Combinations with FAP targeting compounds and conjugates thereof

Abstract

Provided herein are methods for the treatment of cancer (e.g., pancreatic cancer, lung cancer, or breast cancer) comprising administering to a subject in need thereof a FAP-targeting radiotherapeutic agent without any C-S bonds, in combination with one or more chemotherapeutic agents comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

Description

[0001] PAT059981

[0002] COMBINATIONS WITH FAP TARGETING COMPOUNDS AND CONJUGATES THEREOF

[0003] TECHNICAL FIEED

[0004] This application relates to the use of FAP -targeting radiotherapeutic agents for the treatment of cancer, including in combination with chemotherapies.

[0005] BACKGROUND

[0006] Fibroblast activation protein (FAP) is a cell surface protein that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers, whereas limited expression of FAP is observed in normal tissues. In some cancers of mesenchymal origin, notably sarcoma and mesothelioma, FAP expression has also been observed on the tumor cells themselves. Given the restricted expression profile, FAP is a promising target for radionuclide imaging and therapeutic agents in the treatment of cancer, particularly for solid tumors.

[0007] Pancreatic cancer is difficult to treat due to the harsh tumor microenvironment, making chemotherapeutic drug delivery challenging. The tumor microenvironment is rich in stromal cells that are high in FAP expression and there is some suggestion that pancreatic adenocarcinoma cells themselves may also express FAP. FAP has been implicated in cancer progression, immunosuppression and treatment resistance. Unfortunately, FAP expression in pancreatic ductal adenocarcinoma (PDAC) also correlates with poor survival and reiterates the significant need for more therapeutic options in this patient population (Cheng, C-s et al. (2022) Front. Oncol; 12:969731). Thus, PDAC is a good target for FAP directed therapy.

[0008] Lung cancer is the second most common cancer in men and women and the leading cause of cancer related deaths worldwide (Thandra K C, et al. (2021) Contemp Oncol (Pozn); 25 (1): 45-52). These patients are diagnosed with advanced disease with a 5-year survival rate of about 18% (YanagawaN, etal. (2022) Thorac Cancer; 13:2377-2384).

[0009] NSCLC is known to have a tumor microenvironment (TME) with CAFs having high FAP expression. In a recent study, 54.1% of patients with NSCLC (N=126) were found to have high FAP expression as defined by intensity of IHC staining and percentage of FAP-positive cells (Zhao Y, et al. (2023) J Can Res Clin One; 149:3469-3483). FAP expression on lung cancer cellsPAT059981

[0010] and in the CAFs of the tumor microenvironment has also correlated with worse survival outcomes and less response to immunotherapy (Yanagawa et al. 2022, Zhao et al. 2023).

[0011] FAP-expressing NSCLC tumors can also be readily identified through imaging. PET scans using68Ga-FAPI as a tracer demonstrate high uptake by primary lung tumors and metastases allowing for visualization and measurement of FAP expressing disease (Borgonje PE, et al. (2022) Cancers; 14:5566). NSCLC is also a good target for FAP directed therapy.

[0012] Despite recent advances in NSCLC there is a high unmet need in this disease. Once patients progress on first line chemoimmunotherapy, there are a handful of drug options including docetaxel + / - ramucirumab, pemetrexed, gemcitabine or nab-paclitaxel (National Comprehensive Cancer Network (NCCN) (2023). NCCN Clinical Practice Guideline in Oncology. Non-Small Cell Lung Cancer Version 3.2023; National Comprehensive Cancer Network). In general, docetaxel is poorly tolerated and has significant toxicities (Weiss JM, et al.

[0013] 2013). To improve efficacy, new therapies are needed for patients that progress on first line therapy.

[0014] Breast cancer (BC) is the most commonly diagnosed malignancy and leading cause of cancer related death in women worldwide. Despite clinical advances, BC mortality rates have increased in the last decades indicating an urgent need for innovative treatments (Lukasiewicz S, et al. (2021) Cancers; 13:4287). Breast cancer also has a strong FAP signal. A review of available data regarding FAP in the BC literature shows evidence that FAP based imaging may provide superior for diagnostic information in comparison to traditional [18F]-FDG PET (Zhao Y, et al. (2023) J Can Res Clin One; 149:3469-83). Furthermore, a recent imaging trial has correlated [68Ga]Ga-FAPi-46 PET uptake with FAP tissue expression by IHC (Mona CE, et al. (2022) J Nucl Med; 63: 1021-1026). Breast cancer is, therefore, also a good target for FAP directed therapy.

[0015] In sum, FAP overexpression in multiple tumor types both in the tumor cells and surrounding stroma make it a valuable target for directed treatment. Utilizing RLT while targeting FAP represents a unique therapeutic opportunity for the treatment of cancer, for which there is a high need for new therapeutic options which are both efficacious and safe.PAT059981

[0016] SUMMARY

[0017] Provided herein are methods for treating cancer comprising administering a FAP-targeting radiotherapeutic agent.

[0018] In an aspect, provided herein is a method for treating a FAP-expressing cancer (e.g., a solid tumor) in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of:

[0019] (a) a fibroblast activation protein (FAP)-targeting radiotherapeutic agent, or a pharmaceutically acceptable salt thereof;

[0020] wherein the FAP -targeting radiotherapeutic agent does not comprise C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

[0021] In an aspect, provided herein is a pharmaceutical combination comprising (a) a fibroblast activation protein (FAP)-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 1,

[0022] [177Lu]Lu-Compound 2), or a pharmaceutically acceptable salt thereof; wherein the FAP-targeting radiotherapeutic agent does not comprise any C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog. In certain embodiments, the pharmaceutical combination is for use in a method of treating a cancer.

[0023] In an aspect, provided herein is a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 1, [177Lu]Lu-Compound 2), or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a cancer. In certain embodiments, provided herein is a FAP-targeting radiotherapeutic agent which is:

[0024]

[0025] PAT059981

[0026] pharmaceutically acceptable salt or solvate thereof for use in a method of treating a cancer. In certain embodiments, the radiotherapeutic agent is administered in combination with chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

[0027] In certain embodiments, the FAP-targeting radiotherapeutic agent comprises a cyclized peptide ligand. In certain embodiments, the FAP-targeting radiotherapeutic agent comprises177LU. In certain embodiments, the FAP-targeting radiotherapeutic agent is:

[0028]

[0029] acceptable salt or solvate thereof. In certain embodiments, the FAP-targeting radiotherapeutic

[0030]

[0031] pharmaceutically acceptable salt or solvate thereof.

[0032] In certain embodiments, the chemotherapy comprises an antimetabolite agent wherein the antimetabolite agent is an antimetabolite-antineoplastic agent, such as, a nucleoside metabolic inhibitor (e.g., 5-fluorouracil (5-FU)). In certain embodiments, the chemotherapy comprises an antineoplastic agent wherein the antineoplastic agent comprises one or more of a taxanePAT059981

[0033] antineoplastic agent, a Topoisomerase I inhibitor, and / or a platinum-containing antineoplastic agent, for example, wherein the antineoplastic agent comprises one or more of nab-paclitaxel, gemcitabine, irinotecan, and / or oxaliplatin. In certain embodiments, the chemotherapy comprises a B vitamin analog which is leucovorin.

[0034] In certain embodiments, the cancer is bladder cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, endocrine cancer, epithelial cancer, glioblastoma, head and / or neck cancer, mesothelioma, nasopharyngeal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, and / or sarcoma.

[0035] In an aspect, provided herein is a method for treating a FAP-expressing cancer (e.g., a solid tumor) in a subject in need thereof comprising administering to a subject in need thereof a FAP-targeting radiotherapeutic agent, wherein the FAP -targeting radiotherapeutic agent is administered as a single daily dose once about every four weeks ± three days or about every 6 weeks ± three days to achieve a cumulative dose of about 10 to about 70 GBq.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the effects in a PDAC cell line (CAPAN2), when treated with either Compound A or combinations of Compound A with gemcitabine and / or paclitaxel, at the indicated concentrations. For reference, the effects of the indicated chemotherapy alone on growth inhibition are as follows (not depicted in FIG. 1): paclitaxel (2nM) - 60%, gemcitabine (lOnM) - 60% and paclitaxel (2nM) + gemcitabine (6nM) - 85%. The dotted line at 100% represents cell stasis. In FIGS. 1-5, Compound A is [177Lu]Lu-Compound 2.

[0037] FIG. 2 illustrates the effects in a PDAC cell line (PK1), when treated with either Compound A or combinations of Compound A with irinotecan and / or 5 -fluorouracil (5-FU) at the indicated concentrations. For reference, the effects of the indicated chemotherapy alone on growth inhibition alone are as follows (not depicted in FIG. 2): irinotecan (850nM) - 20%, 5-FU (600nM) - 30% and irinotecan (ImM) + 5-FU (ImM) - 60%. The dotted line at 100% represents cell stasis.

[0038] FIG. 3 illustrates the effects in a PDAC cell line (PK1), when treated with either Compound A or combinations of Compound A with oxaliplatin and / or 5-FU at the indicated concentrations. For reference, the effects of the indicated chemotherapy alone on growth inhibition are as follows (not depicted in FIG. 3): oxaliplatin (700nM) - 38%, 5-FU (600nM) -PAT059981

[0039] 30% and oxaliplatin (3.5mM) + 5-FU (ImM) - 97%. The dotted line at 100% represents cell stasis.

[0040] FIG. 4 illustrates the effects in a PDAC cell line (PK1), when treated with either Compound A or combinations of Compound A with irinotecan, 5-FU and / or oxaliplatin at the indicated concentrations. For reference, the effects of the indicated chemotherapy alone on growth inhibition are as follows (not depicted in FIG. 4): irinotecan (850nM) - 20%, 5-FU (600nM) - 30%, oxaliplatin (700nM) - 38%, and irinotecan (ImM) + 5-FU (ImM) + oxaliplatin (3.5mM) - 99%. The dotted line at 100% represents cell stasis.

[0041] FIG. 5 illustrates the effects in NMRI mice bearing ST4454 PDAC patient-derived xenografts, when treated with either Compound A alone, Abraxane (nab-paclitaxel) + gemcitabine, or the combination of Compound A + Abraxane + gemcitabine at the concentrations indicated.

