Anti-trop2 antibody radioconjugates and methods of use thereof

Abstract

Provided are antibody radioconjugates that bind to human TROP2 protein for use in diagnosing and treating TROP2-expressing cancers, such as triple negative breast cancer and metastatic castration-resistant prostate cancer, which may be relapsed and / or refractory with respect to one or more prior therapies such as treatment with an antibody drug conjugate.

Description

ANTI-TROP2 ANTIBODY RADIOCONJUGATES AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patent application serial no. 63 / 691,824 filed September 6, 2024, which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 4, 2025 is named ATNM-027PCT_SL.xml and is 233,366 bytes in size.FIELD OF THE INVENTION

[0003] The presently claimed invention relates to the field of targeted radiotherapy.BACKGROUND

[0004] Tumor-associated calcium signal transducer 2, also known as Trop-2 or TROP2 and as epithelial glycoprotein- 1 antigen (EGP-1), is a protein encoded by the human TACSTD2 gene which is overexpressed in carcinomas. Overexpression of TROP2 is associated with poor survival in human solid tumor patients. Cancers that may be targeted with a TROP2 targeting agent and treated with a radiolabeled TROP2 targeting agent according to the invention include but are not limited to carcinomas, squamous cell carcinomas, adenocarcinomas, non-small cell lung cancer (NSCLC), NRG1 fusion NSCL, Small-cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, triple negative breast cancer (TNBC), prostate cancer, hormone- refractory prostate cancer, pancreatic ductal adenocarcinoma, NRG1 fusion pancreatic cancer, head and neck cancers, renal cell cancer, urinary bladder neoplasms, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and glioblastoma multiforme.

[0005] What is needed and provided by the various aspects of the present invention are new antibody radioconjugates and their use for treating TROP2-expressing cancers.SUMMARY OF THE INVENTION

[0006] One aspect of the invention provides anti-TROP2 antibody radioconjugate including: an anti-TROP2 antibody or TROP2-binding antibody fragment, such as any of those disclosed herein;a radionuclide chelator conjugated to said anti-TR0P2 antibody or TROP2-binding antibody fragment; and a radionuclide chelated by the radionuclide chelator, for treatment of a TR0P2 expressing solid tumor cancer, which may be relapsed and / or refractory with respect to one or more prior treatments.

[0007] Another aspect of the invention provides a radiopharmaceutical composition, for imaging and / or treatment of TROP2 expressing solid tumor cancers in a mammalian subject such as a human patient that includes the aforementioned anti-TROP2 antibody radioconjugate and at least one pharmaceutically acceptable excipient.

[0008] A further aspect of the invention provides methods for diagnosing, radioimaging and / or treating TROP2 expressing cancers in a mammalian subject such as a human patient that include administering one or more anti-TROP2 antibody radioconjugates as disclosed herein to the subject, which may include administering a radiopharmaceutical composition as disclosed herein to the subject.

[0009] Still another aspect of the invention provides a radiolabeled TROP2 targeting agent, such as a monoclonal antibody, antibody fragment, peptide, or small molecule, such as any of those disclosed herein, that binds human TROP2 for the treatment of TROP2 expressing solid tumor cancers, such as any of those disclosed herein, which may be metastatic, locally advanced or non- metastatic, that has been previously treated with one or more prior treatments, such as one or more prior pharmacological treatments and / or non-TROP2-targeted radiotherapies such as EGFR-, HER2-, HER3-, or PSMA-targeted radiotherapies, and / or non-TROP2 targeted antibody drug conjugates such as a HER3 targeted antibody drug conjugate such as patritumab deruxtecan (e.g. Herthena®) and / or EGFR / HER3 bispecific ADC such as Izalontamab brengitecan and / or a HER2 targeted antibody drug conjugate such as trastuzumab deruxtecan (e.g. Enhertu®), and / or a TROP2 antibody drug conjugate such as datopotamab deruxtecan (Datroway®), sacituzumab govitecan (Trodelvy®) or sacituzumab tirumotecan (SKB264 / MK-2870), and / or therapeutic antibodies such as an anti-HER2 therapeutic antibody such as trastuzumab (Herceptin®), an anti-HER3 therapeutic antibody, or a HER2 / HER3 bispecific therapeutic antibody such as zenocutuzumab, and which may, for example, be or have become relapsed and / or refractory and / or resistant to one or more of said prior treatments.

[0010] One or more additional therapeutic agents and / or therapeutic modalities / treatments may also be employed in combination or conjunction with use of the TROP2 targeted radiotherapeutic agent. Such additional therapeutic agents and modalities that may be used include, for example, one or more non-steroidal antiandrogens such as flutamide, and enzalutamide (e.g. Xtandi®), abiraterone (e.g. Zytiga®) or any combination thereof, at least one or more immune checkpoint therapy and / or one or more inhibitors of a component of the DNA damage response pathway (i.e., a DNA damage response inhibitor, DDRi, such as one or more agents against poly(ADP-ribose) polymerase, i.e., PARPi) and / or one or more CD47 / SIRPa axis blockades and / or one or more chemotherapeutic agents such as radiosensitizers, and / or one or more small molecule oncology drugs such as tyrosine kinase inhibitors, and / or one or more targeting agents against different antigens.

[0011] Still another aspect of the invention provides methods for identifying, imaging and / or diagnosing TROP2-positive cancers, such as a prostate cancer, in a subject previously treated with another agent / treatment as described above, such as but not limited to a PSMA- targeted therapeutic agent, such as a PSMA-targeted radiotherapeutic agent or a PSMA-targeted antibody drug conjugate.

[0012] Additional features, advantages, and aspects of the invention may be set forth or apparent from consideration of the following detailed description, drawings if any, and claims. Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows the results of an in vivo efficacy study of225Ac-Sacituzumab in a human nonsmall cell lung cancer xenograft tumor model.

[0014] FIG. 2 shows the results of an in vivo efficacy study of223Ac-Sacituzumab in a human breast cancer xenograft tumor model.DETAILED DESCRIPTION

[0015] The invention provides radiolabeled TROP2 targeting agents, such as anti-TROP2 antibody radioconjugates, and their use in diagnosing, including radioimaging, and / or treating TROP2 expressing cancers in mammalian subjects such as human patients. The cancers treated may, for example, be relapsed and / or refractory to prior treatment with one or more different agentsor modalities such as but not limited to chemotherapy, targeted pharmaceutical agents, antibody therapeutics, targeted radiotherapies, and antibody drug conjugates.

[0016] One aspect of the invention provides an anti-TROP2 antibody radioconjugate including: an anti-TROP2 antibody or TROP2-binding antibody fragment, such as any of those disclosed herein; a radionuclide chelator conjugated to said anti-TROP2 antibody or TROP2-binding antibody fragment; and a radionuclide, such as a beta-particle emitter such as177Lu or149Tb or an alpha-particle emitter such as225Ac or212Pb, chelated by the radionuclide chelator.

[0017] Another aspect of the invention provides a radiopharmaceutical composition, for imaging and / or treatment of TROP2 expressing solid tumor cancers in a mammalian subject such as a human patient that includes a radiolabeled TROP2 targeting agent, such as an anti-TROP2 antibody radioconjugate or anti-TROP2 antibody fragment radioconjugate and at least one pharmaceutically acceptable excipient.

[0018] A further aspect of the invention provides methods for diagnosing, radioimaging and / or treating TROP2 expressing cancers in a mammalian subject such as a human patient that include administering one or more anti-TROP2 antibody radioconjugates or anti-TROP2 antibody fragment radioconjugates as disclosed herein to the subject, which may include administering a radiopharmaceutical composition as disclosed herein to the subject.

