancer awwb

[0253] biosimilar

[0254] Clostri

[0255] Prevent recurrence fully dioides

[0256] bezlotoxumab Zinplava DB13140 intravenous of Clostridioides human difficile

[0257] difficile infection toxin B

[0258] Precursor B-cell mouse,

[0259] blinatumomab Blincyto DB09052 intravenous CD19 acute lymphoblastic bispecific

[0260] leukemia chimeric, a

[0261] brentuximab ntibody- Adcetris DB08870 intravenous CD30 Hodgkin lymphoma vedotin drug

[0262] conjugate

[0263] chimeric, a

[0264] brentuximab ntibody- Anaplastic large-cell Adcetris DB08870 intravenous CD30

[0265] vedotin drug lymphoma conjugate

[0266] IL17R

[0267] brodalumab Siliq DB 11776 subcutaneous chimeric Plaque psoriasis A

[0268] burosumab- fully X- linked Crysvita DB14012 subcutaneous FGF23

[0269] twza human hypophosphatemia Cryopyrin- fully

[0270] canakinumab Ilaris DB06168 subcutaneous IL1B associated periodic human

[0271] syndrome

[0272]

[0273] Attorney Docket No.: 38451-0004WO1

[0274] Diagnostic imaging murine, agent in newly capromab ProstaSc

[0275] DB00089 intravenous radiolabele PSMA diagnosed prostate pendetide int

[0276] d cancer or postprostatectomy certolizumab

[0277] Cimzia DB08904 subcutaneous humanized TNF Crohn's disease pegol

[0278] Metastatic colorecta cetuximab Erbitux DB00002 intravenous chimeric EGFR

[0279] 1 carcinoma Prophylaxis of acute organ daclizumab Zenapax DB00111 intravenous humanized IL2RA

[0280] rejection in renal transplant daclizumab Zinbryta DB00111 subcutaneous humanized IL2R Multiple sclerosis fully

[0281] daratumumab Darzalex DB09331 intravenous CD38 Multiple myeloma human

[0282] Postmenopausal wo Prolia, fully RANK

[0283] denosumab DB06643 subcutaneous men Xgeva human L

[0284] with osteoporosis Pediatric high- dinutuximab Unituxin DB09077 intravenous chimeric GD2

[0285] risk neuroblastoma fully Atopic dupilumab Dupixent DB12159 subcutaneous IL4RA

[0286] human dermatitis, asthma fully Urothelial durvalumab Imfinzi DB11714 intravenous PD-L1

[0287] human carcinoma Comple

[0288] Paroxysmal ment

[0289] eculizumab Soliris DB01257 intravenous humanized nocturnal compo

[0290] hemoglobinuria nent 5

[0291] SLAM

[0292] elotuzumab Empliciti DB06317 intravenous humanized Multiple myeloma F7

[0293] Hemophilia Factor A (congenital Factor emicizumab- Hemlibr humanized,

[0294] DB 13923 subcutaneous IXa, Fa VIII deficiency) kxwh a bispecific

[0295] ctor X with Factor VIII inhibitors. CGRP

[0296] fully Migraine erenumab-aooe Aimovig DB 14039 subcutaneous recepto

[0297] human headache prevention r

[0298]

[0299] Attorney Docket No.: 38451-0004WO1

[0300] Heterozygous famili fully al evolocumab Repatha DB09303 subcutaneous PCSK9

[0301] human hypercholesterolem i a fully Refractory hypercho evolocumab Repatha DB09303 subcutaneous PCSK9

[0302] human lesterolemia humanized,

[0303] gemtuzumab Acute myeloid Mylotarg DB00056 intravenous antibodyCD33

[0304] ozogamicin leukemia drug

[0305] conjugate

[0306] fully

[0307] golimumab Simponi DB06674 subcutaneous TNF Rheumatoid arthritis human

[0308] fully

[0309] golimumab Simponi DB06674 subcutaneous TNF Psoriatic arthritis human

[0310] fully Ankylosing golimumab Simponi DB06674 subcutaneous TNF

[0311] human spondylitis Simponi fully

[0312] golimumab DB06674 intravenous TNF Rheumatoid arthritis Aria human

[0313] fully

[0314] guselkumab Tremfya DB 11834 subcutaneous IL23 Plaque psoriasis human

[0315] ibalizumab- Trogarzo DB 12698 intravenous humanized CD4 HIV uiyk

[0316] Relapsed or refractory’ low- murine,

[0317] ibritumomab grade, follicular, or Zevalin DB00078 intravenous radioimmu CD20

[0318] tiuxetan transformed B- notherapy

[0319] cell non-Hodgkin's lymphoma Emergency reversal humanized dabigat of idarucizumab Praxbind DB09264 intravenous

[0320] Fab ran anticoagulant dabiga Iran Remicad TNF

[0321] infliximab DB00065 intravenous chimeric Crohn's disease e alpha infliximab- Renflexi chimeric,

[0322] DB00065 intravenous TNF Crohn's disease abda s biosimilar

[0323] infliximab- Renflexi chimeric,

[0324] DB00065 intravenous TNF Ulcerative colitis abda s biosimilar

[0325]

[0326] Attorney Docket No.: 38451-0004WO1

[0327] infliximab- Renflexi chimeric,

[0328] DB00065 intravenous TNF Rheumatoid arthritis abda s biosimilar

[0329] infliximab- Renflexi chimeric, Ankylosing DB00065 intravenous TNF

[0330] abda s biosimilar spondylitis infliximab- Renflexi chimeric,

[0331] DB00065 intravenous TNF Psoriatic arthritis abda s biosimilar

[0332] infliximab- Renflexi chimeric,

[0333] DB00065 intravenous TNF Plaque psoriasis abda s biosimilar

[0334] infliximab- chimeric,

[0335] Inflectra DB00065 intravenous TNF Crohn's disease dyyb biosimilar

[0336] infliximab- chimeric,

[0337] Inflectra DB00065 intravenous TNF Ulcerative colitis dyyb biosimilar

[0338] infliximab- chimeric,

[0339] Inflectra DB00065 intravenous TNF Rheumatoid arthritis dyyb biosimilar

[0340] infliximab- chimeric, Ankylosing Inflectra DB00065 intravenous TNF

[0341] dyyb biosimilar spondylitis infliximab- chimeric,

[0342] Inflectra DB00065 intravenous TNF Psoriatic arthritis dyyb biosimilar

[0343] infliximab- chimeric,

[0344] Inflectra DB00065 intravenous TNF Plaque psoriasis dyyb biosimilar

[0345] chimeric,

[0346] infliximab-qbtx Ixifi DB00065 intravenous TNF Crohn's disease biosimilar

[0347] chimeric,

[0348] infliximab-qbtx Ixifi DB00065 intravenous TNF Ulcerative colitis biosimilar

[0349] chimeric,

[0350] infliximab-qbtx Ixifi DB00065 intravenous TNF Rheumatoid arthritis biosimilar

[0351] chimeric, Ankylosing infliximab-qbtx Ixifi DB00065 intravenous TNF

[0352] biosimilar spondylitis chimeric,

[0353] infliximab-qbtx Ixifi DB00065 intravenous TNF Psoriatic arthritis biosimilar

[0354] chimeric,

[0355] infliximab-qbtx Ixifi DB00065 intravenous TNF Plaque psoriasis biosimilar

[0356] humanized,

[0357] Precursor B-cell inotuzumab Bespons

[0358] DB05889 intravenous antibodyCD22 acute lymphoblastic ozogamicin a

[0359] drug leukemia conjugate

[0360] fully CTLA- Metastatic ipilimumab Yervoy DB06186 intravenous

[0361] human 4 melanoma

[0362]

[0363] Attorney Docket No.: 38451-0004WO1

[0364] ixekizumab Taltz DB 11569 subcutaneous humanized IL17A Plaque psoriasis Tissue

[0365] factor

[0366] Hympav fully pathwa

[0367] marstacimab DB17725 intravenous Hemophilia A and B zi human y

[0368] inhibito

[0369] r

[0370] mepolizumab Nucala DB06612 subcutaneous humanized IL5 Severe asthma alpha- natalizumab Tysabri DB00108 intravenous humanized 4 integr Multiple sclerosis in

[0371] Metastatic Portrazz fully

[0372] necitumumab DB09559 intravenous EGFR squamous non-small a human

[0373] cell lung carcinoma Metastatic fully

[0374] nivolumab Opdivo DB09035 intravenous PD-1 squamous non-small human

[0375] cell lung carcinoma fully Metastatic nivolumab Opdivo DB09035 intravenous PD-1

[0376] human melanoma Protecti

[0377] ve

[0378] antigen

[0379] obiltoxaximab Anthem DB05336 intravenous chimeric of Inhalational anthrax the Ant

[0380] hrax

[0381] toxin

[0382] Chronic obinutuzumab Gazyva DB05336 intravenous humanized CD20 lymphocytic leukemia ocrelizumab Ocrevus DB 11988 intravenous humanized CD20 Multiple sclerosis Chronic fully

[0383] ofatumumab Arzerra DB06650 intravenous CD20 lymphocytic human

[0384] leukemia fully PDGF

[0385] olaratumab Lartruvo DB06043 intravenous Soft tissue sarcoma human RA

[0386] Moderate to severe omalizumab Xolair DB00043 subcutaneous humanized IgE

[0387] persistent asthma F

[0388] Respiratory palivizumab Synagis DB00110 intramuscular humanized protein

[0389] syncytial virus ofRSV

[0390]

[0391] Attorney Docket No.: 38451-0004WO1

[0392] fully Metastatic colorecta panitumumab Vectibix DB01269 intravenous EGFR

[0393] human 1 cancer Metastatic pembrolizumab Keytruda DB09037 intravenous humanized PD-1

[0394] melanoma Metastatic breast pertuzumab Perjeta DB06366 intravenous humanized HER2

[0395] cancer fully VEGF

[0396] ramucirumab Cyramza DB05578 intravenous Gastric cancer human R2

[0397] VEGF

[0398] Wet age-related intravitreal Rl;

[0399] ranibizumab Lucentis DB01270 humanized macular injection VEGF

[0400] degeneration R2

[0401] Protecti

[0402] ve

[0403] antigen

[0404] Raxibac fully

[0405] raxibacumab DB08902 intravenous of Baci Inhalational anthrax umab human

[0406] llus

[0407] anthrac

[0408] is

[0409] reslizumab Cinqair DB06602 intravenous humanized IL5 Severe asthma B-cell nonrituximab Rituxan DB00073 intravenous chimeric CD20 Hodgkin's lymphoma DB00073 chimeric,