[0042] FIG. 6 illustrates the effects in NMRI mice bearing ST4454 PDAC patient-derived xenografts, when treated with either Compound A alone, Abraxane (nab-paclitaxel) + gemcitabine, or the combination of Compound A + Abraxane + gemcitabine at the concentrations indicated.

[0043] DETAILED DESCRIPTION

[0044] Provided herein are methods of treating cancer comprising administering: (a) a FAP-targeting radiotherapeutic agent not comprising any C-S bonds to a subject in need thereof, in combination with (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog. Also provided are pharmaceutical combination comprising (a) a fibroblast activation protein (FAP)-targeting radiotherapeutic agent (e.g.,

[0045] [177Lu]Lu-Compound 1, [177Lu]Lu-Compound 2), or a pharmaceutically acceptable salt thereof; wherein the FAP-targeting radiotherapeutic agent does not comprise any C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog. In certain embodiments, the pharmaceutical combination is for use in a method of treating a cancer. Further provided is a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 1, [177Lu]Lu-Compound 2), or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a cancer. In certain embodiments, provided herein is a FAP-targeting radiotherapeutic agent which is [177Lu]Lu-Compound 2, or a pharmaceuticallyPAT059981

[0046] acceptable salt or solvate thereof for use in a method of treating a cancer. In certain embodiments, the radiotherapeutic agent is administered in combination with chemotherapy as disclosed herein, for example, comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog. In certain embodiments, the radiotherapeutic agent is administered in combination with chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

[0047] FAP-targeting radiopharmaceuticals

[0048] As used herein, “FAP-targeting” means that a compound exhibits affinity to fibroblast activation protein (FAP). Techniques for measuring FAP affinity for FAP are known in the art and readily available to one of skill in the art to identify a compound as having affinity for FAP. For example, the dissociation constant (KD) for certain FAP-targeting radiopharmaceuticals disclosed herein can be measured according to the following surface plasmon resonance assay.

[0049] Surface Plasmon Resonance (SPR) for assessment of peptide affinity

[0050] Peptide affinities (KD) were determined by SPR using a Biacore™ 8K device (Cytiva) towards the following proteins: biotinylated His, Avi tag, human FAP (26-760, FAP-H82Q6), biotinylated His, Avi tag, mouse FAP (26-761 , FAP-M82Q5), His tag, human DPP4 (34-766, DP4-H82E3), all purchased from AcroBiosystems and His tag, mouse DPP4 (29-760, 954-SE) from R&D Systems. The FAP proteins and their homologous were diluted to a concentration of 2 pg / mL into acetate buffer pH 5.5, then immobilized onto a CM5 sensorchip (Cytiva, BR-1005-30) to reach a response around 2000 RU. The running buffer HBS-EP+ pH 7.6 (20X from Teknova CAT.No: H8022) contained 10 mMHEPES pH 7.6, 150 mMNaCl, 3 mMEDTA, 0.05% Tween20 and 2% DMSO. Experiments were carried out at 25°C using a flow rate of 30 pL / min. Compounds were tested in single cycle kinetic mode at 8 different concentrations. Curve fitting was performed using the Biacore™ 8K evaluation software. The sensorgrams were fitted by applying a 1:1 binding model to calculate kinetic rate constants and equilibrium dissociation constants (KD).

[0051] When the peptides (or FAP-targeting compound comprising said peptide) reached the nM range of affinity and exhibited slow dissociation rates, the oligo biotin capture method was preferred for human and mouse FAP SPR. For this assay, the setup had the same conditions (flow rate, running buffer, peptide dilution) as described above for the CM5 method. The oligo CAPPAT059981

[0052] reagent obtained in the CAPture Kit (Ref. 28920234) was 1 / 5 diluted into running buffer and used with a contact time of 300 s at a flow rate of 2 pL / min. The human and mouse FAP constructs described above were used (from AcroBiosystems or produced in house). The FAP proteins were diluted to a concentration of 2 pg / mL into acetate pH 5.5, 0.05 % Tween20 and used with a contact time of 600 s at a flow rate of 10 pL / min. The peptides were tested with an association time of 280 s followed by a dissociation time of 3000 s at a flow rate of 30 pL / min. The regeneration was done using the regeneration solution (8 M guanidine-HCl, 1 M NaOH) as obtained with a contact time of 270 s at a flow rate of 10 pL / min. In certain embodiments, the compounds (e.g., peptide, or FAP-targeting radiopharmaceutical comprising said peptide) were tested against human and mouse DDP4. Compounds with a KD above 6 pM indicate a high selectivity of said compounds towards DPP4.

[0053] In certain embodiments, the FAP-targeting radiopharmaceuticals disclosed herein exhibit a dissociation constant (KD) for human FAP of about 10 nM or less as measured by the surface plasmon resonance assays disclosed herein, at a temperature of 25° C.

[0054] In certain embodiments, the FAP-targeting radiopharmaceuticals disclosed herein exhibit a dissociation constant (KD) for human FAP of about 5 nM or less, or about 1 nM or less as measured by the surface plasmon resonance assays disclosed in herein, at a temperature of 25° C.

[0055] The FAP-targeting radiopharmaceutical agents contemplated for use in the methods disclosed herein may also exhibit strong potency toward FAP, as measured by the enzymatic FAP competition assay disclosed herein.

[0056] Enzymatic FAP competition assay for assessment of peptide potency

[0057] The potency of a peptide or FAP-targeting compound comprising said peptide (IC50) to inhibit the FAP enzymatic activity were determined using a fluorescence-based assay towards the biotinylated His, Avi tag, human FAP (26-760, FAP-H82Q6) and the biotinylated His, Avi tag, mouse FAP (26-761, FAP-M82Q5). Standard assay conditions consisted of 20 pL total volume in white 384-well plates (Greiner, Ref. 784075), in 50 mM phosphate buffer pH 7.5 containing 150 mMNaCl, 0.05% Tween20 and 1% final DMSO. Tested peptides at 14 different concentrations up to 1 pM were added to 0.01 nM human or mouse FAP. The peptides were incubated for 24 hours together with the protein before adding the substrate 50 pM Z-Gly-Pro-AMC (1-1145 from Bachem). Samples were then incubated at 22-24 °C for 4 h before readingPAT059981

[0058] the fluorescence at excitation wavelength of 380 nm and emission wavelength of 460 nm using the Tecan Infinite® Ml 000 PRO. The high control (100% activity) was not containing any peptide, and an internal potent peptide was added at 10 pM concentration for the low control (100% inhibition). IC50 values were calculated by curve fitting using an in-house developed software (Novartis Helios software application) using the method described by Fomenko et al., 2006 (regression algorithms for nonlinear dose-response curve fitting). Following normalization of activity values for the wells to % inhibition (% inhibition= [(high control-sample) / (high control-low control)] x 100). IC50 fitting was carried out from the duplicated points. Compounds exhibiting high potency against FAP (that is, inhibiting human and / or mouse FAP enzymatic activity), i.e., exhibit an IC50 for human FAP of about 10 nM or less, about 5 nM or less, or about 1 nM or less, between about 10 nM and about 0.001 nM, between about 5 nM and about 0.001 nM, or between about 1 nM and about 0.001 nM, as measured by an Enzymatic FAP competition assay as disclosed herein.

[0059] FAP -targeting radiopharmaceutical agents are known. Such FAP -targeting radiopharmaceutical agents comprise at least one FAP-targeting moiety and a radionuclide. FAP-targeting radiopharmaceutical agents can further comprise one or more chelating agents. FAP-targeting radiopharmaceutical agents can further comprise one or more linkers that, e.g., connect the at least one FAP-targeting moiety with the radionuclide or when present, a chelator.

[0060] In certain embodiments, the FAP-targeting radiopharmaceutical disclosed herein has the structure:

[0061]

[0062] or a pharmaceutically acceptable salt or solvate thereof,

[0063] wherein F is a FAP-targeting moiety, provided that F does not comprise any C-S bonds; M is a radionuclide or a chelator labeled with a radionuclide; L1is a linker adapted to form a chemical bond between P and M; and n is 0 or 1.

[0064] In some embodiments, M is a DOTA (2,2',2'',2'"-(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid) residue or derivative thereof labeled with a radionuclide.PAT059981

[0065] In some embodiments, M is

[0066]

[0067] which is labeled with a radionuclide.

[0068] When the chelator is labeled, chelated, or complexed to a radionuclide, it can be said that the chelator is radiolabeled.

[0069] The FAP-targeting radiopharmaceutical or radiotherapeutic agent disclosed herein does not comprise any C-S bonds. In certain embodiments, the FAP-targeting radiopharmaceutical or radiotherapeutic agent is not: lutetium (177Lu) oxodotreotide. In certain embodiments, the FAP-targeting radiopharmaceutical or radiotherapeutic agent is not:

[0070]

[0071] pharmaceutically acceptable salt or solvate thereof (i.e., FAP-2286, a radiolabeled form of FAP-2286, such as [177Lu]Lu-FAP-2286, or a pharmaceutically acceptable salt or solvate thereof). In certain embodiments, the FAP-targeting radiopharmaceutical agents (radiotherapeutic and radioimaging agents) is not a compound disclosed and characterized in W02021 / 005125 and US Publication No. 2022 / 0273831; W02021 / 005131 and US Publication No. 2022 / 0315554;PAT059981

[0072] WO2022 / 148851; and WO2022 / 148843; and WO2021 / 195198 and US Publication No.

[0073] 2022 / 0370647, each of which is incorporated by reference in its entirety.

[0074] FAP -targeting Radiotherapeutic Agents

[0075] In certain embodiments, the FAP-targeting radiotherapeutic agent has the structure:

[0076]

[0077] or a pharmaceutically acceptable salt or solvate thereof,

[0078] wherein F is a FAP-targeting moiety, provided that F does not comprise any C-S bonds; M is a therapeutic radionuclide or a chelator labeled with a therapeutic radionuclide; L1is a linker adapted to form a chemical bond between F and M; and n is 0 or 1.

[0079] In some embodiments, the therapeutic radionuclide is selected from177Lu,47Sc,67Cu,90Y,131I,153Sm,161Tb,169Er. In some embodiments, the therapeutic radionuclide is177Lu.

[0080] In some embodiments, M comprises DOTA (2,2',2'',2"'-(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid) or is a DOTA residue or derivative thereof labeled with a therapeutic radionuclide.