[0019] Another aspect of the invention provides a radiolabeled TROP2 targeting agent, such as a monoclonal antibody, antibody fragment, peptide, or small molecule, such as any of those disclosed herein, that binds human TROP2 for the treatment of TROP2 expressing solid tumor cancers, such as any of those disclosed herein, which may be metastatic or non-metastatic, that has been previously treated with one or more prior treatments, such as one or more prior pharmacological treatments and / or non-TROP2-targeted radiotherapies such as EGFR-, HER2-, HER3-, or PSMA-targeted radiotherapies, and / or non-TROP2 targeted antibody drug conjugates such as a HER3 targeted antibody drug conjugate such as patritumab deruxtecan (e.g. Herthena®) and / or EGFR / HER3 bispecific ADC such as Izalontamab brengitecan and / or a HER2 targeted antibody drug conjugate such as trastuzumab deruxtecan (e.g. Enhertu®), and / or a TROP2 antibody drug conjugate such as datopotamab deruxtecan (Datroway®), sacituzumab govitecan (Trodelvy®) or sacituzumab tirumotecan (SKB264 / MK-2870), and / or therapeutic antibodies suchas an anti-HER2 therapeutic antibody such as trastuzumab (Herceptin®), an anti-HER3 therapeutic antibody, or a HER2 / HER3 bispecific therapeutic antibody such as zenocutuzumab, and which may, for example, be or have become relapsed and / or refractory and / or resistant to one or more of said prior treatments. Also provided are corresponding medical uses of said radiolabeled TR0P2 targeting agents for the treatment of said cancers and corresponding methods for treating said cancers by administering said radiolabeled TR0P2 targeting agents to subjects afflicted with said cancers.

[0020] In one aspect, the cancer is breast cancer, such as hormone receptor positive breast cancer, that has been previously treated with endocrine therapy such as one or more non-steroidal antiestrogens such as tamoxifen and / or fluvestrant, and / or with one or more CDK 4 / 6 inhibitors such as palbociclib, ribociclib, and albamaciclib, and / or with a HER2 agent such as trastuzumab, lapatinib and / or an EGFR inhibitor and / or non-TROP2-targeted radiotherapies, and / or non-HER3 targeted antibody drug conjugates such as a TROP2 targeted antibody drug conjugate such as datopotamab deruxtecan (e.g. Datroway®), sacituzumab govitecan (e.g. Trodelvy®) or sacituzumab tirumotecan (SKB264 / MK-2870), and / or a HER2 ADC such as trastuzumab deruxtecan (e.g. Enhertu®) and / or a HER3 targeted antibody drug conjugate such as patritumab deruxtecan (e.g. Herthena®), and / or EGFR / HER3 bispecific ADC such as Izalontamab brengitecan and / or EGFR / HER3 bispecific ADC such as Izalontamab brengitecan, and / or therapeutic antibody an anti-HER2 therapeutic antibody such as trastuzumab (Herceptin®), an anti-HER3 therapeutic antibody, or a HER2 / HER3 bispecific therapeutic antibody such as zenocutuzumab, and which may, for example, be or have become relapsed and / or refractory and / or resistant to one or more of said prior treatments.

[0021] In another aspect, the cancer is non-small cell lung cancer (NSCLC) that has been previously treated with chemotherapy such as one or more of carboplatin, cisplatin and a taxane such as paclitaxel, and / or one or more tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, osimertinib, and aflatinib, and / or non- TROP2 -targeted radiotherapies such as EGFR-, HER2-, HER3-, or PSMA-targeted radiotherapies, such as any of those disclosed herein, and / or non- TROP2-targeted antibody drug conjugates such as a HER3 targeted antibody drug conjugate such as patritumab deruxtecan (e.g. Herthena®) and / or EGFR / HER3 bispecific ADC such as Izalontamab brengitecan and / or a HER2 targeted antibody drug conjugate such as trastuzumab deruxtecan (e g. Enhertu®), and / or a TROP2 antibody drug conjugate such as datopotamabderuxtecan (Datroway®), sacituzumab govitecan (e.g. Trodelvy®) or sacituzumab tirumotecan (SKB264 / MK-2870), and / or therapeutic antibodies such as an anti-HER2 therapeutic antibody such as trastuzumab (Herceptin®), and anti-HER3 therapeutic antibody, or a HER2 / HER3 bispecific therapeutic antibody such as zenocutuzumab, and which may, for example, be or have become relapsed and / or refractory and / or resistant to one or more of said prior treatments.

[0022] In one aspect, the cancer is ovarian cancer that has been previously treated with chemotherapy such as one or more of carboplatin, cisplatin and a taxane such as paclitaxel, and / or one or more PARP inhibitors such as any of those disclosed herein and / or anti-VEGF or anti- VEGF receptor agents such as bevacizumab, and / or non-TROP2-targeted radiotherapies such as EGFR-, HER2-, HER3-, or PSMA-targeted radiotherapies, such as any disclosed herein, and / or non-TROP2-targeted antibody drug conjugates such as a HER3 targeted antibody drug conjugate such as patritumab deruxtecan (e.g. Herthena®) and / or EGFR / HER3 bi specific ADC such as Izalontamab brengitecan and / or a HER2 targeted antibody drug conjugate such as trastuzumab deruxtecan (e.g. Enhertu®), and / or a TROP2 antibody drug conjugate such as datopotamab deruxtecan (Datroway®), sacituzumab govitecan (e.g. Trodelvy®), or sacituzumab tirumotecan (SKB264 / MK-2870), and / or therapeutic antibodies such as an anti-HER2 therapeutic antibody such as trastuzumab (Herceptin®), an anti-HER3 therapeutic antibody or a HER2 / HER3 bispecific therapeutic antibody such as zenocutuzumab, and which may, for example, be or have become relapsed and / or refractory and / or resistant to one or more of said prior treatments.

[0023] Another aspect of the invention provides a radiolabeled TROP2 targeting agent, such as a monoclonal antibody, antibody fragment, peptide, or small molecule, such as any of those disclosed herein, that binds human TROP2 for the treatment of TROP2 expressing cancers, such as prostate cancer, such as metastatic prostate cancer, such as metastatic castration resistant prostate cancer (mCRPC) that has been previously treated with one or more non-steroidal antiandrogens such as flutamide, enzalutamide (e.g. Xtandi®), abiraterone (e.g. Zytiga®) or any combination thereof, and / or a PSMA-targeted therapeutic agent, such as PSMA-targeted radiotherapeutic agent such as177Lu PSMA-617 (e.g. Pluvicto®) or225Ac PSMA-617, or a PSMA- targeted antibody drug conjugate, using the radiolabeled TROP2 targeting agent.

[0024] In a related aspect, the invention provides methods for diagnosing and / or treating TROP2- positive (TROP2-expressing) cancers that have been previously treated with a PSMA-targeted therapeutic agent, such as a PSMA-targeted radiotherapeutic agent or a PSMA-targeted antibodydrug conjugate, using a radiolabeled TR0P2 targeting agent. The cancer may, for example, be a PSMA-expressing and / or initially PSMA-expressing cancer such as a prostate cancer, an advanced prostate cancer, a metastatic prostate cancer, or a metastatic castration-resistant prostate cancer, or a PSMA-expressing / initially-PSMA-expressing non-prostatic cancer such as an acinic cell carcinoma, adenoid cystic carcinoma, breast carcinoma, carcinoma of the salivary gland, glioblastoma multiforme, hepatocellular carcinoma, mutant astrocytoma, metastatic testicular mixed germ-cell tumor, oral squamous cell carcinoma, osteosarcoma, papillary thyroid carcinoma, radioiodine-refractory differentiated thyroid cancer, melanoma, or wild-type glioblastoma. The cancer may have been treated previously with a PSMA-targeted agent and / or be relapsed and / or refractory (R / R) with respect to treatment with a PSMA-targeted agent.

[0025] One or more additional therapeutic agents and / or therapeutic modalities / treatments may also be employed / administered in combination or conjunction with use of the radiolabeled TROP2 targeted therapeutic agent. Such additional therapeutic agents and modalities that may be used include, for example, one or more non-steroidal antiandrogens such as flutamide, and enzalutamide (e.g. Xtandi®), abiraterone (e.g. Zytiga®) or any combination thereof, at least one or more immune checkpoint therapy and / or one or more inhibitors of a component of the DNA damage response pathway (i.e., a DNA damage response inhibitor, DDRi, such as one or more agents against poly(ADP-ribose) polymerase, i.e., PARPi) and / or one or more CD47 / SIRPa axis blockades and / or one or more chemotherapeutic agents such as radiosensitizers, and / or one or more small molecule oncology drugs such as tyrosine kinase inhibitors, and / or one or more targeting agents against different antigens. In one aspect, the cancer is a prostate cancer, such as metastatic prostate cancer, such as metastatic castration-resistant prostate cancer and the one or more additional agents include one or more non-steroidal antiandrogens such as flutamide, enzalutamide (e.g. Xtandi®), abiraterone (e.g. Zytiga®) or any combination thereof.