[0410] rituximab and Rituxan Follicular and subcutaneous coCD20

[0411] hyaluronidase Hycela lymphoma DB06205 formulated

[0412] DB00073 chimeric,

[0413] rituximab and Rituxan Diffuse large B-cell and subcutaneous coCD20

[0414] hyaluronidase Hycela lymphoma DB06205 formulated

[0415] DB00073 chimeric, Chronic rituximab and Rituxan

[0416] and subcutaneous coCD20 lymphocytic hyaluronidase Hycela

[0417] DB06205 formulated leukemia fully

[0418] sarilumab Kevzara DB 11767 subcutaneous IL6R Rheumatoid arthritis human

[0419] Cosenty subcutaneous fully

[0420] secukinumab DB09029 IL17A Plaque psoriasis X (2015) human

[0421] Cosenty intravenous fully Ankylosing secukinumab DB09029 IL17A

[0422] X (2023) human spondylitis

[0423]

[0424] Attorney Docket No.: 38451-0004WO1

[0425] Multicentric Castle siltuximab Sylvant DB09036 intravenous chimeric IL6

[0426] man's disease tildrakizumab- Ilumya DB 14004 subcutaneous humanized IL23 Plaque psoriasis asmn

[0427] tocilizumab Actemra DB06273 intravenous humanized IL6R Rheumatoid arthritis Polyarticular juvenil tocilizumab Actemra DB06273 subcutaneous humanized IL6R

[0428] e idiopathic arthritis Systemic juvenile tocilizumab Actemra DB06273 subcutaneous humanized IL6R

[0429] idiopathic arthritis Hercepti Metastatic breast trastuzumab DB00072 intravenous humanized HER2

[0430] n cancer HER2- overexpressing humanized, breast cancer, trastuzumab- Ogivri DB00072 intravenous HER2 metaststic gastric or dkst

[0431] biosimilar gastroesophageal junction adenocarcinoma fully IL 12,

[0432] ustekinumab Stelara DB05679 subcutaneous Plaque psoriasis human IL23

[0433] fully

[0434] ustekinumab Stelara DB05679 intravenous IL23 Psoriatic arthritis human

[0435] fully

[0436] ustekinumab Stelara DB05679 intravenous IL23 Crohn's disease human

[0437] integrin

[0438] vedolizumab Entyvio DB09033 intravenous humanized recept Ulcerative colitis or

[0439] integrin

[0440] vedolizumab Entyvio DB09033 intravenous humanized recept Crohn's disease or

[0441]

[0442] In some instances the antibody used in one of the antibody drug conjugates is a small molecule antibody. In some instances, the small molecule antibody is conjugated to the drug by a linker (i.e., any one of the linkers described in the next section). In some instances, the small molecule antibody is conjugated directly to the drug (i.e., without a linker).

[0443] In some instances, the small molecule antibody targets prostate-specific membrane antigen (PSMA). In some instances, the small molecule antibody is a Glu-urea-lysine smallAttorney Docket No.: 38451-0004WO1

[0444] molecule antibody. In some instances, the small molecule antibody targets PMSA and comprises the structure of Formula (XVI):

[0445]

[0446] Formula (XVI)

[0447] In some instances, the small molecule antibody is Ludotadipep. In some instances, the small molecule antibody targets PMSA and comprises the structure of Formula (XVII):

[0448]

[0449] Formula (XVII)

[0450] In some instances, the small molecule antibody targets low density

[0451] lipoprotein receptor-related protein 1 (LRP1 receptor). In some instances, the small molecule antibody is Angiopep-2. In some instances, the small molecule antibody targets the LRP1 receptor and comprises the structure of Formula (XVIII):

[0452]

[0453] Formula (XVIII)

[0454] In some instances, the small molecule antibody targets gonadotropin-releasing hormone (GnRH receptor). In some instances, the small molecule antibody is D-LysGHRH. In some instances, the small molecule antibody targets the GnRH receptor and comprises the structure of Formula (XIX):Attorney Docket No.: 38451-0004WO1

[0455]

[0456] Formula (XIX)

[0457] In some instances, the small molecule antibody targets the somatostatin receptor. In some instances, the small molecule antibody is Tyr3-Octrotate. In some instances, the small molecule antibody targets the somatostatin receptor and comprises the structure of Formula (XX):Attorney Docket No.: 38451-0004WO1

[0458] HO^

[0459]

[0460] Formula (XX)

[0461] It is appreciated that the above peptide antibodies and small molecules can be combined with any of the following linkers and drugs described in the next two sections.

[0462] 2. Linkers

[0463] In some instances, the ADC incorporates a non-cleavable linker, selected from all known types, to attach the therapeutic payload to the antibody or antigen-binding fragment. Non-cleavable linkers are characterized by their stability in systemic circulation, ensuring that the drug remains conjugated until the ADC is internalized into the target cell. Upon internalization, the antibody and payload are degraded together within the lysosome, releasing the active drug directly inside the cell. This mechanism minimizes premature drug release, reducing systemic toxicity while maintaining high therapeutic efficacy, making non-cleavable linkers ideal for certain ADC designs.

[0464] In some instances, the ADC employs a cleavable linker, chosen from all known types, to attach the therapeutic payload. Cleavable linkers are engineered to release the pay load in response to specific conditions, such as acidic pH. enzymatic activity, or redox environments, typically found in the tumor microenvironment or inside target cells. This design ensures targeted release of the payload precisely where it is needed, maximizing the therapeutic effect and minimizing off-target toxicity. Cleavable linkers are particularly effective in ADCs designed to exploit tumor-specific biological conditions.Attorney Docket No.: 38451-0004WO1

[0465] The linker in the ADC covalently conjugates the antibody or antigen-binding fragment to the radiolabeled metalloporphyrin or metallophthalocyanine complex. This covalent bond ensures a stable connection between the targeting antibody and the therapeutic payload, preventing premature dissociation in the bloodstream. By securely attaching the radiolabeled complex, the ADC maintains its integrity during delivery,, enhancing its ability to localize to the target site and deliver the radiolabeled payload with precision for therapeutic or diagnostic purposes.

[0466] In some instances, the ADC includes one or more linkers selected from a range of established linker types, including maleimidocaproyl (me), maleimidomethyl cyclohexyl-1-carboxylate, self-stabilizing maleimide, mcc hydrazide, mc-val-ala, mc-val-cit-pabc, SPDB, sulfo-SPDB, and AcBut linkers. Each linker offers distinct properties, such as stability, reactivity, and release mechanisms, enabling customization of the ADC for therapeutic needs. For example, mc-val-cit-pabc linkers are enzy matically cleavable and suitable for targeting tumors with elevated protease activity, while non-cleavable linkers like maleimidocaproyl provide enhanced stability for payload delivery.

[0467] In some instances, the ADC utilizes one or more non-cleavable linkers to attach the therapeutic payload. Non-cleavable linkers provide high stability in circulation, reducing the risk of systemic toxicity. Upon internalization, the payload is released through lysosomal degradation of the entire ADC. This approach ensures precise delivery of the drug while minimizing unintended release, making it particularly suitable for payloads requiring controlled activation within target cells.

[0468] In some instances, the ADC incorporates one or more cleavable linkers to facilitate the targeted release of the therapeutic pay load. Cleavable linkers respond to conditions such as acidic pH, reducing agents, or tumor-associated enzymes, allowing for selective release at the tumor site or within the target cell. This selective release enhances therapeutic efficacy by concentrating the drug’s activity at the intended location while reducing systemic side effects.

[0469] In some instances, the ADC features one or more linkers that covalently conjugate the antibody or antigen-binding fragment to the radiolabeled metalloporphyrin complex and / or the chemotherapeutic agent. The covalent bond provides stability and ensures the accurate delivery of both therapeutic components. This dual -conjugation strategy allows the ADC to achieve a synergistic effect by combining the targeting capabilities of the antibody with the therapeutic actions of the chemotherapeutic and radiolabeled components, enhancing overall efficacy.Attorney Docket No.: 38451-0004WO1

[0470] In some instances, the ADC utilizes one or more linkers selected from maleimidocaproyl (me), maleimidomethyl cy cl ohexy 1-1 -carboxylate, self-stabilizing maleimide, mcc hydrazide, mc-val-ala, mc-val-cit-pabc, SPDB, sulfo-SPDB, and AcBut linkers. These linkers offer a wide range of properties, including cleavability, stability, and compatibility with various pay loads. For instance, mc-val-cit-pabc linkers are cleavable in the presence of proteases, making them suitable for tumor-specific delivery, while sulfo-SPDB linkers provide water solubility and efficient drug conjugation. This versatility allows for the design of ADCs tailored to specific therapeutic goals and disease contexts.

[0471] In some instances, the ADC includes one or more of the following structures:

[0472] Formula (VII);

[0473] Formula (IX);

[0474] o

[0475] Formula (X);

[0476]

[0477] Attorney Docket No.: 38451-0004WO1

[0478] Formula (XI);

[0479] o NH2

[0480] Formula (XII);

[0481] o

[0482]

[0483] HQA^x / SH

[0484] Formula (XIII);

[0485] o

[0486] HO^^SH

[0487] SO3H

[0488] Formula (XIV); or

[0489] o

[0490] HO NNH2

[0491]

[0492] Formula (XV).

[0493] In some instances, the ADCs include a design where the linker or the one or more linkers are not identical to each other. This flexibility allows for the creation of ADCs with more sophisticated and tailored release mechanisms, enhancing therapeutic efficacy. By incorporating different linkers with vary ing properties, such as cleavable and non-cleavable types, the ADC can achieve controlled payload delivery in response to the biochemicalAttorney Docket No.: 38451-0004WO1

[0494] environment of the target cell. For instance, one linker might be designed to release the drug pay load inside the cell, while another linker can ensure the stability of the conjugate during its circulation in the bloodstream. This variability in linker composition provides a strategic advantage in optimizing the pharmacokinetics and biodistribution of the ADC, improving both the therapeutic index and safety profile. Additionally, the use of different linkers allows the ADC to be adapted for a wide range of target diseases, providing the flexibility needed to address diverse clinical needs.