[0081] In some embodiments, M is

[0082]

[0083] , which is labeled with a therapeutic radionuclide. In some embodiments, M isPAT059981

[0084]

[0085] In certain embodiments, the FAP -targeting radiopharmaceutical agents (radiotherapeutic and radioimaging agents) is a radiotherapeutic agent and / or radioimaging agent disclosed in PCT Appl. No. PCT / IB2024 / 057866 and U.S. Appl. No. 18 / 802,972, which are each incorporated by reference in their entirety.

[0086] In an embodiment, the F (FAP-targeting moiety) in the FAP-targeting radiotherapeutic agent is a cyclized peptide ligand or cyclized peptide. In some embodiments, the F (FAP-targeting moiety) in the radiotherapeutic agent comprises a cyclized peptide ligand (cyclized peptide) and comprises a therapeutic radionuclide, e.g.,177Lu. In certain embodiments, the F (FAP-targeting moiety) in the FAP-targeting radiotherapeutic agent has the formula:

[0087]

[0088] or a pharmaceutically acceptable salt or solvate thereof; wherein

[0089] R3ais H or CH3;

[0090] R4bis selected from the group consisting of H and Ci-3-alkyl,

[0091] R4Cis selected from the group consisting of phenyl and 5-6 membered heteroaryl wherein phenyl and 5-6 membered heteroaryl of R4care substituted with a substituent R4d,

[0092] R4dis selected from Ci-6-alkyl, -OH, and -OCi-Ce-alkyl, wherein the Ci-6-alkyl and -OCi-Ce-alkyl of R4dare each optionally substituted with a substituent R4e, andPAT059981

[0093] R4eis selected from -NH2, -NHCi-6-alkyl, -N(Ci-6-alkyl)2, -NHC(O)- (Ci-6-alkyl), -N3, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of R4eis optionally substituted with -Ci-6-alkyl-NH2or -Ci-3-alkyl-OH;

[0094] R5bis selected from the group consisting of H, Ci-3-alkyl, and -OH,

[0095] R5Cis selected from the group consisting of H and Ci-s-alkyl, wherein the Ci-s-alkyl of R5Cis optionally substituted with halo, -OH, -OCi-6-alkyl, and -C(O)R5d, and

[0096] R5dis 4-7 membered heterocyclyl optionally substituted with 1, 2, or 3 groups independently selected from C 1-3 -alkyl, -CN, halo, and -OH;

[0097] R6Cis a 5 to 10 membered heteroaryl optionally substituted with a group selected from Ci-3-alkyl, -CN, halo, -OH, and -OCi-3-alkyl;

[0098] R8bis selected from the group consisting of H, Ci-6-alkyl, -CH2-phenyl, -CH2-(5 to 6 membered heteroaryl), and -Ci-6-alkyl-NH-C(O)R8c, wherein Ci-6-alkyl, -CH2-phenyl, and -CH2-(5 to 6 membered heteroaryl) of R8bare optionally substituted with halo, -NHCi-6-alkyl, -N(CI-6-alkyl)2, -NH2, -OH, -OCi-3-alkyl, or Ci-3-alkyl;

[0099] R8Cis a 4-7 membered heterocyclyl optionally substituted with -Ci-6-alkylC(O)OH; and R9Cis Ci-6-alkyl optionally substituted with a group selected from -CN, -C(O)OH, - C(O)NH2, halo, -NH2, -NHCi-6-alkyl, -N(Ci-6-alkyl)2, -NHC(O)Ci-6-alkyl, -OH, and -OCi-6-alkyl.

[0100] In an embodiment, the F (FAP-targeting moiety) in the FAP-targeting radiotherapeutic agent has the formula:

[0101]

[0102] or a pharmaceutically acceptable salt or solvate thereof; wherein R4d, R5b, R5c, and R8bare as described herein.PAT059981

[0103] In an embodiment, the F (FAP-targeting moiety) in the FAP-targeting radiotherapeutic agent has the formula:

[0104]

[0105] or a pharmaceutically acceptable salt or solvate thereof; wherein R3a, R4b, R4c, R4d, R5b, R5c, R6c, R8b, and R9c, are as described herein.

[0106] In an embodiment, the FAP-targeting radiopharmaceutical agent is a compound of formula (Id-iib):

[0107]

[0108] (Id-iib),

[0109] or a pharmaceutically acceptable salt, solvate, or tautomer thereof, which is optionally radiolabeled with a radionuclide (e.g.,177Lu,47Sc,67Cu,90Y,131I,153Sm,161Tb,169Er), wherein:

[0110] z is 1, 2, 3, or 4;

[0111] A is absent, -CH2-C(O)-N(H)-CH2-, or -CH2-N(H)-C(O)-CH2-; and

[0112] R5b, R5C, R8bare as described herein.PAT059981

[0113] In an embodiment, the FAP-targeting radiopharmaceutical agent comprises a compound of Formula (P-I):

[0114] *a-A1-Gly-A3-A4-A5-A6-Gly-A8-Asp-(D-Pro)- (SEQ ID NO: 1) wherein

[0115] *aindicates the point of attachment of A1to D-Pro;

[0116] indicates the point of attachment of D-Pro to A1, wherein A1and D-Pro are attached so Formula (P-I) is a cyclized (cyclic) peptide (P);

[0117] A1is any amino acid (e.g., Asp, Gly, NMeGly, Glu, Lys, Lys(Cy5), K(COpipzaa), Ser, D-Ser, hSer, Pro, trans4Hyp; for example, Gly);

[0118] A3is: Phe or NMePhe;

[0119] A4is Phe;

[0120] and A4is bound to linker L1, wherein L1is bound to M, and M is an imaging agent, chelating agent, radionuclide, or cytotoxic drug (e.g., M is a chelator optionally radiolabeled with a radionuclide);

[0121] A5is: Ahp, Aoc, hS(Pr), or Q(Pyrro(2CN4F2));

[0122] A6is: Trp, Trp(Boc), W(60H), W(7C1), W(7F), W7N, or W(70Me); and

[0123] A8is: any amino acid (e.g., Tyr, K(COpipzaa)).

[0124] In certain further embodiments, the FAP-targeting radiopharmaceutical agent comprises a compound of Formula (P-I), which is of Formula (P-I- A):

[0125] *a-Gly-Gly-A3-A4-A5-A6-Gly-A8-Asp-(D-Pro)- (SEQ ID NO: 2), wherein

[0126] *aindicates the point of attachment of A1to D-Pro;

[0127] indicates the point of attachment of D-Pro to A1, wherein A1and D-Pro are attached so Formula (P-I-A) is a cyclized peptide (P);

[0128] A3is: Phe or NMePhe;

[0129] A4is Phe;

[0130] and A4is bound to linker L1, wherein L1is bound to M, and M is a chelator (e.g., DOTA (2,2',2'',2"'-(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid) or a DOTA residue or derivative thereof) optionally radiolabeled with a radionuclide (e.g.,177Lu,47Sc,67Cu,90Y,131I,153Sm,161Tb,169Er);

[0131] A5is: Ahp, Aoc, hS(Pr), or Q(Pyrro(2CN4F2));

[0132] A6is: Trp, Trp(Boc), W(60H), W(7C1), W(7F), W7N, or W(70Me); and

[0133] A8is: any amino acid (e.g., Tyr, K(COpipzaa)).PAT059981

[0134] In certain further embodiments, the FAP-targeting radiopharmaceutical agent comprises a compound of Formula (P-I-A-i):

[0135] *a-Gly-Gly-A3-A4-A5-A6-Gly-A8-Asp-(D-Pro)- * , (SEQ ID NO: 3), wherein

[0136] *aindicates the point of attachment of A1to D-Pro;

[0137] indicates the point of attachment of D-Pro to A1, wherein A1and D-Pro are attached so Formula (P-I-A-i) is a cyclized peptide (P);

[0138] where *3 indicates the point of attachment to A3and *5 indicates the point of attachment to A5;

[0139] A3is: Phe or NMePhe;

[0140] A4is Phe;

[0141] and A4is bound to linker L1, wherein L1is bound to M, and M is a chelator (e.g., a chelator disclosed herein, for example, DOTA residue or derivative thereof) optionally radiolabeled with a radionuclide (e.g.,177Lu,47Sc,67Cu,90Y,131I,153Sm,161Tb,169Er);

[0142] wherein A4and L1together have a structure selected from: F(4amPEG2NH2), F(4amPEG2NH), F(4OEtNH2), F(4am), F(4amGly), F(4amMeGly), F(4amMeB Ala), F(4amBAla), F4(MeTnazolylMeNH2), F(4CCH), F(4amPEG2NH-p-SCN)-, F(4amPEG2NHCOPy3(4F)), F(4amPEG2NHCOPy3(4(NMe3))), F((4amPEG2NH)2-bE-NH, or

[0143]

[0144] PAT059981

[0145]

[0146] A5is: Ahp, Aoc, hS(Pr), or Q(Pyrro(2CN4F2));

[0147] A6is: Trp, Trp(Boc), W(60H), W(7C1), W(7F), W7N, or W(70Me); and

[0148] A8is: any amino acid (e.g., Tyr, K(COpipzaa)).

[0149] In some embodiments, the FAP -targeting radiotherapeutic agent is Compound 1

[0150]

[0151] salt or solvate thereof, which is radiolabeled with a therapeutic radionuclide, e.g.,177Lu. In some embodiments, the FAP-targeting radiotherapeutic agent is [177Lu]Lu-Compound 1:PAT059981

[0152]

[0153] acceptable salt or solvate thereof (i.e., [177Lu]Lu-Compound 1, or a pharmaceutically acceptable salt or solvate thereof).

[0154] In some embodiments, the FAP -targeting radiotherapeutic agent is Compound 2

[0155]

[0156] or a pharmaceutically acceptable salt or solvate thereof, which is radiolabeled with a therapeutic radionuclide, e.g.,177Lu. In some embodiments, the FAP-targeting radiotherapeutic agent is [177Lu]Lu-Compound 2:PAT059981

[0157]

[0158] pharmaceutically acceptable salt or solvate thereof (i.e., [177Lu]Lu-Compound 2 or a pharmaceutically acceptable salt or solvate thereof).