[0026] Another aspect of the invention provides methods for identifying, imaging and / or diagnosing TROP2-positive cancer, such as a prostate cancer, in a subject previously treated with another agent / treatment as described above, such as but not limited to a PSMA-targeted therapeutic agent, such as a PSMA-targeted radiotherapeutic agent or a PSMA-targeted antibody drug conjugate. The presently disclosed invention further provides methods for identifying, imaging and / or diagnosing TROP2-positive cancer, such as a prostate cancer in a subject previously treated with a PSMA-targeted therapeutic agent, such as a PSMA-targeted radiotherapeutic agent or aPSMA-targeted antibody drug conjugate, followed by treating those subjects with a TR0P2 targeted radiotherapeutic agent alone or in combination with additional therapeutic agents and / or treatment modalities.

[0027] Exemplary TROP2 targeting agents that may be radiolabeled and used in the diagnosis and / or treatment of a proliferative disorder include the monoclonal antibodies Sacituzumab and Datopotamab, antibodies having one or both of the heavy chain and light chain of said antibodies, and antibodies having one or both of the heavy chain CDRs and the light chain CDRs of said antibodies, or TROP2-binding fragments of any of the aforementioned antibodies. Sacituzumab biosimilar is commercially available as Catalog No. A2175 from BioVision Incorporated (an Abeam company, Waltham, MA, USA). Datopotamab biosimilar is commercially available as Catalog No. PX-TA1653 from ProteoGenix (Schiltigheim, France).

[0028] Exemplary TROP2 targeting agents that may be radiolabeled and used in in the diagnosis and / or the treatment of a proliferative disorder include a monoclonal antibody having a heavy chain SEQ ID NO:61 and / or a light chain SEQ ID NO:66 (reported as the heavy and light chains of Sacituzumab), or an antibody including one or both of the heavy chain variable region (SEQ ID NO:62)or the light chain variable region (SEQ ID NO:67) of said chains, or an antibody including 1, 2, or 3 of the heavy chain CDRs of said heavy chain (CDR Hl-3: SEQ ID NOS:63-65 respectively) and / or 1, 2 or 3 of the light chain CDRs of said light chain (CDR Ll-3: SEQ ID NOS:68-70 respectively), and any of the anti-human TROP antibodies disclosed in Pat. No. 7,238,785 (hRS7), U.S. Pat. No. 9,492,566, U.S. Pat. No. 10,195,517, or U.S. Pat. No. 11,116,846, or an antibody including one or both of the heavy chain and light chain variable regions of said antibodies, or an antibody including a heavy chain including 1, 2 or 3 of the heavy chain CDRs of any of said antibodies and / or a light chain including 1, 2, or 3 of the light chain CDRs of any of said antibodies.

[0029] Further exemplary TROP2 targeting agents that may be radiolabeled and used in the treatment of a proliferative disorder include a monoclonal antibody heavy chain SEQ ID NO:71 and / or a light chain SEQ ID NO:76 (reported as the heavy and light chains of Datopotamab), or an antibody including one or both of the variable region of said heavy chain (SEQ ID NO:72) and the variable region of said light chain (SEQ ID NO:77), or an antibody including 1, 2, or 3 of the heavy chain CDRs of said heavy chain (CDRs 1-3: SEQ ID NOS:73-75 respectively) and / or 1, 2 or 3 of the light chain CDRs of the said light chain (CDR Hl -3: SEQ ID NOS: 78-80 respectively),and any of the anti-human TROP antibodies disclosed in Int’l Pub. No. WO2015098099 or U.S. Pub. No. 20210238303, or an antibody including one or both of the heavy chain and light chain variable regions of said antibodies, or an antibody including a heavy chain including 1, 2 or 3 of the heavy chain CDRs of any of said antibodies and / or a light chain including 1, 2, or 3 of the light chain CDRs of any of said antibodies.

[0030] Exemplary TROP2 targeting agents that may be radiolabeled and used in the diagnosis and / or the treatment of a proliferative disorder include BAT006, BAT007, BAT008, and / or any of the TROP2-binding antibodies or antibody fragments disclosed in U.S. Patent No. 11,192,954.

[0031] Exemplary TROP2 targeting agents that may be radiolabeled and used in the diagnosis and / or the treatment of a proliferative disorder include the TROP2-binding antibodies and antibodies fragments disclosed in U.S. Pub. No. 2024 / 0092930 and any antibodies or antibody fragments including the same heavy chain and light chain CDR sequences thereof, and / or same immunoglobulin heavy and light chain variable regions. SEQ ID NOS: 1-60 of this disclosure correspond to SEQ ID NOS: 1-60 of U.S. Pub. No. 2024 / 0092930. Without limitation, the anti- TROP2 antibody or TROP2 binding antibody fragment may include any one or more of the combinations (nos. 1-30) of immunoglobulin heavy chain and light chain CDR (HCDR1-3 and LCDR1.3) amino acid sequences set forth in Table 1.TABLE 1In a related aspect of the invention, the anti-TROP antibody includes one of the following respectively recited combinations of immunoglobulin heavy chain variable regions and light chain variable regions: SEQ ID NO: 1 and SEQ ID NO: 18; SEQ ID NO:2 and SEQ ID NO: 19; SEQ ID NO:3 and SEQ ID NO 20; SEQ ID NO:4 and SEQ ID NO:20; SEQ ID NO:3 and SEQ ID NO:21; SEQ ID NO:4 and SEQ ID NO:21, SEQ ID NO:3 and SEQ ID NO:22; SEQ ID NO:3 and SEQ ID NO:23; SEQ ID NO:5 and SEQ ID NO:24); SEQ ID NO:6 and SEQ ID NO:25; SEQ ID NO:7 and SEQ ID NO:26; SEQ ID NO:7 and SEQ ID NO:27; SEQ ID NO:8 and SEQ ID NO:27; SEQ ID NO:9 and SEQ ID NO:27; SEQ ID NO: 10 and SEQ ID NO:27; SEQ ID NO:7 and SEQ ID NO:28; SEQ ID NO:8 and SEQ ID NO:28; SEQ ID NO:9 and SEQ IDNO:28; SEQ ID NO: 10 and SEQ ID NO:28; SEQ ID NO:7 and SEQ ID NO:29; SEQ ID NO:8 and SEQ ID NO:29; SEQ ID NO:9 and SEQ ID NO:29; SEQ ID NO: 10 and SEQ ID NO:29; SEQ ID NO: 11 and SEQ ID NO:30; SEQ ID NO: 12 and SEQ ID NO:31; SEQ ID NO: 13 and SEQ ID NO:32; SEQ ID NO: 16 and SEQ ID NO:32; SEQ ID NO: 14 and SEQ ID NO:33; SEQ ID NO: 16 and SEQ ID NO:33; SEQ ID NO: 14 and SEQ ID NO:34; SEQ ID NO: 14 and SEQ ID NO 35; SEQ ID NO: 15 and SEQ ID NO:36; SEQ ID NO: 14 and SEQ ID NO:36; and SEQ ID NO: 16 and SEQ ID NO:36. Also provided by the invention are aspects in which the one or both of the amino acid sequences of the heavy and light chain variable regions in said combinations is 5% or less non-identical to the indicated sequence of the outside CDR regions. Any of these antibodies may, for example, further include a heavy chain constant region having, for example, the amino acid sequence of SEQ ID NO:37 or a sequence at least 90% or at least 95% identical thereto, and a light chain constant region having for example, the amino acid sequence of SEQ ID NO:38 or a sequence at least 90% or at least 95% identical thereto.