[0495] In some instances, the ADC can have a structural arrangement from the N-terminus to the C-terminus, where the radiolabeled metalloporphyrin complex is either positioned before or after the antibody or antigen-binding fragment in the sequence. In one arrangement, the structure follows: (the radiolabeled metalloporphyrin complex)-(a linker)-(antibody or antigen-binding fragment thereof). In this configuration, the radiolabeled metalloporphyrin complex, which can sen e as the therapeutic or diagnostic payload, is directly connected to the targeting component through a linker. This structure can enhance the abi 1 i ty of the ADC to bind and internalize into the target cells efficiently. Alternatively, the structure can be arranged as: (antibody or antigen-binding fragment thereof)-(a linker)-(the radiolabeled metalloporphyrin complex). This variation in orientation offers the advantage of optimizing the spatial configuration between the targeting antibody and the payload, ensuring that the ADC retains its high binding affinity while potentially enhancing the pharmacodynamics of the therapy.

[0496] 3. Drugs

[0497] ADCs as disclosed here include one or more of a radiolabeled metalloporphy rin complex, a radiolabeled metallophthalocyanine complex, a dodecane tetraacetic acid (DOT A), or a chemotherapeutic agent.

[0498] Metalloporphyrins are a class of chemical compounds in which a metal ion is coordinated within the core of a porphyrin ring structure. Porphyrins themselves are large, cyclic compounds composed of four pyrrole units linked by methine bridges, forming a planar structure with a central cavity capable of coordinating metal ions. The metal within the center of the porphyrin can be a variety of elements, including iron, copper, zinc, manganese, or cobalt, each conferring unique chemical properties to the metalloporphyrin. These properties, such as electronic structure and redox potential, make metalloporphyrins valuable in various biological and industrial processes, including catalysis, oxygen transport, and light absorption.Attorney Docket No.: 38451-0004WO1

[0499] Additional approaches to enhance the skeleton of a porphyrin can be found in Lin et al., J Enzyme Inhib Med Chem. 2020 Apr 24;35(1 ): 1080-1099. which is incorporated by reference in its entirety.

[0500] Radiolabeled metalloporphyrins are metalloporphyrin compounds that are tagged with a radioactive isotope, enabling them to be used in both therapeutic and diagnostic applications. The incorporation of a radiolabel, typically a radioisotope such as technetium-99m. iodine-131. or copper-64, allows these compounds to emit detectable radiation, which can be tracked in the body using imaging techniques like positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This radiolabeling makes metalloporphyrins ideal candidates for use in targeted therapies and molecular imaging, particularly in the context of cancer treatment, where precise localization of the drug within the tumor is crucial for effective treatment planning and monitoring.

[0501] In some instances, the radiolabeled metalloporphyrins are integrated into ADCs. Upon binding to the target antigen, the ADC delivers the radiolabeled metalloporphyrin directly to the cancerous tissue, where it can release its radiative energy to either kill the cells via ionizing radiation or enhance the efficacy of other therapeutic agents. Radiolabeled metalloporphyrins offer the advantage of dual functionality, as they can both sen e as therapeutic agents and as tracers for monitoring the distribution and uptake of the drug within the body. This makes them highly valuable in theragnostic, a growing field that combines therapy and diagnostics for personalized treatment approaches.

[0502] The versatility of radiolabeled metalloporphyrins also extends to their use in imaging applications, where they help in the early detection and monitoring of diseases such as cancer, cardiovascular disorders, and neurodegenerative diseases. The radiolabel attached to the metalloporphyrin allows for non-invasive visualization of the distribution of the compound in vivo, providing real-time data on how the drug is accumulating at the site of interest. This imaging capability not only assists in tracking the progress of treatment but also improves the accuracy of diagnosis, guiding clinicians in making more informed decisions about patient care. The high stability and functionalization potential of metalloporphyrins, coupled with their radiolabeling, make them a powerful tool for advancing the precision and effectiveness of medical treatments.

[0503] In some instances, the radiolabeled metalloporphyrin complex comprises a synthetic porphyrin. In some instances, the radiolabeled metalloporphyrin complex comprises:Attorney Docket No.: 38451-0004WO1

[0504]

[0505] Formula (I)

[0506] wherein:

[0507] M is selected from Lu177. Ga68. Ac225, Cu64, Cu67, Pb212, Re188. Ra223, Th227, At211, Sm153, Y90, Tc99, Tb161, Co60, or Sr90;

[0508] R1 is selected from H, Cl, Br, F, CH3, S03-, CN, S02R, CF3, orNO2;

[0509] R2 is selected from H, Cl, Br, CN, COOR', -OCONR’2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, orNCHs.

[0510] R3 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, NHR, NR2, and NCH3.

[0511] R4 is selected from H, Cl, Br, CN, [N(R}1]', COOR', OCONR'2, CON-R', CONR'2, CH=NR'. SO2NR'2, SO2R. CF3, or NO2; and

[0512] X is selected from the group consisting of H, OH, Cl, Br, CN, [N(R}1]', COOR', -OCONR'2, -OMOM, CON-R', CONR'2, CH=NR', SO2NR'2, SO2R, CF3, SH, and NO2.

[0513] In some instances, the radiolabeled metalloporphyrin complex comprises a porphyrin of Formula (II):Attorney Docket No.: 38451-0004WO1

[0514]

[0515] Formula (II).

[0516] In some instances, the radiolabeled metalloporphyrin complex comprises:

[0517]

[0518] Formula (II).

[0519] wherein:

[0520] M is selected from Lu177, Ga68, Ac225, Cu64, Cu67, Pb212, Re188, Ra223, Th227, At211, Sm153, Y90, Tc99, Tb161, Co60, or Sr90.

[0521] Ri is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I-6NH2.

[0522] R2IS selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH. (CH2)I.6OH. or (CH2)I.6NH2.

[0523] R3is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I-6NH2.

[0524] R4 is selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH. (CH2)I.6OH, or (CH2)I.6NH2.

[0525] RS is selected from Me, CH2CH3, CH=CH2, (CH2)I-6COOH, (CH2)I-6OH, or (CH2)I-6NH2.

[0526] Re is selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH. (CH2)I.6OH, or (CH2)I.6NH2.

[0527] R7is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I.6OH, or (CH2)I-6NH2.Attorney Docket No.: 38451-0004WO1

[0528] Rs is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I.6NH2; and

[0529] X = Cl or Br.

[0530] Metallophthalocyanins are a group of synthetic compounds that are structurally similar to porphyrins but feature a phthalocyanine core, a large, planar, aromatic ring system consisting of four isoindole units linked by nitrogen atoms. Just like metalloporphyrins, metallophthalocyanins have a metal ion coordinated at the center of the ring, such as copper, zinc, or cobalt, which imparts unique chemical properties to the molecule. These compounds are highly stable and exhibit intense absorption in the visible and near-infrared regions of the electromagnetic spectrum.

[0531] Radiolabeled metallophthalocyanins are metallophthalocyanin compounds that are tagged with a radioactive isotope, which enables them to be used in both therapeutic and diagnostic applications. The incorporation of a radiolabel, such as copper-64, iodine-131, or technetium-99m, allows these compounds to emit detectable radiation, facilitating their use in medical imaging techniques like positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The unique properties of metallophthalocyanins, including their stability, high light absorption, and the ability to generate reactive oxygen species upon light activation, are enhanced when they are radiolabeled. This dual functionality makes radiolabeled metallophthalocyanins ideal candidates for theragnostic, where they can both serve as targeted therapeutic agents and as tracers to monitor the drug's distribution within the body, helping to visualize tumor cells and other pathological sites with high precision.

[0532] In some instances, radiolabeled metallophthalocyanins are used in targeted therapies, such as in ADCs, where they are delivered specifically to the target cells, such as cancerous cells, via a targeting antibody or antigen-binding fragment. Once the ADC reaches the tumor, the radiolabeled metallophthalocyanin can release its radiation to directly destroy cancer cells through ionizing radiation. In addition, the light-absorbing properties of metallophthalocy anins enable them to be used in photodynamic therapy (PDT), where light exposure leads to the generation of reactive oxygen species that can selectively damage cancer cells.

[0533] In some instances, the radiolabeled metallophthalocyanine complex comprises a radioactive metal and phthalocyanines. In some instances, the radiolabeled metallophthalocyanine complex comprises:Attorney Docket No.: 38451-0004WO1

[0534]

[0535] Formula (III)

[0536] wherein:

[0537] M is selected from Lu177, Ga68, Ac225, Cu64, Cu67, Pb212, Re188, Ra223, Th227, At211, Sm153, Y90, Tc99, Tb161, Co60, or Sr90;

[0538] R1 is selected from H, Cl, Br, CH3, S03-, CN, S02R, CF3, or NO2. R2 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, or NCH3;

[0539] X is selected from the group consisting of H, OH, Cl, Br, CN, [N(R} 1 ]', COOR', -OCONR'2, -OMOM, CON-R', CONR'2, CH=NR', SO2NR'2, SO2R, CF3, SH, and NO2.

[0540] In some instances, the drug is a dodecane tetraacetic acid (DOT A). DOTA (also known as tetraxetan or l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) is an organic compound with the formula CH2CH2NCH2CO2H)4. A representative chemical structure of DOTA is provided below.

[0541] HO OH

[0542] .v> /

[0543] / \ / \

[0544] %. / \ / \ /

[0545] / \

[0546]

[0547] HO OH

[0548] DOTA

[0549] The molecule consists of a central 12-membered tetraaza (i.e., containing four nitrogen atoms) ring. Compositions and methods for use of DOTA are described in Tonon et al., Int J Mol Sci. 2024 Aug 8;25(16):8651; Dai et al, Nature Communications 9: 857 (2018);Attorney Docket No.: 38451-0004WO1

[0550] and Viola-Villegas, Coordination Chemistry Reviews, 253, 13-14, (2009); each of which is incorporated by reference in its entirety.

[0551] DOTA synthesis is described in US Publ. No. 2018 / 0370925 Al and European Patent No. EP0998466 Bl, each of which is incorporated by reference in its entirety.

[0552] DOTA is used as a complexing agent, especially for lanthanide ions, and its complexes have medical applications as cancer treatments and m in vivo imaging and diagnosis.