[0159] Definitions

[0160] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

[0161] Unless otherwise indicated, the following terms have the following meanings. In the chemical arts a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, “Ci-6-alkyl” and “Ci-Ce alkyl” both indicate that the alkyl group has from 1 to 6 carbon atoms.

[0162] The term “alkyl” is a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., Ci-io-alkyl), 1 to 8 carbon atoms (i.e., Ci-s-alkyl), 1 toPAT059981

[0163] 5 carbon atoms (i.e., Ci-5-alkyl), 1 to 4 carbon atoms (i.e., Ci-4-alkyl), or 1 to 3 carbon atoms (i.e., Ci-3-alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (z?-Pr, / ?-propyl, -CH2CH2CH3), isopropyl (z-Pr, z-propyl, -CH(CH3)2), 1 -butyl (z?-bu, z?-butyl, -CH2CH2CH2CH3), 2-butyl (.s-bu, .s-butyl, -CH(CH3)CH2CH3), tert-butyl (z-bu, z-butyl, -CH(CH3)3), 1 -pentyl (z?-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3) CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-tnmethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2)IOCH3), and dodecyl (-(CH2)nCH3). In an embodiment, alkyl refers to Ci-6-alkyl. In another embodiment, alkyl refers to Ci-4alkyl. In another embodiment, alkyl refers to C 1-3 alkyl.

[0164] The term “alkylene” refers to a bivalent alkyl group. For example, an alkylene group can have 1 to 10 carbon atoms (i.e., (Ci-ioalkylene), 1 to 5 carbon atoms (i.e., (Ci-salkylene), 1 to 2 carbon atoms (i.e., (Ci-2alkylene), or 1 carbon atom (i.e., Ci-alkylene). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), z?-propylene (-CH2CH2CH2-), z7-butylene (-CH2CH2CH2CH2-), etc.

[0165] The term “acyl” refers to a substituent containing a carbonyl moiety and a non-carbonyl moiety and is meant to include an amino-acyl. The carbonyl moiety contains a double-bond between the carbonyl carbon and an oxygen heteroatom. The non-carbonyl moiety is selected from straight, branched, and cyclic alkyl, which includes, but is not limited to, a straight, branched, or cyclic C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl. In a non-limiting example, acyl is “C2-7 acyl,” which refers to an acyl group in which the non-carbonyl moiety comprises C1-6 alkyl. Examples of C2-7-acyl, include, but are not limited to C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH(CH3)CH2CH3, and C(O)C(CH3)3.

[0166] The term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, biphenyl, and naphthyl. In some embodiments, aryl groups have from six to sixteen carbon atoms (e.g., Ce-i6-aryl). In some embodiments, aryl groups have from six to twelvePAT059981

[0167] carbon atoms (e.g., Ce-i2-aryl). In some embodiments, aryl groups have six carbon atoms (e.g., Ce-aryl, which may also be referred to as phenyl).

[0168] The term “halo” or “halogen” refers to bromo (-Br), chloro (-C1), fluoro (-F), or iodo (-1). In an embodiment, halo refers to fluoro.

[0169] The term “haloalkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms in the chain optionally substituting one or more H with halo. Examples of “haloalkyl” groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that, in light of the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples. In an embodiment, haloalkyl refers to C(i-6)haloalkyl. In another embodiment, haloalkyl refers to C(i-4)haloalkyl. In another embodiment, alkyl refers to C(i- 3)haloalkyl.

[0170] The term “cycloalkyl” refers to a saturated or partially unsaturated all carbon ring system having 3 to 8 carbon atoms (i.e., Cs-scycloalkyl), or 3 to 6 carbon atoms (i.e., C3-6cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings, e.g., in a spirocyclic or bicyclic form. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Some cycloalkyl groups may exist as spirocycloalkyls, wherein two cycloalkyl rings are fused through a single carbon atom; for

[0171] example and without limitation, an example of a spiropentyl group is

[0172]

[0173] ; for example and

[0174] without limitation, examples of spirohexyl groups include

[0175]

[0176] example and without limitation examples of cycloheptyl groups include

[0177]

[0178]

[0179] for example and without limitation examples of cyclooctyl groupsPAT059981

[0180]

[0181] The term “heterocycle” or “heterocyclyl” refers to a saturated or partially unsaturated ring system that has at least one atom other than carbon in the ring system, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. The heterocyclyl group may, for example, consist of a single ring or multiple rings (e.g., in the form of a spirocyclic or bicyclic ring system). Exemplary heterocycles include, but are not limited to oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

[0182] As used herein, the term “heteroaryl” or “heteroaromatic,” employed alone or in combination with other terms, refers to a heterocycle having aromatic character. Heteroaryl substituents may be defined by the number of carbon atoms, e.g., Ci-9-heteroaryl indicates the number of carbon atoms contained in the heteroaryl group without including the number of heteroatoms. For example, a Ci-9-heteroaryl will include an additional one to four heteroatoms. Alternatively, heteroaryl substituents may be defined by the number of atoms in the heteroaryl core, e.g., 5-6 membered heteroaryl indicates the number of carbon and heteroatoms contained in the heteroaryl core. As used herein, heteroaryl includes polycyclic ring systems wherein at least one ring has aromatic character and thus, may include one or more rings that are partially saturated. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0183] When two terms are combined, such as, for example, “alkylaryl” and “alkylheteroaryl,” it is intended that the elements defined by those terms are covalently attached, and that such covalent attachment may occur at any site of each element. For example, Ci-6-alkyl(5 to 6 membered heteroaryl) indicates a Ci-6-alkyl that is covalently attached to a 5 to 6 membered heteroaryl. In some embodiments, the 5 to 6 membered heteroaryl may be covalently attached toPAT059981

[0184] the Ci-6-alkyl at the Cl or C6 carbon, thereby providing a linear alkylheteroaryl group. In some embodiments, the 5 to 6 membered heteroatom is covalently attached to the Ci-6-alkyl at any one of C2, C3, C4, and C5 carbon atoms, thereby providing a branched alkylheteroaryl group.

[0185] Likewise, the Ci-6-alkyl may be attached to any atom of the 5 to 6 membered heteroaryl. Further, a substituent defined using combined terms, e.g., “alkylaryl” and “alkylheteroaryl,” may be connected to the compound via any atom of either of the elements defined by the combined terms. For example, an “alkylaryl” or “alkylheteroaryl” substituent may be connected to the compound via the alkyl group or the aryl / heteroaryl group. In various embodiments, an “alkylaryl” or “alkylheteroaryl” substituent is connected to the compound via the alkyl group. In various other embodiments, the “alkylaryl” or “alkylheteroaryl” substituent is connected to the compound via the aryl or heteroaryl group.

[0186] The terms “connected to” and “conjugated to” as used herein may be used interchangeably and are meant to indicate that two independent constituents are joined together such as by one or more covalent bonds. In some embodiments, the cyclized peptide is conjugated to or connected to a chelating agent via a covalent bond.

[0187] The terms “chelated to” and “complexed to” as used herein may be used interchangeably and are meant to indicate that two independent constituents are joined together such as by one or more non-covalent bonds, e.g., coordination bonds.

[0188] The term “radiolabeled” as used herein means that a non-radioactive compound is labeled with a radioisotope. Radiolabeling can be achieved, e.g., via chelation or complexation of a chelator with an appropriate radionuclide. Radiolabeling can also refer to chemically substituting one group on a compound for a radionuclide, such as, e.g., in the case of18F.

[0189] Furthermore, it is intended that within the scope of the present invention, any element, in particular when mentioned in relation to a peptide of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (i.e., deuterium or D), and3H (i.e., tritium or T). In some embodiments, the compounds described herein include a2H (i.e., deuterium) isotope. By way of example, the group denoted -C(i-6)alkyl includes not only -CH3, but also CD3; not only CH2CH3, but also CD2CD3, etc. Similarly,PAT059981

[0190] references to carbon and oxygen include within their scope respectively12C,13C and14C and15O and16O and17O and18O. The isotopes may be radioactive or non-radioactive.

[0191] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and typically refer to a molecule comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).

[0192] Unless otherwise indicated, naturally occurring L-amino acids and D-amino acids are both represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, naturally occurring L-amino acids are represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, D-amino acids, are represented by lower-case one-letter amino acid designations corresponding to one-letter designations of Table 1, i.e., g, a, 1, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.

[0193] Table 1. Naturally occurring amino acids

[0194] G Glycine Gly P Proline Pro

[0195] A Alanine Ala V Valine Vai

[0196] L Leucine Leu I Isoleucine He

[0197] M Methionine Met C Cysteine Cys

[0198] F Phenylalanine Phe Y Tyrosine Tyr

[0199] W Tryptophan Trp H Histidine His

[0200] K Lysine Lys R Arginine Arg

[0201] Q Glutamine Gin N Asparagine Asn

[0202] Glutamic Aspartic

[0203] E Glu D Asp

[0204] Acid Acid

[0205] S Serine Ser T Threonine Thr

[0206] The term “L-amino acid,” as used herein, refers to the “L” isomeric form of an amino acid, and conversely the term “D-amino acid” refers to the “D” isomeric form of an amino acid (e.g., (D)Asp or D-Asp; (D)Phe or D-Phe). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, as long as the desired function is retained by thePAT059981

[0207] peptide. D-amino acids may be indicated as customary in lower case when referred to using single-letter abbreviations. For example, D-arginine can be represented as “arg” or “r.” Alternatively, a lower case “d” in front of an amino acid can be used to indicate that it is of the D isomeric form, for example D-lysine can be represented by dK.

[0208] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including, Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (a-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), y-Glu (y-glutamic acid), Gaba (y-aminobutanoic acid), 0-Pro (pyrrolidine-3 -carboxylic acid), and Abu (2-aminobutyric acid).

[0209] Further, non-limiting examples of non-naturally occurring amino acids, that may appear, e.g., in the compounds of disclosed herein appear in Table 2 below.