[0032] In another aspect of the invention, the TROP2 binding agent may include or be a TROP2 binding nanobody (VHH domain), such as a camelid single chain antibody or humanized form thereof. For example, the TROP2 binding agent may be a TROP2 binding domain with no added amino acids or for example, up to 10 added amino acids at the amino and / or carboxyl terminus. In another example, the TROP2 binding agent may be a fusion protein including a TROP2 binding VHH sequence and a human heavy chain constant region (e.g., human Fc region). In one aspect, the TROP2 binding protein may include or be MY6349 (a / k / a HuNBl; Shanghai Novamab Biopharmaceuticals, Ltd.), a VHH domain including the VHH CDRs of MY6349, or any of the TROP2 binding VHH domains set forth in Chinese Patent No. CN 113527496. The TROP2 binding protein may, for example, include or be a TROP2 binding VHH domain including one or more of the following combinations of VHH domain CDRs shown in Table 2.TABLE 2

[0033] In a related aspect, the TROP2 binding protein may include or be one or more humanized VHH domains having amino acid sequences selected from SEQ ID NO: 151 (HuNbl-70), SEQ ID NO: 152 (HuNbl-78), SEQ ID NO: 153 (HuNb-81), SEQ ID NO: 154 (HuNb2-22), SEQ ID NO: 155 (HuNb2-38), SEQ ID NO: 156 (HuNb2-59), and SEQ ID NO:157 (HuNb6-24).An exemplary radiolabeled TROP2 targeting agent that may be used in the diagnosis and / or treatment of a proliferative disorder according to the various aspects of the invention is the nanobody based antibody radioconjugate LNTH-2404 (Lantheus Holdings, Inc.; formerly RAD206, Radiopharm Theranostics Ltd.).

[0034] Exemplary TROP2 targeting agents that may be radiolabeled and used in the diagnosis and / or the treatment of a proliferative disorder include the TROP2-binding antibodies and antibodies fragments disclosed in Int’l Pub. No. W02025 / 020038 (Int’l App. No. PCT / SG2024 / 050432) and any antibodies or antibody fragments including the same heavy chain and light chain CDR sequences thereof, and / or same immunoglobulin heavy and light chain variable regions. According in one aspect, the TROP2 targeting agent is an antibody or TROP2 binding antibody fragment including one or more of the CDR combinations shown Table 3.Table 3

[0035] In a related aspect, the anti-TROP2 antibody includes one or more of the following combinations of immunoglobulin heavy chain variable region (including the recited amino acidsequence) and immunoglobulin light chain variable region (including the recited amino acid sequence), respectively: SEQ ID NO: 180 and SEQ ID NO: 185 (ref: 2D8-gl); SEQ ID NO: 180 and SEQ ID NO: 186 (ref: 2D8); SEQ ID NO: 181 and SEQ ID NO: 187 (ref: 7G7-gl); SEQ ID NO: 182 and SEQ ID NO: 188 (ref: 7G7); SEQ ID NO: 183 and SEQ ID NO: 189 (ref: 5A12); and SEQ ID NO: 184 and SEQ ID NO: 190 (ref: 6C10).

[0036] Anti-TROP2 antibody radioconjugates used in the various aspects of the invention that include an Fc region (such as a native IgG or a VHH-Fc fusion protein) may, for example, use an Fc receptor binding competent Fc region or an Fc region having low or no affinity to Fc receptor and / or has been modified (e.g. mutated) to lower its affinity to Fc receptor versus a naturally occurring amino acid sequence from which it is derived, such as those known in the art.

[0037] Anti-TROP2 antibodies or TROP2-binding antibody fragments may, for example, be linked directly or indirectly via a chemically conjugated chelator, to a radionuclide, such as a beta- particle emitter such as177Lu or an alpha-particle emitter such as225Ac or212Pb, for example, to target cytotoxic radiation to TROP2-expressing cancer / tumor cells in a mammalian subject such as a human patient, and / or to image TROP2 expression in a mammalian subject such as a human patient. For example, the antibody may be conjugated to a chelator using a bifunctional chelator as disclosed in U.S. Patent No. 1 1,964,948 and radiolabeled with a radionuclide as disclosed therein. For example, the antibody may be directly labeled with an iodine isotope such as131I according to the methods disclosed in U.S. Patent No. 10,420,851 or the antibody may be chemically conjugated to a chelator, such as p-SCN-Bn-DOTA and labeled with a radionuclide, such as225Ac, according to the procedures described in U.S. Patent No. 9,603,954 or any suitable methods known in the art.

[0038] The radionuclide may, for example, selected from134Ce,43Sc,44Sc,47Sc,?5Co,60Cu,61Cu,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,82Rb,86Y,87Y,90Y,89Zr,97Ru,105Rh,109Pd,11’in,117raSn,149Pm,149Tb,153Sm,177LU,186Re,188Re,199Au,2O1T1,203Pb,212Pb,212Bi,213Bi,225Ac, and227Th.

[0039] The chelator group in the various aspects of the invention may, for example, include: l,4,7, 10-tetraazacyclododecane-l,4,7-triacetic acid (D03A) or a derivative thereof; 1,4,7- triazacyclononane-l,4-diacetic acid (NODA) or a derivative thereof; 1,4,7-triazacyclononane- 1,4,7-triacetic acid (NOTA) or a derivative thereof; 1,4,7, 10-tetraazacy clododecane- 1,4, 7, 10- tetraacetic acid (DOTA) or a derivative thereof; 1,4,7-triazacyclononane, 1-glutaric acid-4, 7- diacetic acid (NOD AGA) or a derivative thereof; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4.7.10-tri acetic acid (DOT AGA) or a derivative thereof; 1,4,8,11 -tetraazacyclotetradecane- 1,4,8, 11 -tetraacetic acid (TETA) or a derivative thereof; 1,4,8,11- tetraazabicyclo[6.6.2]hexadecane-4, 11 -diacetic acid (CB-TE2A) or a derivative thereof; diethylene triamine pentaacetic acid (DTP A), its diester, or a derivative thereof; 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A"-DTPA) or a derivative thereof; deferoxamine (DFO) or a derivative thereof; l,2-[[6-carboxypyridin-2-yl]methylamino]ethane (FEdedpa) or a derivative thereof; DADA or a derivative thereof; 1,4,7, 10-Tetraazacyclododecane-l,4,7, 10- tetra(methylene phosphonic acid) (DOTP) or a derivative thereof; 4-amino-6-[[16-[(6- carboxypyridin-2-yl)m ethyl]- 1 ,4, 10, 13-tetraoxa-7, 16-diazacyclooctadec-7 -yl]methyl]pyridine-2- carboxylic acid (MACROP A-NH2) or a derivative thereof; MACROPA or a derivative thereof;1.4.7.10-tetrakis(carbamoylmethyl)-l,4,7,10-tetraazacyclododecane (TCMC) or a derivative thereof; {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l, 4, 7]triazonan-l-yl (-acetic acid (NETA) or a derivative thereof; Diamsar or a derivative thereof; 1,4,7-triazacyclononane- l,4,7-tris[methyl(2-carboxyethyl)phosphinic acid (TRAP, PRP9, TRAP-Pr) or a derivative thereof; N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H4octapa) or a derivative thereof; N,N'-[ 1 -benzyl- 1 ,2,3 -triazole-4-yl]methyl-N,N'-[6-(carboxy)pyridin-2-yl]- 1 ,2- diaminoethane (H2azapa) or a derivative thereof; N,N''-[[6-(carboxy)pyridin-2- yl]methyl]diethylenetriamine-N,N',N''-triacetic acid (H5decapa) or a derivative thereof; N,N'- bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED) or a derivative thereof; N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) or a derivative thereof; 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3, 6, 9, -triacetic acid (PCTA) or a derivative thereof; desferri oxamine B (DFO) or a derivative thereof; N,N'- (methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyri din-2 -yl]methyl-l,2-diaminoethane (H6phospa) or a derivative thereof; 1,4,7,10,13,16-hexaazacyclohexadecane- N,N',N",N"',N''",N"'"-hexaacetic acid (HEHA) or a derivative thereof; 1,4,7,10,13- pentaazacyclopentadecane-N,N',N'',N"',N""-pentaacetic acid (PEPA) or a derivative thereof; or 3,4,3-LI(l,2-HOPO) or a derivative thereof.