[0553] When DOTA is used as part of cancer therapies it typically functions as a chelating agent for the radioisotope90Y3+. DOTA can also be conjugated to monoclonal antibodies by attachment of one of the four carboxyl groups as an amide. The remaining three carboxylate anions bind to the yttrium ion Modified antibody accumulates in tumor cells, concentrating the effects of the radioactivity of90Y. Drugs containing this module receive an International Nonproprietary Name ending in “tetraxetan”.

[0554] DOTA also forms particularly stable chelates with contrast-generating paramagnetic metal ions and especially those that are lanthanide ions The gadolinium-DOTA chelate (Dotarem) is one commercially available MRI agent.

[0555] In some instances, the drug is a chemotherapeutic agent. Chemotherapeutic agents are a class of drugs used primarily to treat cancer by targeting and inhibiting the growth of rapidly dividing cells. These agents can work through various mechanisms, including the disruption of DNA replication, inhibition of cell division, or interference with the processes that regulate cell growth and survival. In some instances, chemotherapeutic agents are cytotoxic. In other instances, they act by preventing the spread or metastasis of tumors, or by sensitizing cancer cells to radiation or other treatments. Some chemotherapeutic drugs, such as alkylating agents, antimetabolites, and taxanes, are designed to specifically target the molecular pathways that are often upregulated in cancer cells, making them more vulnerable to treatment compared to normal, healthy cells.

[0556] While chemotherapeutic agents have proven to be effective in treating various types of cancer, they also come with the challenge of side effects due to their lack of specificity for cancer cells alone. Many chemotherapy drugs also affect normal, healthy cells that divide rapidly, such as those in the bone marrow, digestive system, and hair follicles, leading to common side effects like nausea, hair loss, and immune suppression. To overcome these limitations, one or more chemotherapeutic agent is linked to an antibody of ADCs as disclosed herein.Attorney Docket No.: 38451-0004WO1

[0557] In some instances, the ADC can include a broad range of chemotherapeutic agents, providing significant flexibility in therapeutic applications. Chemotherapeutic agents like daunorubicin, doxorubicin, and epirubicin are well-known anthracycline antibiotics that are commonly used in cancer treatment. These agents function primarily by intercalating into DNA, disrupting the replication process and inducing cell death. Doxorubicin, in particular, is widely used in the treatment of various cancers, including breast cancer, lymphomas, and sarcomas. The inclusion of such agents in an ADC allows for a targeted delivery of these powerful drugs directly to tumor cells, thereby minimizing their toxic effects on normal, healthy tissues, which is a common limitation in traditional chemotherapy.

[0558] The use of liposomal formulations, such as doxorubicin liposomal and irinotecan liposomal, in the ADC increases the drug's solubility and stability, and also helps to improve its pharmacokinetics by reducing systemic toxicity. Liposomal encapsulation enhances drug delivery by facilitating the selective accumulation of the drug in tumor tissues due to the enhanced permeability and retention (EPR) effect. This targeted delivery mechanism is particularly beneficial in treating cancers with challenging-to-reach tumors or those that exhibit resistance to conventional formulations of chemotherapy. Moreover, the incorporation of such liposomal chemotherapeutic agents in ADCs further enhances the therapeutic potential of the drug while reducing side effects, which is a key objective in modern oncology.

[0559] Other chemotherapeutic agents, such as the taxanes (cabazitaxel, docetaxel, nab-paclitaxel, and paclitaxel) and vinca alkaloids (vinblastine, vincristine, vinorelbine), also play an important role in cancer treatment. Taxanes, for instance, work by stabilizing microtubules, thereby preventing their depolymerization and inhibiting cell division. They are widely used in the treatment of breast cancer, lung cancer, and ovarian cancer. Vinca alkaloids, on the other hand, inhibit microtubule formation and disrupt mitosis, making them effective in treating a variety of cancers, including Hodgkin's lymphoma and leukemia. The ability to conjugate these agents to an antibody allows for the precise targeting of cancer cells, where the ADC will be selectively internalized, minimizing exposure to healthy cells and improving overall treatment efficacy.

[0560] Chemotherapeutic agents such as etoposide, irinotecan, and topotecan, which are topoisomerase inhibitors, are also commonly included in ADC formulations due to their ability to interfere with DNA replication and repair, leading to cell death. These agents are often used in the treatment of cancers like lung cancer, colorectal cancer, and various pediatric cancers. The versatility of the chemotherapeutic agents herein allows for theAttorney Docket No.: 38451-0004WO1

[0561] tailoring of ADCs to address different types of cancers and their associated characteristics. By incorporating such a wide variety’ of chemotherapeutic agents into ADC formulations, this disclosure provides a robust framework for developing highly effective, personalized cancer therapies with the potential to improve patient outcomes while minimizing the side effects traditionally associated with chemotherapy.

[0562] In some instances, the ADCs described herein include one or more chemical drugs. Chemical drugs can include, but are not limited to, Anthracyclines (e.g., Adriamycin (doxorubicin), Doxil (doxorubicin), daunorubicin, Ellence® (epirubicin), and mitoxantrone); Taxanes (e.g., Taxol (paclitaxel), Abraxane® (nab-paclitaxel), and Taxotere® (docetaxel); Antitumor antibiotics; Alkylating agents (e.g., cisplatin); interferons; and hormone therapies (e.g., leuprolide (Lupron®), anastrozole (Arimidex®). letrozole (Femara®), tamoxifen (Nolvadex®), and fulvestrant (Faslodex®)).

[0563] 4. Antibody-Drug Conjugate Structure

[0564] Disclosed are several structural arrangements for the antibody-drug conjugate (ADC), specifying the sequence of components from the N-terminus to the C-terminus of the conjugate. This structural flexibility allows for the optimization of therapeutic and pharmacokinetic properties by varying the order in which the chemotherapeutic agent, radiolabeled metalloporphyrin complex, and antibody or antigen-binding fragment are connected. The first arrangement, where the chemotherapeutic agent is linked to the radiolabeled metalloporphyrin complex, and then connected to the antibody or antigenbinding fragment via linkers, offers a unique approach in which the therapeutic agents are positioned in close proximity to one another. This arrangement can be beneficial for enhancing the synergistic effect of the chemotherapeutic agent and the radiolabeled complex, potentially increasing the overall cytotoxicity to the target cancer cells.

[0565] In some instances, the arrangement in which the radiolabeled metalloporphyrin complex is positioned between the chemotherapeutic agent and the antibody or antigenbinding fragment allows for a different type of interaction between the therapeutic components. The radiolabeled complex can provide targeted imaging capabilities, helping to visualize the distribution of the ADC within the body before or during treatment. This order might be particularly useful in therapeutic applications that require precise localization of the ADC, especially in tumors that express specific antigens. The placement of the metalloporphyrin complex between the drug and the antibody could also influence the internalization of the conjugate by the cancer cells, as the targeting moiety (antibody or fragment) remains in the final position for optimal binding.Attorney Docket No.: 38451-0004WO1

[0566] In some instances, structural configuration described herein places the antibody or antigen-binding fragment at the N-terminus. followed by the radiolabeled metalloporphyrin complex and chemotherapeutic agent. This arrangement allows the antibody to bind first to the target antigen, ensuring that the conjugate is directed specifically to the tumor cells before the chemotherapeutic agent and radiolabeled complex are released. This ty pe of structural order can offer a more controlled release of the therapeutic payloads, minimizing systemic exposure to the drug and reducing side effects. By strategically positioning the components, this design could enhance the ADC's therapeutic efficacy, ensuring that the drug is efficiently delivered to the tumor site while preserving the stability of the conjugate in the bloodstream.

[0567] In some instances, the antibody is conjugated with the chemotherapeutic agent followed by the radiolabeled metalloporphyrin complex, offers an alternative strategy for the placement of the therapeutic components. In this configuration, the chemotherapeutic agent could be the first to act once the conjugate reaches the target cells, with the radiolabeled metalloporphyrin complex potentially contributing to diagnostic imaging and further enhancing treatment efficacy.

[0568] In some instances, the addition of one or more linking peptides (LPs) is included in the ADC, which further enhances the conjugation and stability of the therapeutic construct. Linking peptides are short chains of amino acids that are strategically placed between different components of the ADC, such as the radiolabeled metalloporphyrin complex, the chemotherapeutic agent, and the antibody or antigen-binding fragment. These peptides serve to provide flexibility in the overall structure, enabling better spatial arrangement and ensuring that the functional components of the ADC are optimally positioned for effective targeting and drug delivery. The use of linking peptides can improve the stability of the ADC in circulation, reduce premature cleavage of the drug before reaching the target, and enhance the overall therapeutic efficacy of the conjugate by facilitating the precise delivery of cytotoxic agents to cancer cells.

[0569] In some instances, the structure of the ADC includes two linking peptides: a first linking peptide (LP 1) and a second linking peptide (LP2). These peptides are incorporated into the ADC's structural arrangement from N-terminus to C-terminus in a manner that allows for strategic positioning of the radiolabeled metalloporphyrin complex and the antibody or antigen-binding fragment. In the first configuration, the radiolabeled metalloporphyrin complex is positioned at the N-terminus and linked to LP1, followed by a linker and LP2 before the antibody or antigen-binding fragment. Alternatively, the antibody or antigenbinding fragment can be placed at the N-terminus, with LP2 linked to the radiolabeledAttorney Docket No.: 38451-0004WO1

[0570] complex via the second linker. This arrangement offers flexibility in how the therapeutic components are connected and allows for the optimization of the conjugate's functionality, particularly in targeting tumor cells and enhancing drug delivery.

[0571] In some instances, the ADC includes a structural arrangement that involves both a chemotherapeutic agent and the radiolabeled metalloporphyrin complex, in addition to the linking peptides. In this configuration, the chemotherapeutic agent is placed at the N-terminus. followed by a first linker and the radiolabeled metalloporphyrin complex, which is then connected to LP1 and LP2 before being conjugated to the antibody or antigen-binding fragment. Alternatively, the structure can be reversed, with the antibody or fragment at the N-terminus and the chemotherapeutic agent positioned at the C-terminus. This arrangement ensures that the chemotherapeutic agent and the radiolabeled complex are closely associated with the tumor-targeting antibody, potentially enhancing the efficacy of the treatment by enabling more efficient drug delivery and minimizing systemic exposure to toxic agents.