[0210] Table 2. Non-limiting list of non-naturally occurring amino acids that may be incorporated into the FAP targeting cyclic peptides or compounds of the present disclosure:

[0211]

[0212] PAT059981

[0213] >

[0214] ""

[0215]

[0216] PAT059981

[0217] "

[0218]

[0219] PAT059981

[0220] <

[0221] <

[0222] >

[0223] <

[0224]

[0225] PAT059981

[0226] "

[0227] <

[0228] >

[0229]

[0230] FAP -targeting radioimaging agents

[0231] In certain embodiments, the FAP-targeting radioimaging agent has the structure:PAT059981

[0232]

[0233] or a pharmaceutically acceptable salt or solvate thereof,

[0234] wherein F is a FAP-targeting moiety, provided that F does not comprise any C-S bonds; M is a diagnostic radionuclide or a chelator labeled with a diagnostic radionuclide; L1is a linker adapted to form a chemical bond between F and M; and n is 0 or 1.

[0235] In some embodiments, the diagnostic radionuclide is selected from68Ga,64Cu, and18F. In some embodiments, M comprises a chelator suitable for chelating A118F, e.g., NOTA (where NOTA is 2,2',2"-(l,4,7-triazonane-l,4,7-triyl)triacetic acid).

[0236] In some embodiments, M comprises DOTA (2,2',2'',2"'-(l,4,7,10-tetraazacyclododecane-1 ,4,7, 10-tetrayl)tetraacetic acid) or is a DOTA residue or derivative thereof labeled with diagnostic radionuclide.

[0237] In some embodiments, M is

[0238]

[0239] which is labeled with a diagnosticPAT059981

[0240] "

[0241] radionuclide. In some embodiments, M is:

[0242]

[0243] In certain embodiments, the FAP -targeting radioimaging agent is disclosed in PCT Appl. No. PCT / IB2024 / 057866 and U.S. Appl. No. 18 / 802,972, which are each incorporated by reference in their entirety. In certain embodiments, the FAP-targeting radioimaging agent is

[0244] Compound

[0245]

[0246] pharmaceutically acceptable salt or solvate thereof, which is radiolabeled with68Ga. When Compound 1 is radiolabeled with68Ga, it can also be referred to as [68Ga]Ga-Compound 1. In certain embodiments, the FAP-targeting radioimaging agent is Compound 2:PAT059981

[0247]

[0248] or a pharmaceutically acceptable salt or solvate thereof, which is radiolabeled with68Ga. When Compound 2 is radiolabeled with68Ga, it can also be referred to as [68Ga]Ga-Compound 2. In some embodiments, the FAP-targeting radioimaging agent is:

[0249]

[0250] salt or solvate thereof. In some embodiments, the FAP-targeting radioimaging agent is:

[0251]

[0252] salt or solvate thereof.PAT059981

[0253] Methods for treating cancer

[0254] Disclosed herein are methods for treating cancer comprising administering a FAP-targeting radiotherapeutic agent. The methods disclosed herein provide for greater efficacy than current standard of care treatment for cancer with an acceptable safety profile.

[0255] As used herein, “treating” or “treatment” is the means for obtaining beneficial or desired results in a subject, i.e., clinical results. These results may include one or more of (a) reducing the extent of the disease, stabilizing the disease; (b) decreasing or lessening the symptoms resulting from the disease; (c) preventing or delaying spread of the disease (e.g., preventing or delaying metastases); (d) preventing or delaying recurrence of the disease; (e) ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other therapeutic agents for treating the disease in the subject; (f) increasing the quality of life of the subject; and / or (g) prolonging survival whether overall or progression- free.

[0256] In various embodiments, the methods described herein are directed to treating cancer. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer or solid tumor expresses FAP (i.e., the cancer is a FAP-expressing cancer). In certain embodiments, the cancer is selected from bladder cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, endocrine cancer, epithelial cancer, glioblastoma, head and / or neck cancer, mesothelioma, nasopharyngeal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, and sarcoma. In certain embodiments, the solid tumor is selected from breast, colorectal, head and neck, lung, and pancreatic solid tumors. In some embodiments, the cancer is pancreatic cancer, lung cancer, or breast cancer. In certain embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC)). In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In another embodiment, the cancer is breast cancer (BC).

[0257] Solid Tumors

[0258] In an aspect, provided herein is a method for treating cancer in a subject in need thereof comprising administering to the subject a FAP -targeting radiotherapeutic agent, wherein the FAP-targeting radiotherapeutic agent is administered intravenously as a single dose once everyPAT059981

[0259] three weeks ± three days, four weeks ± three days, five weeks ± three days, or six weeks ± three days, to achieve a cumulative dose of about 10 to about 70 GBq, wherein the cancer is a FAP-expressing solid tumor.

[0260] In another aspect, provided herein is a method for treating cancer (e.g., FAP-expressing solid tumor) in a subject in need thereof comprising administering to the subject a FAP -targeting radiotherapeutic agent (e.g., a FAP-targeting radiotherapeutic agent comprising177Lu), wherein the FAP-targeting radiotherapeutic agent is administered intravenously as a single dose once three weeks ± three days, four weeks ± three days, five weeks ± three days, or six weeks ± three days to achieve a cumulative dose of about 10 to about 100 GBq (e.g., about 10 to about 70 GBq). In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is selected from bladder cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, endocrine cancer, epithelial cancer, glioblastoma, head and / or neck cancer, mesothelioma, nasopharyngeal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, and sarcoma. In certain embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)).

[0261] A FAP-targeting radiotherapeutic may allow delivery of targeted radiation directly to the tumor bed. Through the expression of FAP on CAFs, administration of a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 2) can lead to destruction of the tumor stroma via direct radiation damage. In addition, tumor cells in proximity to the FAP positive target cells may also see their demise through radiation effect causing DNA damage leading to cell death. Thus, administration of a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 2) may lead to improved tumor control.

[0262] In some embodiments, the FAP-targeting radiotherapeutic agent comprises177Lu,47Sc,67Cu,90Y,131I,153Sm,161Tb, or169Er. In an embodiment, the FAP-targeting radiotherapeutic agent comprises177Lu. In an embodiment, the FAP-targeting radiotherapeutic agent is:PAT059981

[0263]

[0264] acceptable salt or solvate thereof. In an embodiment, the FAP -targeting radiotherapeutic agent is:

[0265]

[0266] acceptable salt or solvate thereof.

[0267] In an embodiment, the PDAC is FAP-expressing. In an embodiment, the PDAC is metastatic. In an embodiment, the PDAC is not an endocrine or neuroendocrine tumor. In an embodiment, the subject has received at least one prior therapy for the treatment of PDAC, wherein each of the at least one prior therapy is other than a therapy comprising a fibroblast activation protein (FAP)-targeting radiotherapeutic agent. In an embodiment, the subject has progressed after at least one, but no more than two, prior chemotherapy regimens for locally advanced unresectable or metastatic PDAC. In an embodiment, the subject has received at least two prior therapies for the treatment of PDAC, wherein each of the prior therapies is other than a therapy comprising a fibroblast activation protein (FAP)-targeting radiotherapeutic agent.PAT059981

[0268] Combination

[0269] By directly targeting the tumor microenvironment by the administration of a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 2), chemotherapy may have the opportunity for improved delivery to the tumor cells and lead to additional cytotoxic destruction. By combining chemotherapy with a FAP -targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 2), there is a potential for a multimodal approach to tumor destruction.

[0270] Chemotherapy given with a FAP-targeting radiotherapeutic (e.g., [177Lu]Lu-Compound 2) may therefore show improved efficacy over and above each treatment as monotherapy.

[0271] FOLFIRINOX is a common first line regimen for metastatic PDAC in participants with good performance status (Conroy T, et al. (2011) The New England Journal of Medicine;

[0272] 364(19):1817-1825). mFOLFIRINOX was developed to decrease the incidence and severity of cytopenias and GI toxicity. In a study of participants with both localized and metastatic PDAC, mFOLFIRINOX has demonstrated a more favorable safety profile while not compromising efficacy (Mahaseth H, et al. (2013) Pancreas; 42(8): 1311 -1315). Additional studies have shown an improved safety profile with mFOLFIRINOX (Stein SM, et al. (2016) Br J Cancer;

[0273] 114(7):737-743). Therefore, mFOLFIRINOX every two weeks (14 days) may be a suitable chemotherapy partner with a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 2) every three weeks ± three days, four weeks ± three days, five weeks ± three days, or six weeks ± three days, in participants with IL PDAC. Other variations on FOLFIRINOX, such as NALIRIFOX, may also be a suitable chemotherapy partner with a FAP-targeting radiotherapeutic agent (e.g., [177Lu]Lu-Compound 2) (see, e.g., Wainberg Z, et al. (2023) Lancet; 402: 1272-1281).

[0274] A FAP-targeting radiotherapeutic (e.g., [177Lu]Lu-Compound 2) in combination with mFOLFIRINOX (or a variation thereof, such as NALIRIFOX) in patients with PDAC may further demonstrate improved tumor response in comparison to chemotherapy alone. The FAP-targeting radiotherapeutic may cause direct cell death to FAP-positive cells in the tumor microenvironment as well as surrounding cells through “cross-fire” radiation effect. In addition, modulation of the tumor microenvironment may improve the cytotoxic drug delivery to the tumor cells creating synergy with cytotoxic chemotherapy. Lastly, 5-FU based chemotherapy may sensitize the tumor to the effects of radiation. Therefore, FAP-targeting radiotherapeutic agents (such as, e.g., [177Lu]Lu-Compound 2) in combination with mFOLFIRINOX is aPAT059981

[0275] promising combination approach for tumor destruction. mFOLIRINOX comprises (modified) leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin. NALIRIFOX comprises liposomal irinotecan, oxaliplatin, 5 -fluorouracil, and leucovorin.

[0276] Accordingly, in an aspect, provided herein is a method of treating a cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of:

[0277] (a) a fibroblast activation protein (FAP)-targeting radiotherapeutic agent, or a pharmaceutically acceptable salt thereof;

[0278] wherein the FAP -targeting radiotherapeutic agent does not comprise any C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

[0279] Any of the agents in part (b) may be in a pharmaceutically acceptable salt form. For example, recitation of leucovorin includes its pharmaceutically acceptable salts, e.g., leucovorin calcium. When an amount of the agent is specified, the amount corresponds to the active agent in its free acid or base form.