[0040] In the experiments presented herein, anti-TROP2 antibody radioconjugate was prepared by chemically conjugating antibody to p-SCN-Bn-DOTA (Catalog # B205; Macrocyclics, Inc., Plano, TX, USA) and subsequently radiolabeling the chelator-conjugated antibody with225Ac (solid nitrate dissolved in 0.2M HC1) to a specific activity of 0.33 pCi / pg in a1 : 1 volumetric ratio with Sodium Acetate 3M The reaction was then incubated at 37°C for 1.5 hours. Analysis of the radiolabeling was performed using instant thin-layer chromatography (iTLC) and a radiochemical purity greater than 90% was achieved. The solution was formulated in 2% bovine serum albumin (BSA). Any suitable methods for preparing radiolabeled antibodies, antibody fragments, or other peptide or protein-based targeting agents, as known in the art, such as but not limited to those disclosed in U.S. Patent No. 9,603,954, may be used in implementing the various aspects of the invention.

[0041] According to certain aspects, when the radiotherapeutic targeting agent is225Ac-labeled, the effective amount is below 50 pCi / kg, 40 pCi / kg, 30 pCi / kg, 20 pCi / kg, 10 pCi / kg, 5 pCi / kg, 4 pCi / kg, 3 pCi / kg, 2 pCi / kg, 1 pCi / kg, or even 0.5 pCi / kg. According to certain aspects, the effective amount is at least 0.05 pCi / kg, or 0.1 pCi / kg, 0.2 pCi / kg, 0.3 pCi / kg, 0.4 pCi / kg, 0.5 pCi / kg, 1 pCi / kg, 2 pCi / kg, 3 pCi / kg, 4 pCi / kg, 5 pCi / kg, 6 pCi / kg, 7 pCi / kg, 8 pCi / kg, 9 pCi / kg, 10 pCi / kg, 12 pCi / kg, 14 pCi / kg, 15 pCi / kg, 16 pCi / kg, 18 pCi / kg, 20 pCi / kg, 30 pCi / kg, or 40 pCi / kg. According to certain aspects, the223Ac-labeled targeting agent may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from 0.1 pCi / kg to 5.0 pCi / kg, from 0.5 pCi / kg to 5.0 pCi / kg from 0.5 pCi / kg to 4.0 pCi / kg, from 1.0 pCi / kg to 4.0 pCi / kg from, or from 5 pCi / kg to at or below 20 pCi / kg.

[0042] According to certain aspects, the radiotherapeutic targeting agent is225Ac-labeled, and the effective amount may be below 2 mCi (i.e., wherein the225Ac is administered to the subject in a non-weight-based dosage). According to certain aspects, the effective amount may be below 1 mCi, such as 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 pCi, 80 pCi, 70 pCi, 60 pCi, 50 pCi, 40 pCi, 30 pCi, 20 pCi, 10 pCi, or 5 pCi. The effective amount may be at least 2 pCi, such as at least 5 pCi, 10 pCi, 20 pCi, 30 pCi, 40 pCi, 50 pCi, 60 pCi, 70 pCi, 80 pCi, 90 pCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 1.1 mCi, 1.2 mCi, 1.3 mCi, 1.4 mCi, or 1.5 mCi. According to certain aspects, the225Ac-labeled TROP2 targeting agent may be administered in an amount that includes any combination of upper and lower limits as described herein, such as from at least 2 pCi to at or below ImCi, or from at least 2 pCi to at or below 250 pCi, or from 75 pCi to at or below 400 pCi.

[0043] According to certain aspects, the225Ac-labeled radiotherapeutic targeting agent includes a single dose that delivers less than 12Gy, or less than 8 Gy, or less than 6 Gy, or less than 4 Gy, orless than 2 Gy, such as doses of 2 Gy to 8 Gy, to the subject, such as predominantly to the targeted solid tumor.

[0044] According to certain aspects, the radiotherapeutic targeting agent is radiolabeled with177Lu (“177Lu-labeled”), and the effective amount may be, for example, below 1 mCi / kg (i.e., where the amount of177Lu-labeled targeting agent administered to the subject delivers a radiation dose of below 1000 mCi per kilogram of subject’s body weight). According to certain aspects, the effective amount is below 900 pCi / kg, 800 pCi / kg, 700 pCi / kg, 600 pCi / kg, 500 pCi / kg, 400 pCi / kg, 300 pCi / kg, 200 pCi / kg, 150 pCi / kg, 100 pCi / kg, 80 pCi / kg, 60 pCi / kg, 50 pCi / kg, 40 pCi / kg, 30 pCi / kg, 20 pCi / kg, 10 pCi / kg, 5 pCi / kg, or 1 pCi / kg. According to certain aspects, the effective amount is at least 1 pCi / kg, 2.5 pCi / kg, 5 pCi / kg, 10 pCi / kg, 20 pCi / kg, 30 pCi / kg, 40 pCi / kg, 50 pCi / kg, 60 pCi / kg, 70 pCi / kg, 80 pCi / kg, 90 pCi / kg, 100 pCi / kg, 150 pCi / kg, 200 pCi / kg, 250 pCi / kg, 300 pCi / kg, 350 pCi / kg, 400 pCi / kg or 450 pCi / kg. According to certain aspects, an177Lu- labeled targeting agent may be administered in an amount that includes any combination of upper and lower limits as described herein, such as from at least 5 mCi / kg to at or below 50 pCi / kg, or from at least 50 mCi / kg to at or below 500 pCi / kg.

[0045] According to certain aspects, the radiotherapeutic targeting agent is177Lu-labeled, and the effective amount may be below 45 mCi, such as below 40 mCi, 30 mCi, 20 mCi, 10 mCi, 5 mCi, 3.0 mCi, 2.0 mCi, 1.0 mCi, 800 pCi, 600 pCi, 400 pCi, 200 pCi, 100 pCi, or 50 pCi. According to certain aspects, the effective amount may be at least 10 pCi, such as at least 25 pCi, 50 pCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 10 mCi, 15 mCi, 20 mCi, 25 mCi, 30 mCi. According to certain aspects, an177Lu-labeled targeting agent may be administered in an amount that includes any combination of upper and lower limits as described herein, such as from at least 10 mCi to at or below 30 mCi, or from at least 100 pCi to at or below 3 mCi, or from 3 mCi to at or below 30 mCi.

[0046] According to certain aspects, the radiotherapeutic targeting agent is radiolabeled with131I (“131I4abeled”), and the effective amount may be below, for example, 1200 mCi (i.e., where the amount of131I administered to the subject delivers a total body radiation dose of below 1200 mCi in a non-weight-based dose). According to certain aspects, the effective amount may be below 1100 mCi, below 1000 mCi, below 900 mCi, below 800 mCi, below 700 mCi, below 600 mCi, below 500 mCi, below 400 mCi, below 300 mCi, below 200 mCi, below 150 mCi, or below 100 mCi. According to certain aspects, the effective amount may be below 200 mCi, such as below190 mCi, 180 mCi, 170 mCi, 160 mCi, 150 mCi, 140 mCi, 130 mCi, 120 mCi, l lO mCi, l OO mCi, 90 mCi, 80 mCi, 70 mCi, 60 mCi, or 50 mCi. According to certain aspects, the effective amount may be at least 1 mCi, such as at least 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, 20 mCi, 30 mCi, 40 mCi, 50 mCi, 60 mCi, 70 mCi, 80 mCi, 90 mCi, 100 mCi, 110 mCi, 120 mCi, 130 mCi, 140 mCi, 150 mCi, 160 mCi, 170 mCi, 180 mCi, 190 mCi, 200 mCi, 250 mCi, 300 mCi, 350 mCi, 400 mCi, 450 mCi, 500 mCi. According to certain aspects, an131I-labeled targeting agent may be administered in an amount that includes any combination of upper and lower limits as described herein, such as from at least 1 mCi to at or below 100 mCi, or at least 10 mCi to at or below 200 mCi.