[0572] In some instances, the length of the linking peptides (LP 1 and LP2) is about 1 to 20 amino acids each. This short peptide sequence ensures that the linkers are compact yet functional, providing enough flexibility to accommodate the spatial arrangement of the different components without introducing steric hindrance or compromising the stability of the ADC. In some instances, shorter peptides in ADC design can result in a lowered immune response, and they can be synthesized with high efficiency and precision. Furthermore, the flexibility’ in peptide length allows for fine-tuning of the conjugate's properties, enabling the optimization of drug release, binding affinity, and overall therapeutic performance. The use of linking peptides in combination with the radiolabeled metalloporphyrin complex and the chemotherapeutic agent offers a versatile and effective approach to enhancing cancer treatment through antibody-drug conjugates.

[0573] 5. Pharmaceutical Compositions

[0574] In some instances, the ADC is formulated as a pharmaceutical composition, enabling its administration to patients in a controlled and effective manner. This composition ensures that the ADC is stable, bioavailable, and capable of reaching the target site for therapeutic action. In one embodiment, the pharmaceutical composition further includes a carrier, which serves to facilitate the delivery of the ADC to the desired location within the body. Carriers can be various substances, such as saline solutions, buffers, or other excipients, that help stabilize the conjugate, maintain its integrity during storage and transport, and ensure its proper absorption and distribution after administration. The carrier can also enhance theAttorney Docket No.: 38451-0004WO1

[0575] solubility, pharmacokinetics, or bio-distribution of the ADC, thereby optimizing the therapeutic outcome. The composition is designed to provide the ADC in an efficient and reproducible manner, ensuring that the cancer-targeting properties of the antibody and the potency of the cytotoxic drug are maximized while minimizing side effects.

[0576] In addition to a carrier, the pharmaceutical composition of the ADC can also contain various excipients, stabilizers, and agents to further enhance the formulation's stability, bioavailability, and overall performance. Common excipients in ADC formulations include buffers such as phosphate-buffered saline (PBS) or histidine buffers, which help maintain the pH of the solution and stabilize the conjugate during storage and administration. Other stabilizers, such as sugars (e.g., sucrose or trehalose), can be included to protect the ADC from degradation due to freeze-thaw cycles and to preserve its structural integrity. Surfactants like polysorbate 80 or cetyltrimethylammonium bromide can also be added to prevent aggregation and maintain the solubility of the ADC in solution. Additional agents, such as antioxidants (e g., ascorbic acid or methionine), can be incorporated to protect the ADC from oxidative degradation. These excipients and stabilizers work in concert to ensure the ADC remains effective, safe, and stable over time, providing an optimal formulation for clinical use in cancer therapy.

[0577] C. Method and Uses

[0578] Disclosed herein are methods of treatment in a subject in need thereof. The methods include administering any one of the ADCs described in this application. Methods of treatment using antibody-drug conjugates for cancer therapy involve administering an ADC to a patient in need of treatment for a specific cancer type. The specificity of ADCs enables precise targeting of tumors with minimal off-target effects, which is particularly beneficial in cancers that are resistant to traditional treatments.

[0579] In some instances, disclosed is a method for treating, preventing, and / or delaying the onset or progression of cancer, as well as alleviating symptoms associated with the presence, growth, proliferation, metastasis, and / or activity of cancer cells. This method involves administering a therapeutically effective amount of any one of the ADCs disclosed in this application to a patient in need of treatment. The ADC, which targets specific tumor antigens, works by selectively binding to cancer cells and delivering a cytotoxic payload, such as a chemotherapeutic agent or a radiolabeled complex, directly to the site of the tumor. This approach can halt or slow cancer progression, reduce symptoms associated with tumorAttorney Docket No.: 38451-0004WO1

[0580] growth, and, in some cases, eliminate cancer cells, leading to improved clinical outcomes for patients.

[0581] In some instances, the methods include inhibiting the growth of cancer cells by treating the cells with any one of the ADCs disclosed in this application. The ADC is designed to specifically target and bind to cancer cells expressing a particular antigen, which results in the internalization of the conjugate and the subsequent release of the cytotoxic drug. The chemotherapeutic agent or radiolabeled metalloporphyrin complex delivered by the ADC inhibits the proliferation of the cancer cells, leading to the suppression of tumor growth. This method is particularly useful for treating cancers that are known to have a high rate of cell division and proliferation, thereby improving therapeutic efficacy and potentially preventing further metastasis.

[0582] Also disclosed is a method for treating a subj ect diagnosed with cancer by administering a therapeutically effective amount of any one of the ADCs disclosed herein. The ADC delivers targeted therapy that not only directly impacts cancer cells but also minimizes damage to surrounding healthy tissues, making it a more precise treatment option compared to conventional chemotherapy. By specifically targeting tumor antigens, the ADC enhances the delivery of the therapeutic agent, allowing for greater effectiveness in shrinking tumors, preventing their spread, and managing symptoms. This method is applicable to various types of cancer, including both solid and hematologic malignancies, and provides an innovative therapeutic strategy for patients in need of cancer treatment.

[0583] In some aspects disclosed is a method for diagnosing a subject as having cancer, involving at least two steps. First, an ADC disclosed herein is administered to the subject. The ADC is designed to target specific cancer cell antigens, enabling precise imaging of tumors within the body. Once the ADC has been administered, the second step involves imaging the subject using techniques such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), depending on the properties of the radiolabeled components of the ADC. This imaging allows for the visualization of the distribution of the ADC within the subject, highlighting areas where cancer cells are present, and thereby aiding in the diagnosis of cancer. The targeted nature of the ADC ensures that it accumulates at tumor sites, providing high specificity’ and accuracy in identifying cancerous tissues.

[0584] In some instances, after diagnosing the subject, the methods further include administration of a therapeutically effective amount of the ADC. In addition to its diagnostic function, the ADC serves a therapeutic role by delivering a cytotoxic drug to cancer cellsAttorney Docket No.: 38451-0004WO1

[0585] once it has bound to the target antigen. This dual-purpose approach allows for the concurrent diagnosis and treatment of cancer, potentially improving the early detection of tumors while providing targeted therapy to inhibit cancer cell growth or induce tumor regression. The combination of diagnostic imaging and therapeutic action enhances the overall clinical management of cancer, providing both an accurate diagnosis and an effective treatment strategy.

[0586] The ADC described herein is suitable for the treatment of various cancer types in a wide range of patients, including humans and other animals. In some instances, the subject is human. In some instances, the ADC may be administered to human patients suffering from solid tumors, hematologic cancers, or other malignancies that express a target antigen specific to the antibody or antigen-binding fragment of the conjugate. In addition to humans, the ADC can also be used in veterinary applications, where it may be administered to animals, including but not limited to companion animals (such as dogs and cats), livestock (such as cattle, pigs, and horses), and other domesticated or non-domesticated animals that may benefit from cancer treatment. The ADC's ability to target specific tumor antigens makes it suitable for use across various species, provided that the target antigen is expressed or overexpressed in the cancer cells of the animal. The treatment may be adjusted based on the species, cancer type, and the specific pharmacokinetic and pharmacodynamic properties of the ADC in each animal model, enabling the safe and effective application of the ADC across a broad range of patients.

[0587] The ADCs described herein are applicable to the treatment of a wide variety of cancers, both in human and veterinary patients. The ADC can be utilized for targeting solid tumors, such as breast cancer, lung cancer (including non-small cell and small cell types), colorectal cancer, prostate cancer, and ovarian cancer. It is also effective for hematologic malignancies, including leukemia (acute and chronic forms), lymphoma (Hodgkin's and non-Hodgkin's lymphoma), and multiple myeloma. In some instances, the methods can be used to treat solid tumor cancers, including advanced or metastatic stages. In some instances, this therapeutic approach is effective for treatment of breast cancer, lung cancer, particularly non-small cell lung cancer, stomach cancer, prostate cancer, ovarian cancer, colorectal cancer, colon cancer, esophageal cancer, tracheal cancer, gastric cancer, bladder cancer, uterine cancer, rectal cancer, cancer of the small intestine, pancreatic cancer, head and neck cancer, thyroid cancer, endometrial cancer, and epithelial cancers, as well as the metastases associated with these cancers. The ADC may be particularly beneficial for cancers that exhibit overexpression of specific target antigens, such as HER2 in breast and gastric cancers,Attorney Docket No.: 38451-0004WO1

[0588] EGFR in non-small cell lung cancer and colorectal cancer, and CD20 in certain ty pes of B-cell lymphomas. Additionally, the ADC could be applied to other malignancies, such as pancreatic cancer, liver cancer (hepatocellular carcinoma), esophageal cancer, endometrial cancer, head and neck cancer, thyroid cancer, renal cell carcinoma, bladder cancer, melanoma, and glioblastoma.

[0589] The administration of ADCs is typically performed through intravenous infusion, although other routes of administration can be suitable depending on the drug formulation and the clinical context. In some instances, the administering is by continuous infusion, intramuscularly, subcutaneously, parenterally, intra-articularly, intrasynovially, intrathecally, orally, topically, intratumorally, peritumorally, intralesionally, or via perilesionally, or via inhalation.

[0590] The treatment efficacy of ADCs is monitored through a combination of clinical assessments, imaging studies, and biomarker analysis. Clinical evaluations often involve regular imaging scans, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), to assess the tumor response to therapy. Additionally, the use of radiolabeled components within the ADC can provide real-time information about the distribution and accumulation of the drug within the body. Biomarker analysis can also be employed to assess the expression of the target antigen on tumor cells, as this can influence the efficacy of the ADC.

[0591] In some instances, the methods also include synthesis of the ADCs provided herein. The synthesis of ADCs involves a series of steps to ensure the successful attachment of the cytotoxic drug (or radiolabeled complex, or additional linkers and / or LPs) to the antibody or antigen-binding fragment. In some instances, the first step is to provide the antibody or antigen-binding fragment, which is typically selected for its specificity to a particular cancer-related antigen. The antibody may be a monoclonal antibody, a peptide antibody, or any other type of fragment, such as Fab, scFv, or F(ab')2. Along with the antibody, the linker or one or more linkers are also provided, which are designed to covalently attach the drug to the antibody. These linkers can be cleavable or non-cleavable, depending on the desired release mechanism for the drug. Additionally, the radiolabeled metalloporphyrin complex, the radiolabeled metallophthalocyanine complex, and / or the chemotherapeutic agent are prepared, which will be the therapeutic pay load of the ADC. This complex is typically synthesized in a separate step, where, for instance, a metal ion is coordinated to the porphyrin or phthalocyanine ring system, and it is then radiolabeled to facilitate imaging or therapeutic action once delivered to the tumor site.Attorney Docket No.: 38451-0004WO1

[0592] Once the components are provided, the next step in the synthesis process involves the actual conjugation of the drug to the antibody. The linker is used to non-covalently or covalently bind the radiolabeled metalloporphyrin complex to the antibody or antigenbinding fragment. In some instances, the linker is used to non-covalently or covalently bind the radiolabeled metallophthalocyanine complex to the antibody or antigen-binding fragment. In some instances, the linker is used to non-covalently or covalently bind the radiolabeled metallophthalocyanine complex to the chemotherapeutic agent. This step often involves the use of chemical reactions, such as thiol-maleimide chemistry, amide bond formation, or other coupling techniques, depending on the type of linker and antibody used. The goal of this step is to ensure a stable, but controlled, attachment of the drug to the antibody, allowing for targeted delivery to cancer cells while minimizing premature release or degradation of the drug during circulation. The efficiency of this conjugation process is crucial to achieving the correct drug-to-antibody ratio (DAR), which influences the overall therapeutic efficacy and safety of the ADC.