[0280] In some embodiments, the FAP -targeting radiotherapeutic agent comprises177Lu,47Sc,67Cu,90Y,131I,153Sm,161Tb, or169Er. In some embodiments, the FAP -targeting radiotherapeutic agent comprises177Lu. In some embodiments, the FAP-targeting radiotherapeutic agent comprises a cyclized peptide ligand and comprises177Lu. In some embodiments, the FAP-targeting radiotherapeutic agent comprises a cyclized peptide ligand. In some embodiments, the FAP-targeting radiotherapeutic agent is [177Lu]Lu-Compound 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the FAP-targeting radiotherapeutic agent is [177Lu]Lu-Compound 2.

[0281] In some embodiments, the chemotherapy comprises an antimetabolite agent. In some embodiments, the antimetabolite agent is gemcitabine. In some embodiments, the antimetabolite agent is an antimetabolite-antineoplastic agent. In some embodiments, the antimetabolite-antineoplastic agent is a nucleoside metabolic inhibitor (e.g., 5-fluorouracil (5-FU), gemcitabine). In some embodiments, the antimetabolite agent is a nucleoside metabolic inhibitor (e.g., 5-fluorouracil (5-FU), gemcitabine). In some embodiments, the antimetabolite agent is a nucleoside metabolic inhibitor (e.g., nucleic acid synthesis inhibitor). In some embodiments, thePAT059981

[0282] nucleoside metabolic inhibitor is gemcitabine. In some embodiments, the nucleoside metabolic inhibitor is 5 -fluorouracil (5-FU).

[0283] In some embodiments, the chemotherapy comprises an antineoplastic agent. In some embodiments, the antineoplastic agent comprises one or more of a taxane antineoplastic agent, a Topoisomerase I inhibitor, and / or a platinum- containing antineoplastic agent. In some embodiments, the antineoplastic agent comprises a taxane antineoplastic agent (e.g., paclitaxel, nab-paclitaxel, docetaxel). In some embodiments, the antineoplastic agent comprises a Topoisomerase inhibitor (e.g., irinotecan, liposomal irinotecan). In some embodiments, the antineoplastic agent comprises a Topoisomerase I inhibitor (e.g., a campothecin, for example, irinotecan). In some embodiments, the Topoisomerase I inhibitor is irinotecan. In some embodiments, the antineoplastic agent comprises a platinum-containing antineoplastic agent (e.g., cisplatin, carboplatin, nedaplatin, oxaliplatin). In some embodiments, the platinum-containing antineoplastic agent is oxaliplatin.

[0284] In some embodiments, the chemotherapy comprises (e.g., further comprises) a B vitamin analog (e.g., a B12 vitamin analog). In some embodiments, the B vitamin analog is leucovorin.

[0285] In some embodiments, the chemotherapy comprises a B vitamin analog (e.g., a Bl 2 vitamin analog) and at least one, at least two, or at least three antineoplastic agents. In some embodiments, the chemotherapy comprises at least one, at least two, or at least three antineoplastic agents. In some embodiments, the antineoplastic agent comprises one or more of paclitaxel, nab-paclitaxel, gemcitabine, irinotecan, and / or oxaliplatin. In some embodiments, the antineoplastic agent comprises one or more of nab-paclitaxel, gemcitabine, irinotecan, and / or oxaliplatin. In certain embodiments, the chemotherapy comprises an antimetabolite agent (e.g., an antimetabolite-antineoplastic agent) and at least one antineoplastic agent. In certain embodiments, the chemotherapy comprises an antimetabolite-antineoplastic agent and at least one antineoplastic agent. In some embodiments, the chemotherapy comprises an antimetabolite agent and an antineoplastic agent. In some embodiments, the chemotherapy comprises an antimetabolite agent and an antineoplastic agent (e.g., taxane antineoplastic agent, a Topoisomerase I inhibitor, and / or a platinum- containing antineoplastic agent). In some embodiments, the chemotherapy comprises an antimetabolite agent and a taxane antineoplastic agent. In certain embodiments, the chemotherapy comprises gemcitabine and nab-paclitaxel. In certain embodiments, the chemotherapy comprises gemcitabine and paclitaxel. In somePAT059981

[0286] embodiments, the chemotherapy comprises 5-FU and irinotecan. In some embodiments, the chemotherapy comprises 5-FU and oxaliplatin.

[0287] In some embodiments, the chemotherapy comprises an additional antineoplastic agent. In some embodiments, the chemotherapy comprises an antimetabolite-antineoplastic agent and two antineoplastic agents. In certain embodiments, the chemotherapy comprises a B vitamin analog, a nucleoside metabolic inhibitor, a Topoisomerase I inhibitor, and a platinum-containing antineoplastic agent. In certain embodiments, the chemotherapy comprises a nucleoside metabolic inhibitor, a Topoisomerase I inhibitor, and a platinum-containing antineoplastic agent. In certain embodiments, the chemotherapy comprises a nucleoside metabolic inhibitor (e.g., 5-FU), a Topoisomerase I inhibitor (e.g., a campothecin, for example, irinotecan), and a platinum-containing antineoplastic agent (e.g., cisplatin, carbop latin, nedaplatin, oxaliplatin). In certain embodiments, the chemotherapy comprises 5-FU, irinotecan, and oxaliplatin.

[0288] In certain embodiments, the chemotherapy comprises one or more, two or more, or three or more of a taxane antineoplastic agent, an antimetabolite-antineoplastic agent, a B vitamin analog (e.g., a B12 vitamin analog), a Topoisomerase I inhibitor, and / or a platinum-containing antineoplastic agent. In certain embodiments, the chemotherapy comprises one or more, two or more, or three or more of paclitaxel, nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises one or more, two or more, or three or more of nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises one or more of paclitaxel, nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises one or more of nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises two or more of paclitaxel, nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises two or more of nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises 5-FU and one or more of leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises: (1) 5-FU; and (2) irinotecan and / or oxaliplatin. In certain embodiments, the chemotherapy comprises: (1) 5-FU; (2) leucovorin; and (3) irinotecan and / or oxaliplatin. In certain embodiments, the chemotherapy comprises: (1) 5-FU;PAT059981

[0289] (2) leucovorin; and (3) irinotecan (e.g., “FOLFIRI”). In certain embodiments, the chemotherapy comprises: (1) 5-FU; (2) leucovorin; and (3) oxaliplatin (e.g., “FOLFOX”). In certain embodiments, the chemotherapy comprises 5-FU, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises 5 -fluorouracil (5-FU), leucovorin, irinotecan or formulation thereof (e.g., liposomal irinotecan), and oxaliplatin (e.g., “FOLFIRINOX,” “mFOLFIRINOX,” “NALIRIFOX”). In certain embodiments, the chemotherapy comprises 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In certain embodiments, the chemotherapy comprises 5 -fluorouracil (5-FU), leucovorin, liposomal irinotecan, and oxaliplatin (e.g., “NALIRIFOX”). In certain embodiments, the chemotherapy comprises nab-paclitaxel, gemcitabine, FOLFIRINOX, mFOLFIRINOX, FOLFOX, or FOLFIRI. In certain embodiments, the mFOLFIRINOX chemotherapy protocol is outlined in Table 3.

[0290] Table 3. mFOLFIRINOX administration protocol

[0291]

[0292] In some embodiments, the chemotherapy is administered to the subject in parallel with administration of the FAP-targeting radiotherapeutic agent. In some embodiments, the chemotherapy is administered to the subject prior to administration of the FAP-targeting radiotherapeutic agent. In some embodiments, the chemotherapy is administered to the subject in one to two cycles prior to the administration of the FAP-targeting radiotherapeutic agent. In some embodiments, the chemotherapy is administered on a 14-day cycle.

[0293] In some embodiments, the chemotherapy is administered on a 14-day cycle, wherein: i. oxaliplatin is administered on the first day of the 14-day cycle;

[0294] ii. leucovorin is administered on the first day of the 14-day cycle;

[0295] iii. irinotecan is administered on the first day of the 14-day cycle; andPAT059981

[0296] iv. 5 -fluorouracil is administered on the first and second day of the 14-day cycle (e.g., the 5-FU is administered as a continuous IV infusion over 46 hours).

[0297] In some embodiments, the oxaliplatin is administered intravenously at a dose from about 60 mg / m2to about 100 mg / m2(e.g., about 65 mg / m2, about 85 mg / m2). In some embodiments, the oxaliplatin is administered intravenously at a dose of about 65 mg / m2. In some embodiments, the oxaliplatin is administered intravenously at a dose of about 85 mg / m2. In some embodiments, the leucovorin is administered intravenously at a dose from about 50 mg / m2to about 500 mg / m2.

[0298] In some embodiments, the leucovorin is administered intravenously at a dose from about 150 mg / m2to about 500 mg / m2(e.g., about 200 mg / m2, about 400 mg / m2). In some embodiments, the leucovorin is administered intravenously at a dose of about 200 mg / m2. In some embodiments, the leucovorin is administered intravenously at a dose of about 400 mg / m2. In some embodiments, the irinotecan is administered intravenously at a dose from about 100 mg / m2to about 200 mg / m2(e.g., about 150 mg / m2). In some embodiments, the irinotecan is administered intravenously at a dose of about 150 mg / m2. In some embodiments, the 5-fluorouracil is administered intravenously at a dose from about 1000 mg / m2to about 3000 mg / m2(e.g., about 2400 mg / m2). In some embodiments, the 5 -fluorouracil is administered intravenously at a dose of about 2400 mg / m2.

[0299] In some embodiments, the nab-paclitaxel is administered intravenously at a dose from about 50 mg / m2to about 150 mg / m2. In some embodiments, the gemcitabine is administered intravenously at a dose of about 1000 mg / m2.

[0300] In certain embodiments, the FAP-targeting radiotherapeutic agent is administered intravenously as a single dose once every three weeks ± three days, four weeks ± three days, five weeks ± three days, or six weeks ± three days. In some embodiments, the FAP-targeting radiotherapeutic agent is administered intravenously as a single dose once every four weeks ± three days. In certain embodiments, the single dose of the FAP-targeting radiotherapeutic agent is from about 1 GBq to about 20 GBq. In some embodiments, the single dose of the FAP-targeting radiotherapeutic agent is about 1.85 GBq, about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, about 8.5 GBq, or about 9.3 GBq. In certain embodiments, the FAP-targeting radiotherapeutic agent is administered intravenously to achieve a cumulative dose of about 10 GBq to 100 GBq (e.g., about 10 to about 70 GBq). In some embodiments, the FAP-targeting radiotherapeutic agent is administered to the subject as a single dose once every four weeks ±PAT059981

[0301] three days for a length of time to achieve a cumulative dose of about 10 GBq to 70 GBq. In some embodiments, the FAP-targeting radiotherapeutic agent is administered to the subject as a single dose once every six weeks ± three days for a length of time to achieve a cumulative dose of about 10 GBq to 70 GBq.