[0047] As used herein the term antibody includes fully length monoclonal antibodies of any type such as IgG, IgA, IgM and single domain antibodies such as nanobodies (VHH domains) such as isolated VHH domains as well as fusion proteins thereof such as VHH-Fc fusion proteins, irrespective of source or manner of production, as well as antigen-binding antibody fragments such as Fab', F(ab')2 and scFv molecules. As used herein, an antibody may be a monospecific antibody or a multi-specific antibody, such as a bispecific antibody. Various antibodies are defined herein with respect to their immunoglobulin heavy chain and / or light chain complementarity determining region (CDR) amino acid sequences. CDR regions can be delineated according to numbering conventions such as the Kabat numbering convention and the IMGT numbering convention. While various CDR sequences are specifically set forth herein, it should be understood that the invention encompasses and provides corresponding aspects in which the CDR sequences of a subject antibody are defined or delineated somewhat differently according to alternative numbering conventions. In addition, the invention also provides corresponding embodiments in which non-antibody radiolabeled TROP2 targeting agents, such as radiolabeled antibody mimetic proteins, are used rather than radiolabeled antibody-based TROP2 targeting agents. Suitable antibody mimetics that may be used include, for example, designed ankyrin repeat proteins (Darpins), Affibodies, Anticalins, Affimers (Adhirons), Avimers, Fynomers, Kunitz domains, Knottins, Affitins, and Centryrins.

[0048] Although throughout the present disclosure and claims various aspects or elements thereof are described in terms of “including” or “comprising,” corresponding aspects or elements thereof described in terms of “consisting essentially of’ or “consisting of’ are similarly disclosed. For example, while certain aspects of the invention have been described in terms of a method“including” or “comprising” administering a radiolabeled protein, corresponding methods instead reciting “consisting essentially of’ or “consisting of’ administering the radiolabeled protein are also within the scope of said aspects and provided by this disclosure.

[0049] In addition, compositions including an anti-TROP2 antibody radioconjugate may include one or more pharmaceutically acceptable carriers or pharmaceutically acceptable excipients. Such carriers are well known to those skilled in the art. For example, injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can include excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's). An exemplary formulation may be as substantially described in U.S. Patent 10,420,851 or International Pub. No. WO 2017 / 155937, incorporated by reference herein. For example, according to certain aspects, the formulation may include 0.5% to 5.0% (w / v) of an excipient selected from the group consisting of ascorbic acid, polyvinylpyrrolidone (PVP), human serum albumin (HSA), a water-soluble salt of HSA, and mixtures thereof. Certain formulations may include 0.5-5% ascorbic acid; 0.5-4% polyvinylpyrrolidone (PVP); and antibody radioconjugate in 50 mM PBS buffer, pH 7. In a radiopharmaceutical composition, the total population of anti-TROP2 antibody molecules may include antibody molecules that are radiolabeled and also antibody molecules that are not radiolabeled.

[0050] Without limitation, the following aspects of the invention are provided by this disclosure:

[0051] Aspect 1. An anti-TROP2 antibody radioconjugate including: an anti-TROP2 antibody or TROP2-binding antibody fragment such as any of those disclosed herein; a radionuclide chelator conjugated to said anti-TROP2 antibody or TROP2-binding antibody fragment; and a radionuclide chelated by the radionuclide chelator.

[0052] Aspect 2. The anti-TROP2 antibody radioconjugate of claim 1, wherein the radionuclide chelator includes DOTA or a DOTA-derivative.

[0053] Aspect 3. The anti-TROP2 antibody radioconjugate of claim 1, wherein the conjugated radionuclide chelator is the residue of conjugation of p-SCN-BN-DOTA to the anti-TROP2 antibody or TROP2 -binding antibody fragment thereof.

[0054] Aspect 4. The anti-TROP2 antibody radioconjugate of any one of the preceding aspects, wherein the radionuclide is selected from the group consisting of90Y,177Lu,186Re, 188Re,89Sr,153Sm,32P,225Ac,213PO,211At,212Bi,213Bi,223Ra,227Th,149Tb,137Cs,212Pb and103Pd.

[0055] Aspect 5. The anti-TROP2 antibody radioconjugate of any one of aspects 1-3, wherein the radionuclide includes 225Ac and the anti-TROP2 antibody radioconjugate is prepared according to a method set forth in U.S. Patent No. 9,603,954.

[0056] Aspect 6. The anti-TROP2 antibody radioconjugate of any one of the preceding aspects, wherein the anti-TROP2 antibody or TROP2-binding antibody fragment includes:(a) an anti-TROP2 antibody or TROP2-binding antibody fragment disclosed in U.S. Pub. No. 2024 / 0092930; and / or(b) an anti-TROP2 antibody or TROP2-binding antibody fragment including the immunoglobulin light chain CDRs and the immunoglobulin heavy chain CDRs of any of the anti- TROP2 antibodies or TROP2-binding antibody fragments disclosed in U.S. Pub. No. 2024 / 0092930.

[0057] Aspect 7. The anti-TROP2 antibody radioconjugate according to any one of aspects 1-6, wherein the antibody radioconjugate includes an Fc region.

[0058] Aspect 8. The anti-TROP2 antibody radioconjugate of aspect 7, wherein the Fc region has low or no affinity to Fc Receptor and / or has been modified (e.g. mutated) to lower its affinity to Fc Receptor versus a naturally occurring amino acid sequence from which it is derived.

[0059] Aspect 9. A method for treating a TROP2 expressing cancer in a human subj ect, including: administering a therapeutically effective amount of an antibody radioconjugate according to any one of the preceding aspects to the subject.

[0060] Aspect 10. The method of claim 9, wherein the TROP2-expressing cancer includes: carcinomas, squamous cell carcinomas, adenocarcinomas, non-small cell lung cancer (NSCLC), NRG1 fusion NSCLC, small-cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, gastric cancer, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2 -positive (HR / HER2+) breast cancer, triple negative breast cancer (TNBC), prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), pancreatic ductal adenocarcinoma, pancreatic cancer, NRG1 fusion pancreatic cancer, head and neck cancers, head and neck squamous cell carcinoma (HNSCC), renal cell cancer,urinary bladder neoplasms, bladder cancer, urothelial cancer, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and / or glioblastoma multiforme.

[0061] Aspect 11. The method of claim 9 or 10, wherein the cancer is relapsed and / or refractory.

[0062] Aspect 12. The method of any one of aspects 9-11, wherein the subject has been previously treated with an anti-TROP2 antibody drug conjugate (ADC) such as Sacituzumab govitecan (e g. Trodelvy®, Gilead Sciences), or Sacituzumab tirumotecan (SKB264 / MK-2870; Merck), Datopotamab deruxtecan (a / k / a Dato-DXd; e.g. Datroway® Daiichi Sankyo), or 9MW2921 (Mabwell Shanghai Bioscience Co Ltd, Shanghai).

[0063] Aspect 13. The method of any one of aspects 9-12, wherein the cancer is resistant to treatment with an anti-TROP2 ADC, such as Sacituzumab govitecan, Datopotamab deruxtecan, or 9MW2921.

[0064] Aspect 14. The method according to any one of aspects 9-13, wherein the subject is a human patient.

[0065] Aspect 15. The method according to any one of aspects 9-14, wherein the antibody radioconjugate includes an Fc region, such as a human Fc region.

[0066] Aspect 16. The method of aspect 15, wherein the Fc region has low or no affinity to Fc Receptor and / or has been modified (e.g. mutated) to lower its affinity to an Fc Receptor versus a naturally occurring amino acid sequence from which it is derived.

[0067] Aspect 17. A radiolabeled TROP2 targeting agent, including: an anti-TROP2 antibody, a TROP2-binding antibody fragment or a TROP2-binding antibody mimetic protein; and a radionuclide directly or indirectly bound to the anti-TROP2 antibody, a TROP2-binding antibody fragment or TROP2-binding antibody mimetic protein, for treatment of a relapsed and / or refractory TROP2-expressing solid tumor cancer in a human subject.

[0068] Aspect 18. The radiolabeled TROP2 targeting agent of aspect 17, wherein (i) the anti- TROP2 antibody, TROP2-binding antibody fragment or TROP2-binding antibody mimetic protein is chemically bound (bonded) to the radionuclide, for example211At, or (ii) the anti-TROP2 antibody, TROP2-binding antibody fragment or TROP2-binding antibody mimetic protein further includes a radionuclide chelator such as DOTA or a DOTA-derivative, conjugated to said anti-TR0P2 antibody, TROP2-binding antibody fragment; or TROP2-binding antibody mimetic protein, and the radionuclide is chelated by the radionuclide chelator.