[0593] In some instances, the production methods can also involve the incorporation of a chemotherapeutic agent. This addition may require additional steps to ensure that the chemotherapy drug is properly attached to the linker or to the antibody. For instance, the chemotherapeutic agent can be conjugated to a separate linker, which then binds to the radiolabeled metalloporphyrin complex or a radiolabeled metallophthalocyanine complex. In some instances, this method provides a versatile platform for the synthesis of ADCs that are tailored to deliver both targeted therapy and potent cytotoxic agents directly to the cancer cells.

[0594] Synthesis of compounds is further described in US Pat. Publ. No. 2018 / 0370925 Al, which is incorporated by reference in its entirety.

[0595] EXAMPLES

[0596] Example 1. Antibody Drug Synthesis having a Radiolabeled Metalloporphyrin Complex

[0597] Methods of ADC synthesis are described. The methods result in an ADC that include — as shown in FIG. 1 — an antibody, a linker, and a radiolabeled metalloporphyrin complex. In this approach, radiolabeled metalloporphyrin complex is attached to an antibody covalently via a non-cleavable linker. The methods also can result in a dual-acting ADC, as shown in FIG. 2. A specific resulting ADC having a Lu-177 radioactive metal incorporated into a synthetic porphyrin, a non-cleavable linker, and an antibody is shown in FIG. 3.Attorney Docket No.: 38451-0004WO1

[0598] An exemplary synthesis is provided in FIGs. 4A-4D. Briefly, synthesis of antibody linker conjugate XXVII (dimethyl (((S)-6-((R)-2-((lr.4R)-4-(aminomethyl)cyclohexane-l-carboxamido)-2-(naphthalen-2-yl)acetamido)-l -methoxy- l-oxohexan-2-yl)carbamoyl)-D-glutamate): dimethyl (((S)-6-amino-I -methoxy- l-oxohexan-2-yl)carbamoyl)-D-glutamate XXV (1 eq) and (R)-2-((lr,4R)-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-l-carboxamido)-2-(naphthalen-2-yl)acetic acid XXVI (1 eq) were taken in a round bottom flask and dissolved in anhydrous DMF. To this solution EDCI (1.2 eq). HOBt (1.2eq) and DIEA (3 eq) were added and stirred overnight. This crude reaction mixture was evaporated in vacuo and purified by chromatography to get tri ester. This N-Boc protected tri methyl ester conjugate was treated with 30%THF in DCM / DMF. The reaction mixture was evaporated, and the crude product was purified to obtain pure antibody linker conjugate XXVII

[0599] As an additional example, synthesis of porphyrin linker antibody conjugate XXIX ((((S)-l -carboxy -5-((R)-2-(naphthalen-2-yl)-2-((l r,4R)-4-((4-(2,3,7,8, 12,13,17,18-octabromo- 10, 15,20-tris(4-carboxyphenyl)porphy rin-5-yl)benzamido)methyl)cy clohexane- 1-carboxamido)acetamido)pentyl)carbamoyl)-D-glutamic acid: dimethyl (((S)-6-((R)-2-((lr,4R)-4-(aminomethyl)cyclohexane-l-carboxamido)-2-(naphthalen-2-yl)acetamido)-l-methoxy-l-oxohexan-2-yl)carbamoyl)-D-glutamate XXVII (1 eq) and (4, 4', 4", 4"'-(2,3,7,8,12,13,17,18-octabromoporphyrin-5,10,15,20-tetrayl)tetrabenzoic acid XXVIII(leq) were taken in a round bottom flask and dissolved in anhydrous DMF. To this solution EDCI (1.2 eq), HOBt (1.2eq) and DIEA (3 eq) were added and stirred overnight. This crude reaction mixture was evaporated in vacuo and purified by chromatography to get crude product. This crude product was purified and was dissolved in anhydrous NMP and LiOH (5eq) was added and stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude was treated with 3NHC1 solution in NMP for an hour. The reaction mixture was evaporated in vacuo to get the crude de zinc product and this was purified by chromatography to get pure XXIX

[0600] Syyl) benzamidoadiometalloporphyrin linker antibody conjugate XXX (177Lu(III)(((S)-l-carboxy-5-((R)-2-(naphthalen-2-yl)-2-((lr,4R)-4-((4-(2,3,7,8,12,13,17,18-octabromo- 10, 15, 20-tris(4-carboxyphenyl)porphyrin-5-yl)benzamido)methyl)cy clohexane- 1-carboxamide) acetamido)pentyl)carbamoyl)-D-glutamicacid chloride): ((((S)-l-carboxy-5-((R)-2-(naphthalen-2-yl)-2-((lr,4R)-4-((4-(2,3,7,8,12,13,17,18-octabromo-10,15,20-tris(4-carboxyphenyl)porphyrin-5-yl)benzamido)methyl)cyclohexane-l-carboxamido)acetamido)pentyl)carbamoyl)-D-glutamic acid XXXI (1 eq) was dissolved in anhydrous DMF and177Lu(III)Cl3(1.1 eq) was added to the solution and gently heated toAttorney Docket No.: 38451-0004WO1

[0601] 50OC overnight. This reaction mixture was evaporated in vacuo and the crude was purified by chromatography to obtain pure antibody drug conjugate XXX.Attorney Docket No.: 38451-0004WO1

[0602] Example 2. Specific Antibody-Drug Synthesis having a Radiolabeled Metalloporphyrin Complex

[0603] Using the methods from Example 1, additional exemplary ADCs are produced. The ADCs include radioactive metal incorporated natural metalloporphyrins, as shown below:

[0604]

[0605] In addition, an ADC having a radioactive metal incorporated synthetic metalloporphyrin can be synthesized. For instance, the ADC can include lutetium-177 or acteni um-225 as radioactive metal:

[0606]

[0607] Lutetium-177 as radioactive metal

[0608]

[0609] Actenium-225 as radioactive metal

[0610] These radioactive metal incorporated porphyrins are conjugated with selected antibodies for cancer specific antigens (or other cellular targets). This conjugation isAttorney Docket No.: 38451-0004WO1

[0611] accomplished by covalently bonding with specific linkers to both metalloporphyrins and antibodies. These conjugated radiometal labelled metalloporphyrins will be used in targeted radiotherapy and as tracers in radio imaging diagnostics.

[0612] Additional examples of targeted ADCs are provided below:

[0613] • ADC-1: Targeted radiotherapy for prostate cancer with Lu-177 radioactive metal incorporated natural metalloporphyrin:

[0614] N 3 p h >. h y ■ 312 n i: "■ Q ( N <3 H

[0615] Sma!l molecule based Antibody: urea bond linked Lysine withglutamic acid

[0616]

[0617] • ADC-2: Targeted radiotherapy for colon cancer and non-small cell lung cancer (NSCLC) with radioactive metal incorporated natural metalloporphyrin:

[0618]

[0619] • ADC -3: ADC having Ga-68 radioactive metal incorporated natural metalloporphyrin as diagnostic radio tracer for prostate cancer:Attorney Docket No.: 38451-0004WO1

[0620] Naphthylaianine (Nal)

[0621]

[0622] Ga-68 radioactive metal Small molecule incorporated \ ^-OH based Antibody:

[0623] 4

[0624] natural porphyrin urea bond linked Lysine (Protoporphyrin IX) withglutamic acid

[0625] • ADC-4: An ADC having Ga-68 radioactive metal incorporated synthetic metalloporphyrin as diagnostic radio tracer for prostate cancer:

[0626]

[0627] Ga-68 radioactive metal incorporated synthetic porphyrin

[0628] Small molecule

[0629] based Antibody:

[0630] urea bond linked Lysine withglutamic acid

[0631] • ADC-5: An ADC having Ga-68 radioactive metal incorporated natural metalloporphyrin as diagnostic radio tracer for HER2 positive breast cancer, colon cancer and non-small cell lung cancer (NSCLC):Attorney Docket No.: 38451-0004WO1

[0632]

[0633] • ADC-6: An ADC having Ga-68 radioactive metal incorporated synthetic metalloporphyrin as diagnostic radio tracer for HER2 positive breast cancer,

[0634] colon cancer and non-small cell lung cancer (NSCLC):

[0635]

[0636] incorporated Non Cleavable

[0637]

[0638] synthetic porpyrin Linker

[0639]

[0640] hh'dmg antibody

[0641] • ADC-7: An ADC having Ga-68 radioactive metal incorporated natural metalloporphyrin as diagnostic radio tracer for ovarian cancer:Attorney Docket No.: 38451-0004WO1

[0642]

[0643] • ADC-8: An ADC having Ga-68 radioactive metal incorporated synthetic metalloporphyrin as diagnostic radio tracer for ovarian cancer:

[0644]

[0645] incorporated Non Cleavable synthetic porpyrin Linker

[0646]

[0647] • ADC-9: An ADC targeted for radiotherapy for ovarian cancer using a

[0648] radioactive metal incorporated synthetic metalloporphyrin:Attorney Docket No.: 38451-0004WO1

[0649]

[0650] natural Protoporphyrin IX

[0651] • ADC-10: An ADC targeted radiotherapy for ovarian cancer with a radioactive metal incorporated natural metalloporphyrin:

[0652] i-'ol.ste Paoeptor Alpha

[0653]

[0654] IFRafcha} biadbra rsrsdhady nature! Protoporphyrin IX

[0655] • ADC-11: Targeted radiotherapy for prostate cancer with Cu-67 radioactive

[0656] metal incorporated synthetic metalloporphyrin:Attorney Docket No.: 38451-0004WO1

[0657] F

[0658]

[0659] synthetic porphyrin

[0660] Smai! molecule based Antibody: urea bond linked Lysine withglutamic acid

[0661] Example 3 Synthesis of Dual-Acting ADCs

[0662] In this approach radiolabeled metalloporphyrin complex is covalently linked with antibody via suitable non-cleavable linker and linked with a selected tumoricidal chemotherapeutic agent via a cleavable linker, as shown in FIG. 2.