[0302] In another aspect, provided herein is a pharmaceutical combination comprising a therapeutically effective amount of:

[0303] (a) a fibroblast activation protein (FAP)-targeting radiotherapeutic agent, or a pharmaceutically acceptable salt thereof;

[0304] wherein the FAP-targeting radiotherapeutic agent does not comprise any C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin,

[0305] for use in any of the methods for treating cancer (e.g., pancreatic cancer, such as PDAC) disclosed herein, for example, wherein the chemotherapy comprises one or more or two or more of: a B vitamin analog, an antimetabolite agent, and / or an antineoplastic agent(s), for example, wherein the chemotherapy comprises one or more or two or more of: a B vitamin analog, a taxane antineoplastic agent, a nucleoside metabolic inhibitor, a Topoisomerase I inhibitor, and a platinum-containing antineoplastic agent. In the pharmaceutical combination the chemotherapy, in some embodiments, comprises paclitaxel, nab-paclitaxel, gemcitabine, 5 -fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. In the pharmaceutical combination the chemotherapy, in some embodiments, comprises nab-paclitaxel, gemcitabine, 5 -fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin.

[0306] In another aspect, provided herein is a fibroblast activation protein (FAP) -targeting radiotherapeutic agent for use in the treatment of cancer (e.g., pancreatic cancer, such as PDAC), wherein the FAP-targeting radiotherapeutic agent does not comprise any C-S bonds; further comprising administration of chemotherapy comprising one or more of a B vitamin analog, an antimetabolite agent, and / or an antineoplastic agent(s), for example, wherein the chemotherapy comprises one or more or two or more of: a B vitamin analog, a taxane antineoplastic agent, a nucleoside metabolic inhibitor, a Topoisomerase I inhibitor, and a platinum-containing antineoplastic agent. In some embodiments, the chemotherapy comprises one or more or two or more of: leucovorin, paclitaxel, nab-paclitaxel, gemcitabine, 5 -fluorouracil (5-FU), irinotecan,PAT059981

[0307] and oxaliplatin. In some embodiments, the chemotherapy comprises one or more or two or more of: leucovorin, nab-paclitaxel, gemcitabine, 5 -fluorouracil (5-FU), irinotecan, and oxaliplatin.

[0308] FAP-Expression and Subject Selection

[0309] In certain embodiments, the cancers to be treated by the methods disclosed herein express FAP (also referred to as “FAP-expressing”). For a cancer to express FAP or be a FAP-expressing cancer means that any of the cancer cells, the extracellular matrix (ECM), or the cancer-associated fibroblasts (CAFs) express FAP.

[0310] FAP-expressing solid tumors can be imaged by positron emission tomography (PET) scanning after administration of a FAP-targeting radioimaging agent. In certain embodiments, the subject is selected for treatment by any of the methods described herein through a diagnostic process comprising administering a FAP-targeting radioimaging agent to the subject and then imaging the subject by positron emission tomography (PET) scanning.

[0311] In certain embodiments, the subject has a cancer suitable for treatment by any of the methods disclosed herein if a target lesion has positive uptake, defined as having > 1.5 times higher SUVmax (maximum standardized uptake value) compared with the SUVmean (mean standardized uptake value) of the mediastinal blood pool that is not attributable to other etiologies of tracer distribution.

[0312] In certain embodiments, the subject has a cancer suitable for treatment by any of the methods disclosed herein if a target lesion has positive uptake, defined as FAP-targeting radioimaging agent uptake in at least 50% of the target lesions with an SUVmax > 8 (wherein SUVmax is maximum standardized uptake value), and the remaining target lesions with uptake above the surrounding background.

[0313] Accordingly, in some embodiments of any of the methods disclosed herein, the method further comprises administering a FAP-targeting radioimaging agent (e.g., comprising68Ga,18F) prior to administration of the FAP-targeting radiotherapeutic agent. In some embodiments, the method further comprises administering a FAP-targeting radioimaging agent prior to administration of the FAP-targeting radiotherapeutic agent. In some embodiments, the FAP-targeting radioimaging agent comprises68Ga or18F. In some embodiments, the FAP-targetingPAT059981

[0314]

[0315] [68Ga]Ga-Compound 2), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the FAP-targeting radioimaging agent is:

[0316]

[0317] pharmaceutically acceptable salt or solvate thereof. In some embodiments, the FAP-targetingPAT059981

[0318]

[0319] Compound 2), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the FAP-targeting radioimaging agent is [68Ga]Ga-Compound 1). In some embodiments, the FAP- targeting radioimaging agent is [68Ga]Ga-Compound 2).

[0320] Dosing, Scheduling, and Administration

[0321] The methods described herein include administration of a therapeutically effective amount, (which can also be referred to as “a therapeutically effective dose”), of a FAP -targeting radiotherapeutic agent alone or in combination with one or more chemotherapeutic agents.

[0322] A therapeutically effective amount is an amount that is 1) effective to ameliorate a symptom of the disease (e.g., a cancer as described herein); 2) arrest or reduce cancer cell proliferation or expansion; and / or 3) reduce cancer cells, tumor size, and / or tumor burden.

[0323] A therapeutically effective amount may also be an amount that achieves an anti-tumor effect. An “anti-tumor effect” or “anti-tumor activity” may be achieved by administration of a therapeutically effective amount of a FAP -targeting radiotherapeutic agent alone or in combination with one or more chemotherapeutic agents. An anti-tumor effect (or anti-tumor activity) refers to a biological effect that can present as a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, a decrease in the number of metasteses, an increase in overall or progression-free survival, an increase in life expectancy, or amelioration of various physiological symptoms associated with the tumor.

[0324] In some embodiments of any of the methods disclosed herein, the anti-tumor activity will exceed an ORR (objective response rate) of about 10% or more, of about 15% or more, more of about 20% or more, of about 25% or more, of about 30% or more, of about 35% or more, ofPAT059981

[0325] about 40% or more, or about 45% or more, of about 50% or more, of about 55% or more, of about 60% or more, of about 65% or more, of about 70% or more, or of about 75% or more. It is understood to one of skill in the art that that the ORR cannot exceed 100%.

[0326] A therapeutically effective dose of the FAP-targeting radiotherapeutic agent will also be determined by the particular radionuclide, and whether said radionuclide is a 0" emitter (can also be referred to in the art as a beta-minus emitter) (e.g.,32P,47Sc,67Cu,89Sr,90Y,131I,153Sm,161Tb,166HO,169Er,177LU,188Re,212Pb) or an a-emitter. In some embodiments of the methods provided herein, the FAP-targeting radiotherapeutic comprises177Lu, a beta-minus emitting radionuclide.

[0327] In some embodiments, the total dose (over the course of a treatment regimen, also referred to herein as a “cumulative dose”) of the FAP-targeting radiotherapeutic radiolabeled with a 0-emitter such as, e.g.,177Lu, is from about 1 GBq to about 200 GBq. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of from about 10 to about 100 GBq of radiation. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of from about 5 GBq to about 70 GBq (e.g., about 10 GBq to about 70 GBq, about 5 GBq to about 60 GBq) of radiation. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of about 5 GBq to about 60 GBq of radiation. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of about 10 GBq to about 70 GBq of radiation. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of from about 5 GBq to about 20 GBq, or about 20 GBq to about 60 GBq of radiation.

[0328] As used herein and throughout the disclosure, the term “about” can mean ± 10%.

[0329] Accordingly, in some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of 10 to 100 GBq ± 10% (e.g., 10 to 70 GBq ± 10%). In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of from 5-20 GBq ± 10%, or 20-60 GBq ± 10% of radiation. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose of about 12.95 GBq, about 14.8 GBq, about 16.65 GBq, about 22.2 GBq, about 25.5 GBq, about 29.6 GBq, or about 34.0 GBq of radiation. In some embodiments, the FAP-targeting radioligand comprising a 0-emitter is administered to achieve a cumulative dose ofPAT059981

[0330] 12.95 GBq ± 10%, 14.8 GBq ± 10%, 16.65 GBq ± 10%, 22.2 GBq ± 10%, 25.5 GBq ± 10%, 29.6 GBq ± 10%, or abut 34.0 GBq ± 10% of radiation.

[0331] In some embodiments, the FAP-targeting radioligand comprising the P-emitter is administered in a single dose (e.g., once within a 24-hour period) to deliver from about 1 GBq to about 20 GBq of radiation. In some embodiments, the FAP-targeting radiotherapeutic agent comprising the P-emitter is administered in a single dose (once within a 24-hour period) to deliver from about 1 GBq to about 15 GBq of radiation. In some embodiments, the FAP-targeting radiotherapeutic agent comprising the P-emitter is administered in a single dose (once within a 24-hour period, followed by a period of FAP-targeting radiotherapeutic agent dose free days, e.g., 28 ± 3 days) to deliver from about 1 GBq to about 10 GBq of radiation. In some embodiments, the FAP-targeting radiotherapeutic agent comprising the P-emitter is administered at a single dose of about 1.85 GBq, about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, about 8.5 GBq, or about 9.3 GBq. In some embodiments, the FAP-targeting radiotherapeutic agent comprising the P-emitter is administered at a single dose of about 1.85 GBq, about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 8.5 GBq. In some embodiments, the FAP-targeting radiotherapeutic agent comprising the P-emitter is administered at a single dose of 1.85 GBq ± 10%, 3.7 GBq ± 10%, 5.6 GBq ± 10%, 7.4 GBq ± 10%, 8.5 GBq ± 10%, or 9.3 GBq ±10%. In some embodiments, the FAP-targeting radiotherapeutic agent comprising the P-emitter is administered at a single dose of 1.85 GBq ± 10%, 3.7 GBq ± 10%, 5.6 GBq ± 10%, 7.4 GBq ± 10%, or 8.5 GBq ± 10%.