[0069] Aspect 19. The radiolabeled TROP2 targeting agent of aspect 18, wherein the conjugated radionuclide chelator is the residue of conjugation of p-SCN-BN-DOTA to the anti-TROP2 antibody, TROP2-binding antibody fragment or TROP2-binding antibody mimetic protein.

[0070] Aspect 20. The radiolabeled TROP2 targeting agent of any one of aspects 17-19, wherein the radionuclide is selected from the group consisting of90Y,177Lu,186Re,188Re,89Sr,153Sm,32P,225Ac,213Po,211At,212Bi,213Bi,223Ra,227Th,149Tb,137Cs,212Pb and103Pd.

[0071] Aspect 21. The radiolabeled TROP2 targeting agent of any one of aspects 17-20, wherein the TROP2-expressing cancer includes: a carcinoma, a squamous cell carcinoma, an adenocarcinomas, non-small cell lung cancer (NSCLC), NRG1 fusion NSCLC, small-cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, gastric cancer, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2-positive (HR7HER21) breast cancer, triple negative breast cancer (TNBC), prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), pancreatic ductal adenocarcinoma, pancreatic cancer, NRG1 fusion pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), head and neck cancers, renal cell cancer, urinary bladder neoplasms, bladder cancer, urothelial cancer, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and / or glioblastoma multiforme.

[0072] Aspect 22. The radiolabeled TROP2 targeting agent of aspect 21, wherein the cancer is metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2- positive (HR7HER2+) breast cancer, or triple negative breast cancer (TNBC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, an anti-HER2 therapeutic antibody, an anti-HER3 therapeutic antibody, and a therapeutic antibody such as any of those disclosed herein.

[0073] Aspect 23. The radiolabeled TROP2 targeting agent of aspect 22, wherein the subject has been previously treated with one or more selective estrogen receptor modulators (SERMs) and the method further includes administering one or more selective estrogen receptor modulators (SERMs) to the subject.

[0074] Aspect 24. The radiolabeled TROP2 targeting agent of aspect 21, wherein the cancer is prostate cancer, locally advanced prostate cancer, hormone-refractory prostate cancer, castrationresistant prostate cancer (CRPC), metastatic CRPC (mCRPC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, a PSMA targeted radiotherapy,177Lu PSMA-617, and225Ac PSMA-617.

[0075] Aspect 25. The radiolabeled TROP2 targeting agent of aspect 24, wherein the subject has been previously treated with one or more non-steroidal antiandrogen agents and the method further includes administering one or more non-steroidal antiandrogen agents to the subject.

[0076] Aspect 26. The radiolabeled TROP2 targeting agent of any one of aspects 17-25, wherein the cancer is locally advanced or metastatic.

[0077] Aspect 27. A method for treating a TROP2 expressing cancer in a human subject, including: administering a composition including a therapeutically effective amount of an radiolabeled TROP2 targeting agent according to any one of the aspects 17-26 or as otherwise disclosed herein to the subject.

[0078] Aspect 28. The method of aspect 27, wherein the composition further includes at least one pharmaceutically acceptable excipient.

[0079] Aspect 29. The method of aspect 27 or 28, wherein the subject has been previously treated with an anti-TROP2 antibody drug conjugate (ADC) such as Sacituzumab govitecan (Trodelvy®, Gilead Sciences), Sacituzumab tirumotecan (SKB264 / MK-2870; Merck), Datopotamab deruxtecan (a / k / a Dato-DXd; e.g. Datroway® Daiichi Sankyo), or 9MW2921 (Mabwell, Shanghai) and is relapsed and / or refractory with respect to said previous treatment.

[0080] Aspect 30. A method for treating a TROP2 expressing, relapsed and / or refractory solid tumor cancer in a human subject, including: administering a therapeutically effective amount of a radiolabeled anti-TROP2 antibody, radiolabeled TROP2-binding antibody fragment, or radiolabeled TROP2-binding antibody mimetic protein to the subject, wherein the subject has been previously treated with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, a PSMA targeted radiotherapy,177Lu PSMA-617,223Ac PSMA-617,an anti-HER2 therapeutic antibody, an anti-HER3 therapeutic antibody, and a therapeutic antibody such as any of those disclosed herein, and wherein the cancer is relapsed and / or refractory with respect to said previous treatment.

[0081] Aspect 31. The method of aspect 30, wherein the cancer is locally advanced or metastatic.

[0082] Aspect 32. The method of aspect 30 or 31, wherein the cancer includes a carcinoma, squamous cell carcinoma, adenocarcinoma, non-small cell lung cancer (NSCLC), NRG1 fusion NSCLC, small-cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, gastric cancer, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2 -positive (HR' / HER2+) breast cancer, triple negative breast cancer (TNBC), prostate cancer, locally advanced prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), pancreatic ductal adenocarcinoma, pancreatic cancer, NRG1 fusion pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), head and neck cancers, renal cell cancer, urinary bladder neoplasms, bladder cancer, urothelial cancer, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and / or glioblastoma multiforme.

[0083] Aspect 33. The method of aspect 32, wherein the cancer is metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2-positive (HR' / HER2+) breast cancer, or triple negative breast cancer (TNBC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, an anti- HER2 therapeutic antibody, an anti-HER3 therapeutic antibody, and a therapeutic antibody such as any of those disclosed herein.

[0084] Aspect 34. The method of aspect 33, wherein the subject has been previously treated with one or more selective estrogen receptor modulators (SERMs) and the method further includes administering one or more selective estrogen receptor modulators (SERMs) to the subject.

[0085] Aspect 35. The method of aspect 32, wherein the cancer is prostate cancer, locally advanced prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, a PSMA targeted radiotherapy,177Lu PSMA-617, and225Ac PSMA-617.

[0086] Aspect 36. The method of aspect 35, wherein the subject has been previously treated with one or more non-steroidal antiandrogen agents and the method further includes administering one or more non-steroidal antiandrogen agents to the subject.

[0087] Still another aspect of the invention provides a radiopharmaceutical composition that may, for example, be for radioimaging and / or treatment of a TROP2 expressing cancer, such as a TROP2 expressing solid tumor, in a mammalian subject such as a human patient, which includes a radiolabeled TROP2 targeting agent such as an anti-TROP2 antibody radioconjugate such as any of those disclosed herein and at least one pharmaceutically acceptable excipient such as ascorbic acid and / or polyvinylpyrrolidone (PVP). Such a composition may, for example, be used in any of the methods of treatment and / or methods of diagnosis / radioimaging disclosed herein.

[0088] Various aspect of the invention are further illustrated by the following experiments.

[0089] Experiment 1

[0090] In vivo efficacy study of225Ac-Sacituzumab in human lung cancer (LC) xenograft models.

[0091] NCI-H1975 human non-small cell lung cancer cell line cells were cultured in complete RPMI 1640 medium supplemented with 10% non-heat-inactivated FBS, 1% penicillin / streptomycin and 1% L-glutamine. All cell lines were passaged at least two times postthaw and were harvested with Trypsin. Female Balb / c nu / nu mice were injected subcutaneously with 5xl06NCI-H1975 cells / mouse in serum free (SF) media on the anatomical right flank. When tumors reach -120 mm3, mice were randomized in groups of 7 mice / group and treatments were administered intravenously (iv.) as described in Table 4.225Ac-Sacituzumab was prepared by chemically conjugating p-SCN-Bn-DOTA to the antibody followed by radiolabeling with225Ac by chelation to the conjugated DOTA moiety.Table 4Overview of treatment groups and administration schedule for225Ac-Sacituzumab dose efficacy in human NCI-H1975 mouse model of Lung Cancer

[0092] FIG. 1 shows the results for the NCI-H1975 cell line tumor lung cancer model. The effect of HER2-ADC on tumor growth was essentially indistinguishable from the vehicle-only control. TROP2-ADC slowed tumor growth but did not halt its progression. In contrast225Ac-Sacituzumab caused profound, statistically significant tumor regression.