[0663] These radioactive metal incorporated metalloporphyrins as described in method of claim 1 will be conjugated with selected antibody for cancer specific antigen and cancer chemo drug. This double conjugation is accomplished by covalently bonding between radiolabeled metalloporphyrins with specific non cleavable linkers to specific antibodies and by covalently bonding with cleavable linkers to cancer specific chemotherapy drugs. This targeted antibody therapy carries both a radioactive and a chemotherapeutic drug payload to the target site. These tumoricidal mechanisms work simultaneously and synergistically.

[0664] In this method, cancer killing chemotherapeutic agents are conjugated to radio-metalloporphyrins with antibodies. Examples of targeted ADCs are provided below:

[0665] • ADC-12: Targeted dual therapy with conjugated chemo drug and radiotherapy for prostate cancer with Lu-177 radioactive metal incorporated natural metalloporphyrin:Attorney Docket No.: 38451-0004WO1

[0666]

[0667] • ADC-13: Targeted dual therapy with conjugated chemo drug and radiotherapy for prostate cancer with Lu-177 radioactive metal incorporated synthetic metalloporphyrin:Attorney Docket No.: 38451-0004WO1

[0668] Lu-177 incorporated synthetic porphyrin

[0669] Cleavable \ Linker / '

[0670] Antibody

[0671]

[0672] • ADC-14: Ga-68 radioactive metal incorporated natural metalloporphyrin as diagnostic radio tracer in dual therapy approach for prostate cancer diagnosis:Attorney Docket No.: 38451-0004WO1

[0673] radioactive metal Ga-68 incorporated natural porphyrin

[0674] NH (Protoporphyrin iX)

[0675]

[0676] Cieavable

[0677] Linker / HN-- \ Non Cleavable s— S / \ Linker < ) f 0

[0678] Antibody

[0679]

[0680] • ADC-15: Ga-68 radioactive metal incorporated synthetic metalloporphyrin as diagnostic radio tracer in dual therapy approach for prostate cancer diagnosis:Attorney Docket No.: 38451-0004WO1

[0681]

Claims

Attorney Docket No.: 38451-0004WO1WHAT IS CLAIMED IS:

1. An antibody-drug conjugate comprising:(a) an antibody or antigen-binding fragment thereof that specifically binds to an antigen;(b) a linker; and(c) a radiolabeled metalloporphyrin complex or a radiolabeled metallophthalocyanine complex.

2. An antibody-drug conjugate comprising:(a) an antibody or antigen-binding fragment thereof that specifically binds to an antigen;(b) one or more linkers;(c) a radiolabeled metalloporphyrin complex, a radiolabeled metallophthalocyanine complex; a dodecane tetraacetic acid (DOTA), or other known metal carriers; and(d) a chemotherapeutic or one or more other chemical drug agents.

3. The antibody-drug conjugate of claim 1 or 2, wherein the radiolabeled metalloporphyrin complex comprises:Formula (I)wherein:M is selected from Lu177, Ga68, Ac225, Pb212, Re188, Ra223, Sm153, Y90, Tc99, Tb161, Co60, or Sr90;Attorney Docket No.: 38451-0004WO1R1 is selected from H, Cl, Br, F, CH3, S03-, CN, S02R, CF3, orNO2;R2 is selected from H, Cl, Br, CN, COOR', -OCONR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, or NCH3;R3 is selected from H, Cl, Br, CN, COOR’, -OCONR’2, CON-R', CONR’2, SO2NR’2, SO2R, CF3, NHR, NR2, and NCH3;R4 is selected from H, Cl, Br, CN, [N(R}1]', COOR', OCONR’2, CON-R', CONR'2. CH=NR'. SO2NR'2, SO2R. CF3, or NO2; andX is selected from the group consisting of H, OH, Cl, Br, CN, [N(R} 1 ]’, COOR’, -OCONR’2, -OMOM, CON-R’, CONR’2, CH=NR’, SO2NR’2, SO2R, CF3, SH, and NO2.

4. The antibody-drug conjugate of claim 1 or 2, wherein the radiolabeled metalloporphyrin complex comprises:Formula (I)wherein:M is selected from Cu64, Cu67, or At211;R1 is selected from H, Cl, Br, F, CH3, SO3-, CN, SO2R, CF3, or NO2;R2 is selected from H, Cl, Br, CN, COOR', -OCONR’2, CON-R’, CONR’2, SO2NR'2, SO2R, CF3, or NCH3;R3 is selected from H, Cl, Br, CN, COOR', -OCONR’2, CON-R’, CONR’2, SO2NR’2, SO2R, CF3, NHR, NR2, and NCH3;Attorney Docket No.: 38451-0004WO1R4 is selected from H, Cl, Br, CN, [N(R}1]', COOR', OCONR'2, CON-R', CONR'2, CH=NR'. SO2NR'2, SO2R. CF3, or NO2; andX is selected from the group consisting of H, OH, Cl, Br, CN, [N(R}1]', COOR', -OCONR'2, -OMOM, CON-R', CONR'2, CH=NR', SO2NR'2, SO2R, CF3, SH, and NO2.

5. The antibody-drug conjugate of any one of claims 1-4, wherein the radiolabeled metallophthalocyanine complex comprises a radioactive metal and phthalocyanines.

6. The antibody -drug conjugate of claim 1 or 2, wherein the radiolabeled metalloporphyrin complex comprises a porphyrin of Formula (II):

7. The antibody-drug conjugate of any one of claims 1, 2, and 6, wherein the radiolabeled metalloporphyrin complex comprises:Formula (II),wherein:M is selected from Lu177, Ga68, Ac225, Pb212, Re188, Ra223, Sm153, Y90, Tc99, Tb161, Co60, or Sr90;Attorney Docket No.: 38451-0004WO1Ri is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I.6NH2;R2IS selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I.6OH, or (CH2)I.6NH2;R3is selected from Me, CH2CH3, CH CH2. (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I.6NH2;R4is selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH. (CH2)I.6OH. or (CH2)I.6NH2;RS is selected from Me, CH2CH3, CH=CH2, (CH2)I-6COOH, (CH2)I-6OH, or (CH2)I.6NH2;R6is selected from Me. CH2CH3, CH=CH2, (CH2)I-6COOH. (CH2)I-6OH, or (CH2)I.6NH2;R7is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I-6NH2;Rs is selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I.6OH, or (CH2)I.6NH2; andX = Cl or Br.

8. The antibody-drug conjugate of any one of claims 1, 2, and 7, wherein the radiolabeled metalloporphyrin complex comprises:Formula (II),wherein:M is Cu64, Cu67, or At211;Ri is selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I.6OH, or (CH2)I.6NH2;R2is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I.6OH, or (CH2)I.6NH2;Attorney Docket No.: 38451-0004WO1R3is selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I.6NH2;R4IS selected from Me, CH2CH3, CH=CH2, (CH2)I.6COOH, (CH2)I.6OH, or (CH2)I.6NH2;RS is selected from Me, CH2CH3, CH CH2. (CH2)I.6COOH, (CH2)I-6OH, or (CH2)I.6NH2;R6is selected from Me. CH2CH3, CH=CH2, (CH2)I.6COOH. (CH2)I.6OH. or (CH2)I.6NH2;R7is selected from Me, CH2CH3, CH=CH2, (CH2)I-6COOH, (CH2)I-6OH, or (CH2)I.6NH2;Rs is selected from Me. CH2CH3, CH=CH2, (CH2)I-6COOH. (CH2)I-6OH, or (CH2)I.6NH2; andX = Cl or Br.

9. The antibody-drug conjugate of any one of claims 1-3 of 5-7, wherein the radiolabeled metallophthalocyanine complex comprises:Formula (III)wherein:M is selected from Lu177. Ga68. Ac225, Pb212, Re188, Ra223, Sm153, Y90, Tc99, Tb161, Co60, or Sr90;R1 is selected from H, Cl, Br, CH3, S03-, CN, S02R, CF3, orNO2; R2 is selected from H, Cl, Br, CN, COOR', -0C0NR'2, CON-R', CONR'2, SO2NR'2. SO2R, CF3, or NCH3; andAttorney Docket No.: 38451-0004WO1X is selected from the group consisting of H, OH, Cl, Br, CN, [N(R}1]', COOR', -OCONR'2, -OMOM, CON-R', CONR'2, CH=NR', SO2NR'2, SO2R, CF3, SH, and NO2.

10. The antibody -drug conjugate of claims 4 or 7, wherein the radiolabeled metallophthalocyanine complex comprises:Formula (III)wherein:M is selected from Cu64, Cu67, or At211;R1 is selected from H, Cl, Br, CH3. SO3-. CN, S02R, CF3, or NO2; R2 is selected from H, Cl, Br, CN, COOR', -0C0NR'2, CON-R', CONR'2, SO2NR'2, SO2R, CF3, orNCHs; andX is selected from the group consisting of H, OH, Cl, Br, CN, [N(R}1]', COOR', -OCONR'2, -OMOM, CON-R', CONR'2, CH=NR', SO2NR'2, SO2R, CF3, SH, and NO2.

11. The antibody -drug conjugate of claim 1 or 2, wherein the radiolabeled metalloporphyrin complex comprises a synthetic porphyrin.

12. The antibody -drug conjugate of any one of claims 1-11, wherein the antibody-drugAttorney Docket No.: 38451-0004WO1conjugate has a drug-to-antibody ratio (DAR) of 1, 2, 4, or 8, wherein the drug is any one, two, or all three of the radiolabeled metalloporphyrin complex, the radiolabeled metallophthalocyanine complex, or the chemotherapeutic and other chemical drug agents.

13. The antibody -drug conjugate of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof is selected from a small molecule antibody, optionally wherein the small molecule antibody is selected from Formula (XVI) to Formula (XX).

14. The antibody -drug conjugate of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof is selected from a peptide or a cyclic peptide antibody.

15. The antibody-drug conjugate of any one of claims 1-12 or 14, wherein the antigen binding fragment thereof is selected a Fab fragment, a F(ab')2 fragment, a scFv, a scAb, and a dAb or any other kind of antibody fragment.

16. The antibody-drug conjugate of any of claims 1-12, 14, or 15, wherein the antibody or antigen-binding fragment thereof is selected from gemtumab, moxetumamab, trastuzumab, or cetuximab.

17. The antibody -drug conjugate of claim 16,wherein the antibody or antigen-binding fragment thereof comprises a light chain sequence comprising SEQ ID NO: 1 and a heavy chain sequence comprising SEQ ID NO: 2, orwherein the antibody or antigen-binding fragment thereof comprises one or more of SEQ ID NOs: 3-5; orwherein the antibody or antigen-binding fragment thereof comprises a light chain sequence comprising SEQ ID NO: 6 and a heavy chain sequence comprising SEQ ID NO: 7; orwherein the antibody or antigen-binding fragment thereof comprises a light chain sequence comprising SEQ ID NO: 8 and a heavy chain sequence comprising SEQ ID NO: 9.

18. The antibody-drug conjugate of any one of claims 1-17, wherein the antibody or antigen-binding fragment thereof is selected from an antibody sequence of Table 1.Attorney Docket No.: 38451-0004WO119. The antibody -drug conjugate of any one of claims 1 and 3-18, the linker comprises a non-cleavable linker.

20. The antibody -drug conjugate of any one of claims 1 and 3-18, the linker comprises a cleavable linker.

21. The antibody -drug conjugate of any one of claims 1 and 3-20. wherein the linker covalently conjugates the antibody or the antigen-binding fragment thereof to the radiolabeled metalloporphyrin or metallophthalocyanine complex.

22. The antibody-drug conjugate of any one of claims 1 and 3-21. wherein the one or more linkers is selected from a maleimidocaproyl (me) linker, a maleimidomethyl cyclohexyl-1-carboxylate linker, a self-stabilizing maleimide linker, a mcc hydrazide linker, an mc-val-ala linker, an mc-val-cit-pabc linker, an SPDB linker, a sulfo-SPDB linker, or an AcBut linker.

23. The antibody -drug conjugate of any one of claims 2-18, wherein the one or more linkers comprises a non-cleavable linker.

24. The antibody -drug conjugate of any one of claims 2-18. wherein the one or more linkers comprises a cleavable linker.

25. The antibody -drug conjugate of any one of claims 2-13, 23, and 24, wherein the one or more linkers covalently conjugate the antibody or the antigen-binding fragment thereof to the radiolabeled metalloporphyrin complex and / or the chemotherapeutic or other chemical drug agents.

26. The antibody -drug conjugate of any one of claims 2-18, and 23-25, wherein the one or more linkers is selected from a maleimidocaproyl (me) linker, a maleimidomethyl cyclohexyl-1-carboxylate linker, a self-stabilizing malemide linker, a mcc hydrazide linker, an mc-val-ala linker, an mc-val-cit-pabc linker, an SPDB linker, a sulfo-SPDB linker, or an AcBut linker.Attorney Docket No.: 38451-0004WO127. The antibody -drug conjugate of claim 22 or 26, wherein the one or more linkers comprises:a maleimidocaproyl (me) linker comprising the following structure:Formula (VII); ora maleimidomeythy cyclohexyl- 1 -carboxylate linker comprising the following structure:Formula (VIII); ora self-stabilizing malemide linker comprising the following structure:Formula (IX); ora mcc hydrazide linker comprising the following structure:oFormula (X); ora mc-val-ala linker comprising the following structure:Formula (XI); ora mc-val-cit-pabc linker comprising the following structure:Attorney Docket No.: 38451-0004WO1Formula (XII); ora SPDB linker comprising the following structure:oFormula (XIII); ora sulfo-SPDB linker comprising the following structure:oHOAY"^SHSO3HFormula (XIV); oran AcBut linker comprising the following structure:Formula (XV).

28. The antibody -drug conjugate of any one of claims 1 -27, wherein the linker or the one or more linkers are not identical to each other.

29. The antibody -drug conjugate of any one of claims 1 and 3-28. wherein the antibodydrug conjugate has a structural arrangement from N-terminus to C-terminus as follows:(the radiolabeled metalloporphyrin complex)-(a linker)-(antibody or antigen-binding fragment thereof); or(antibody or antigen-binding fragment thereof)-(a linker)-(the radiolabeled metalloporphyrin complex).Attorney Docket No.: 38451-0004WO130. The antibody-drug conjugate of any one of claims 2-29, wherein the chemotherapeutic agent is selected from daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, mitoxantrone, valrubicin, bleomycin, dactinomycin, mitomycin-c, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine, vincristine liposomal, vinorelbine, etoposide, irinotecan, irinotecan liposomal, mitoxantrone, teniposide, topotecan or any other known chemotherapy or other chemical drugs.

31. The antibody -drug conjugate of any one of claims 2-30, wherein the antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows:(the chemotherapeutic agent)-(a linker)-(the radiolabeled metalloporphyrin complex)-(a linker)-(antibody or antigen-binding fragment thereof);(the radiolabeled metalloporphyrin complex)-(a linker)-(the chemotherapeutic agent)-(a linker)-(antigen-binding fragment thereof);(antibody or antigen-binding fragment thereof)-(a linker)-(the radiolabeled metalloporphyrin complex)-(a linker)-(the chemotherapeutic agent); or(antibody or antigen-binding fragment thereof)-(a linker)-(the chemotherapeutic agent)-(a linker)-(the radiolabeled metalloporphyrin complex).

32. The antibody-drug conjugate of any one of claims 1-31. wherein the antibody-drug conjugate further comprises one or more linking peptides (LPs).

33. The antibody -drug conjugate of claim 32, wherein the one or more linking peptides comprise a first linking peptide (LP1) and a second linking peptide (LP2), wherein the antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows:(the radiolabeled metalloporphyrin complex)-LPl-(a linker)-LP2-(antibody or antigen-binding fragment thereof); or(antibody or antigen-binding fragment thereof)-(LP2)-(a linker)-(LPl)-(the radiolabeled metalloporphyrin complex).

34. The antibody -drug conjugate of claim 33, wherein the one or more linking peptides comprise a first linking peptide (LP1) and a second linking peptide (LP2), wherein theAttorney Docket No.: 38451-0004WO1antibody-drug conjugate has a structural arrangement from N-terminus to C-terminus as follows:(a chemotherapeutic agent)-(a first linker of the one or more linkers)-(the radiolabeled metalloporphyrin complex)-LP1-(a second linker of the one or more linkers)-LP2-(the antibody or antigen-binding fragment thereof); or(the antibody or antigen-binding fragment thereof)-(LP2)-(a linker of one or more linkers)-(LP 1 )-(the radiolabeled metalloporphyrin complex)-(a first linker of the one or more linkers)-(a chemotherapeutic agent) wherein each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length.

35. The antibody -drug conjugate of any one of claims 1-34, which is formulated as a pharmaceutical composition, optionally wherein the pharmaceutical composition further comprises a carrier.

36. A method of synthesizing the antibody-drug conjugate of any one of claims 1-35. the method comprising:(a) providing the antibody or antigen-binding fragment thereof; the linker or the one or more linkers; and the radiolabeled metalloporphyrin complex; and(b) synthesizing the antibody-drug conjugate.

37. The method of claim 36, further comprising providing the chemotherapeutic agent in step (a) or (b).

38. A method of treating, preventing, and / or delaying the onset or progression of. or alleviating a symptom associated with the presence, growth, proliferation, metastasis, and / or activity of a cancer cell, the method comprising administering a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1-35.

39. A method of inhibiting growth of a cancer cell, the method comprising treating the cancer cell w ith the antibody-drug conjugate of any one of claims 1-35.

40. A method of treating a subject having cancer, the method comprising administering a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1-35.Attorney Docket No.: 38451-0004WO141. The method of claim 40, wherein the cancer is a solid tumor cancer; or wherein the cancer is advanced or metastatic cancer; or wherein the cancer is breast cancer, lung cancer, non-small cell lung cancer, stomach cancer, prostate cancer, ovarian cancer, colorectal cancer, colon cancer, esophageal cancer, tracheal cancer, gastric cancer, bladder cancer, uterine cancer, rectal cancer or cancer of the small intestine, pancreatic cancer, head and neck cancer, thyroid cancer, endometrial cancer, epithelial cancer, or metastases associated therewith.

42. The method of any one of claims 40 or 41, wherein the subject is human.

43. The method of any one of claims 40-42, wherein the administering method is intravenous administration.

44. The method of any one of claims 40-42, wherein the administering is by continuous infusion, intramuscularly, subcutaneously, parenterally, intra-articularly, intrasynovially, intrathecally, orally, topically, intratumorally, peritumorally. intralesionally. or via perilesionally, or via inhalation.

45. A method of diagnosing a subject as having cancer, the method comprising:(a) administering to the subject the antibody-drug conjugate of any one of claims 1-35; and(b) imaging the antibody drug conjugate in the subject,thereby diagnosing the subj ect as having cancer.

46. The method of claim 45, further comprising administering to the subject a therapeutically effective amount of the antibody-drug conjugate.

47. The method of claim 45 or 46, wherein the cancer is a solid tumor cancer; and / or wherein the cancer is advanced or metastatic cancer; and / or wherein the cancer is breast cancer, lung cancer, non-small cell lung cancer, stomach cancer, prostate cancer, ovarian cancer, colorectal cancer, colon cancer, esophageal cancer, tracheal cancer, gastric cancer, bladder cancer, uterine cancer, rectal cancer or cancer of the small intestine, pancreatic cancer, head and neck cancer, thyroid cancer, endometrial cancer, epithelial cancer, or metastases associated therewith.Attorney Docket No.: 38451-0004WO148. The method of any one of claims 45-47, wherein the subject is human.

49. The method of any one of claims 45-48, wherein the administering is intravenous administration.

50. The method of any one of claims 45-48, wherein the administering is by continuous infusion, intramuscularly, subcutaneously, parenterally, intra-articularly, intrasynovially, intrathecally, orally, topically, intratumorally, peritumorally, intralesionally, or via perilesionally, or via inhalation.

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