[0093] Experiment 2

[0094] In vivo efficacy study of225Ac-Sacituzumab in human breast cancer (BC) xenograft model.

[0095] MCF-7 human breast cancer cell line cells were cultured in complete RPMI-1640 medium supplemented with 10% non-heat-inactivated FBS, 1% penicillin / streptomycin and 1% L- glutamine. MDA-MB-468 BC cells were cultured in RPMI-1640 Medium supplemented with 10% FBS and 1% Penicillin-Streptomycin. All cell lines were passaged at least two times post-thaw and were harvested with Trypsin. 24 hours prior to MCF-7 cell implant, each female HSD athymic Foxlnl-nu mice were implanted with a 17-beta estradiol pellet (0.5 mg / pellet 90-day release) subcutaneously between the scapulae. Subsequently, these mice were injected with 5xl06MCF-7 cells / mouse in serum free (SF) media:Matrigel (1 :1) subcutaneously on the anatomical right flank. When tumors reached -150 mm3, mice were randomized in groups of 7 mice / group, and treatments were administered intravenously (iv.) as described in Table 5.Table 5Overview of treatment groups and administration schedule for 225Ac-Sacituzumab dose efficacy in human MCF-7 mouse model of Breast Cancer

[0096] FIG. 2 shows the results for the MCF-7 cell line tumor breast cancer model. HER2-ADC treatment very briefly partially regressed tumor volume followed by slowed tumor growth versus vehicle-only control. In contrast both, TROP2-ADC and225Ac-Sacituzumab caused profound, statistically significant tumor regression through the duration of the study with225Ac-Sacituzumab demonstrating even greater tumor regression than TROP2-ADC at the end of the study.

[0097] All patents, patent applications, other publications, and appendices hereto are hereby incorporated by reference in their entities as if fully set forth herein.

[0098] While various aspects and embodiments have been illustrated and described herein, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s). Moreover, features described in connection with one aspect of the invention may be used in conjunction with other aspects of the invention, even if not explicitly exemplified in combination within.

Claims

WHAT IS CLAIMED IS:

1. An anti-TR0P2 antibody radioconjugate, comprising: an anti-TROP2 antibody or TROP2-binding antibody fragment; a radionuclide chelator conjugated to said anti-TROP2 antibody or TROP2-binding antibody fragment; and a radionuclide chelated by the radionuclide chelator, for treatment of a relapsed and / or refractory TROP2-expressing solid tumor cancer in a human subject.

2. The anti-TROP2 antibody radioconjugate of claim 1, wherein the radionuclide chelator comprises DOTA or a DOTA-derivative.

3. The anti-TROP2 antibody radioconjugate of claim 1, wherein the conjugated radionuclide chelator is the residue of conjugation of p-SCN-BN-DOTA to the anti-TROP2 antibody or TROP2-binding antibody fragment thereof.

4. The anti-TROP2 antibody radioconjugate of any one of claims 1-3, wherein the radionuclide is selected from the group consisting of90Y,177Lu,186Re,188Re,89Sr,153Sm,32P,225Ac,213Po,211At,212Bi,213Bi,223Ra,227Th,149Tb,137Cs,212Pb and103Pd.

5. The anti-TROP2 antibody radioconjugate of any one of claims 1-4, wherein the TR0P2- expressing cancer comprises: a carcinoma, a squamous cell carcinoma, an adenocarcinomas, nonsmall cell lung cancer (NSCLC), NRG1 fusion NSCLC, small-cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, gastric cancer, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2-positive (HR / HER2+) breast cancer, triple negative breast cancer (TNBC), prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), pancreatic ductal adenocarcinoma, pancreatic cancer, NRG1 fusion pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), head and neck cancers, renal cell cancer, urinary bladder neoplasms, bladder cancer, urothelial cancer, cervicalcancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and / or glioblastoma multiforme.

6. The anti-TROP2 antibody radioconjugate of claim 5, wherein the cancer is metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2-positive (HR / HER2+) breast cancer, or triple negative breast cancer (TNBC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, an anti-HER2 therapeutic antibody, an anti-HER3 therapeutic antibody, and a therapeutic antibody.

7. The anti-TROP2 antibody radioconjugate of claim 6, wherein the subject has been previously treated with one or more selective estrogen receptor modulators (SERMs) and the method further comprises administering one or more selective estrogen receptor modulators (SERMs) to the subject.

8. The anti-TROP2 antibody radioconjugate of claim 5, wherein the cancer is prostate cancer, locally advanced prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, a PSMA targeted radiotherapy,177Lu PSMA-617, and223Ac PSMA-617.

9. The anti-TROP2 antibody radioconjugate of claim 8, wherein the subject has been previously treated with one or more non-steroidal antiandrogen agents and the method further comprises administering one or more non-steroidal antiandrogen agents to the subject.

10. The anti-TROP2 antibody radioconjugate of any one of the preceding claims, wherein the cancer is locally advanced or metastatic.

11. A method for treating a TROP2 expressing cancer in a human subject, comprising:administering a composition comprising a therapeutically effective amount of an antibody radioconjugate according to any one of the preceding claims to the subject.

12. The method of claim 11, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

13. The method of claim 11 or 12, wherein the subject has been previously treated with an anti- TROP2 antibody drug conjugate (ADC) such as Sacituzumab govitecan (Trodelvy®, Gilead Sciences), Sacituzumab tirumotecan (SKB264 / MK-2870; Merck), Datopotamab deruxtecan (a / k / a Dato-DXd; e.g. Datroway® Daiichi Sankyo), or 9MW2921 (Mabwell, Shanghai) and is relapsed and / or refractory with respect to said previous treatment.

14. A method for treating a TROP2 expressing, relapsed and / or refractory solid tumor cancer in a human subject, comprising: administering a therapeutically effective amount of a radiolabeled anti-TROP2 antibody or radiolabeled TROP2-binding antibody fragment to the subject, wherein the subject has been previously treated with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, a PSMA targeted radiotherapy,177Lu PSMA-617,225Ac PSMA-617, an anti-HER2 therapeutic antibody, an anti-HER3 therapeutic antibody, and a therapeutic antibody, and wherein the cancer is relapsed and / or refractory with respect to said previous treatment.

15. The method of claim 14, wherein the cancer is locally advanced or metastatic.

16. The method of claim 14 or 15, wherein the cancer comprises a carcinoma, squamous cell carcinoma, adenocarcinoma, non-small cell lung cancer (NSCLC), NRG1 fusion NSCLC, smallcell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, gastric cancer, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2-positive (HR / HER2+) breast cancer, triple negative breast cancer (TNBC), prostate cancer, locally advanced prostate cancer,hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), pancreatic ductal adenocarcinoma, pancreatic cancer, NRG1 fusion pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), head and neck cancers, renal cell cancer, urinary bladder neoplasms, bladder cancer, urothelial cancer, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and / or glioblastoma multiforme.

17. The method of claim 16, wherein the cancer is metastatic breast cancer, tamoxifen-resistant breast cancer, hormone receptor negative HER2-positive (HR / HER2+) breast cancer, or triple negative breast cancer (TNBC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti- HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, an anti-HER2 therapeutic antibody, trastuzumab, an anti-HER3 therapeutic antibody, zenocutuzumab, and a therapeutic antibody.

18. The method of claim 17, wherein the subject has been previously treated with one or more selective estrogen receptor modulators (SERMs) and the method further comprises administering one or more selective estrogen receptor modulators (SERMs) to the subject.

19. The method of claim 16, wherein the cancer is prostate cancer, locally advanced prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC) that is relapsed and / or refractory with respect to prior treatment with one or more of an anti-TROP2 antibody drug conjugate (ADC), an anti-HER2 ADC, an anti-HER3 ADC, a HER2 targeted radiotherapy, a HER3 targeted radiotherapy, a PSMA targeted radiotherapy,177Lu PSMA-617, and225Ac PSMA-617.

20. The method of claim 19, wherein the subject has been previously treated with one or more non-steroidal antiandrogen agents and the method further comprises administering one or more non-steroidal antiandrogen agents to the subject.

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