[0332] In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once about every 2 weeks to 10 weeks. In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once about every 2 weeks to 6 weeks. In some embodiments, FAP-targeting radiotherapeutic agent is administered as a single dose once about every 3 weeks. In some embodiments, FAP-targeting radiotherapeutic agent is administered as a single dose once about every 4 weeks. In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once about every 5 weeks. In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once about every 6 weeks. In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once every 6 weeks with a window of minus one day and plus 7 days (i.e., about every 41-49 days).PAT059981

[0333] In some embodiments, FAP -targeting radiotherapeutic agent is administered as a single dose once every three weeks ± three days (i.e., 21 ± 3 days). In some embodiments, FAP-targeting radiotherapeutic agent is administered as a single dose once every four weeks ± three days (i.e., 28 ± 3 days). In some embodiments, the FAP -targeting radiotherapeutic agent is administered as a single dose once every five weeks ± three days (i.e., 35 ± 3 days). In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once every six weeks ± three days (i.e., 42 ± 3 days). In some embodiments, the FAP-targeting radiotherapeutic agent is administered as a single dose once every six weeks with a window of minus one day and plus 7 days (i.e., once every 41-49 days).

[0334] In some embodiments of the methods provided herein, when the FAP-targeting radiotherapeutic agent is combined with a chemotherapeutic agent, the combination exhibits synergy. The terms “synergy,” “synergism,” and “synergistic” each refer to a measured effect of compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the agents were said agents administered alone (i.e., as a single agent).

[0335] In some embodiments, administration of the FAP-targeting radiotherapeutic agent and a chemotherapeutic agent allows for lower doses of the chemotherapeutic agents as compared to administration of the chemotherapeutic agent as a single agent for the treatment of the same cancer or tumor type.

[0336] In some embodiments of any of the methods disclosed herein, the FAP-targeting pharmaceutical (whether a FAP-targeting radiotherapeutic agent or FAP-targeting radioimaging agent) is administered to the subject intravenously (IV administration).

[0337] Kits

[0338] Also described herein are kits comprising one or more unitary doses of the active agents, e.g., a FAP-targeting radiotherapeutic agent or the components for on-site production of the FAP-targeting radiotherapeutic agent. The kit may further include one or more further chemotherapeutic agents (e.g., FOLFIRINOX / mFOLFIRINOX / NALIRIFOX components and / or nab-paclitaxel, gemcitabine). The kit may further include a FAP-targeting radioimaging agent or the components for on-site production of the FAP-targeting radioimaging agent. Kits may alsoPAT059981

[0339] include a label indicating the intended use of the contents of the kit, as well as instructions for the use of the kit components.

[0340] Medical Use Formats

[0341] Any aspect or embodiment herein formulated as method of treatment aspect or embodiment may be likewise formulated into other medical use formats.

[0342] Incorporation by Reference

[0343] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entireties for all purposes.

[0344] EXAMPLES

[0345] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same or similar results.

[0346] Example 1: Preparation of a FAP-targeting Radiotherapeutic Agent and a FAP-targeting Radioimaging Agent

[0347] The synthesis of FAP-targeting compounds is described in PCT Appl. No.

[0348] PCT / IB2024 / 057866 and U.S. Appl. No. 18 / 802,972, which are each hereby incorporated by

[0349]

[0350] PAT059981

[0351] described in Examples 2, 2.2, 3, 3.1.1, A2, and B2 of PCT Appl. No. PCT / IB2024 / 057866 and U.S. Appl. No. 18 / 802,972. The synthesis and characterization of Compound 2:

[0352]

[0353] (Compound 2) is described in Examples 2, 2.2, 3, 3.1.1, A2, and Bl of PCT Appl. No.

[0354] PCT / IB2024 / 057866 and U.S. Appl. No. 18 / 802,972. Methods of labeling Compounds 1 and 2 with radioisotopes are provided in Examples 6.3, 6.3.1 (Method 1), 6.3.2 (Method 2), Method 6.3.3 (Method 3), and 6.4 of PCT Appl. No. PCT / IB2024 / 057866 and U.S. Appl. No.

[0355] 18 / 802,972.

[0356] Provided below are examples of radiolabeling with [177Lu]LuC13.

[0357] Example [177Lu] Radiolabeling Method 1

[0358] Materials:

[0359] >

[0360]

[0361] PAT059981

[0362] Labeling buffer: The labeling buffer consists of 5 pL gentisic acid solution (31.4 mg / mL), 5 pL sodium acetate solution (47.0 mg / mL), and 140 pL TraceSELECT™ water, adjusted to pH 5.5 with HC130%. The labeling buffer was stored at room temperature.

[0363] Formulation solution (5% EtOH in saline): The formulation solution was prepared by mixing 2.5 mL ethanol in 47.5 mL NaCl 0.9%. The formulation solution was stored at room temperature.

[0364] Peptide stock solution for radiolabeling (1 mM): The DOTA precursors (“B” Examples) were dissolved in 1.0 mL 5% ethanol in TraceSELECT™ water. The solution was fractionated and stored in a freezer at -20 °C.

[0365] Radiolabeling (4-74 MBq / nmol): In a low protein binding tube, [177Lu]LuCh in 0.04 M HC1 (50-670 MBq) was diluted in labeling buffer up to a volume of 100-300 pL, mixed, and briefly heated at 95 °C in a shielded Thermoshaker Incubator. After that, 1.0-25.5 nmol of the DOTA-peptide stock solution (1 mM) was added to the reaction mixture to fulfill a molar activity between 4-74 MBq / nmol. Ethanol was added to the reaction mixture up to a final concentration of 5%. This reaction mixture, with a pH between 4.0 and 4.5, was left to stir (600 rpm) at 95 °C for 15 min. After cooling at room temperature, the completion of the reaction was confirmed by radio-iTLC and radio-HPLC and there was no need for further purification steps. The final product was diluted with formulation solution to an activity concentration of 27-740 MBq / mL and this formulated solution was used for further stability evaluation or biological experiments.

[0366] Example [177Lu] Radiolabeling Method 2

[0367] Materials:

[0368] >

[0369] >

[0370] >

[0371]

[0372] PAT059981

[0373] >

[0374] >

[0375] >

[0376]

[0377] Sodium acetate solution (1,5 M): Sodium acetate trihydrate (204.0 mg) was dissolved in 1 mL TraceSELECT™ water. The solution was stored in a refrigerator at 4 °C.

[0378] Ascorbic acid solution (0,04 M): Ascorbic acid (7.1 mg) was dissolved in 1 mL TraceSELECT™ water. The solution was stored in a refrigerator at 4 °C.

[0379] DOTA-peptide stock solution for radiolabeling (2 mM): The DOTA precursors (“B” Examples) were dissolved in 1.0 mL TraceSELECT™ water. The solution was fractionated and stored in a freezer at -20 °C.

[0380] Radiolabeling (37 MBq / nmol): In a low protein binding tube containing 35 pL sodium acetate solution (1.5 M), 35 pL ascorbic acid solution (0.04 M), 1.5 pL acetic acid, and 58 pL ethanol, was added 250 pL [177Lu]LuC13 in 0.04 M HC1 (55-530 MBq). After that, 1.5-13.8 nmol of the DOTA-peptide stock solution (2 mM) was added to the reaction mixture to fulfill a molar activity of approximately 37 MBq / nmol. This reaction mixture, with a pH of 4.7, was left to stir (450 rpm) at 95 °C for 15 min in a shielded Thermoshaker Incubator. After cooling at room temperature, the reaction mixture was diluted with PBS pH 7.4 to keep the final formulation with less than 9% of ethanol and an activity concentration of approximately 370 MBq / mL. This solution was used for further extended stability studies over time and biological assays.PAT059981

[0381] The initial radiochemical purity of [177Lu]Lu-labeled peptides was analyzed by radio-HPLC and radio-iTLC and the stability in solution at 24°C was evaluated 1 - 96 h after the end of synthesis by radio-HPLC.

[0382] Provided below are examples of radiolabeling with [68Ga]GaCh.

[0383] Example [68Ga] Radiolabeling Method

[0384] Materials:

[0385]

[0386] Gentisic acid solution (2,6 mg / mL): Gentisic acid (2.6 mg) was dissolved in 1 m of EMSURE® water. The solution was stored in a refrigerator at 4 °C.

[0387] Gentisic acid solution (126,0 : Gentisic acid (6.3 mg) was dissolved in 50 mL of

[0388]

[0389] EMSURE® water. The solution was stored in a refrigerator at 4 °C.

[0390] DOTA-peptide stock solution for radiolabeling (2,0 mg / mL): The DOTA precursors (“B” Examples) were dissolved in EMSURE® water. The solution was stored at 4-8 °C.

[0391] Radiolabeling Method 3: In a glass vial containing 200 pL of gentisic acid solution (2.6 mg / mL) it was added approximately 1.1 mL of [68Ga]GaCh in 0.1 M HC1 (approx. 870 MBq) directly transferred from the68Ge / 68Ga generator. After that, 110 pL of sodium formate and 30 nmol of the DOTA-peptide stock solution (2.0 mg / mL) were added to the reaction mixture to fulfill a molar activity of approximately 23 MBq / nmol at the end of the synthesis. This reaction mixture, with pH 3.7, was left incubating at 95 °C for 10 min in a shielded heating block. After cooling at room temperature, the radiochemical purity was followed by radio-HPLC and no further purification or formulation was performed.

[0392] Radiolabeling Method 4: In a glass vial containing 5985 pL of gentisic acid solution (126.0 pg / mL) it was added approximately 1.1 mL of [68Ga]GaCh in 0.1 M HC1 (approx. 905 MBq) directly transferred from the68Ge / 68Ga generator. After that, 250 pL of sodium formate and 150 nmol of the DOTA-peptide stock solution (2.0 mg / mL) were added to the reaction mixture to fulfillPAT059981

[0393] a molar activity of approximately 5 MBq / nmol at the end of the synthesis. This reaction mixture, with pH of approximately 3.7, was left incubating at 95 °C for 14 min in a shielded heating block. After cooling at room temperature for 5 min, the radiochemical purity was followed by radio-HPLC and no further purification or formulation was performed.

[0394] Example 2: In vitro Combination of Standard of Care (SoC) Chemotherapy with Compound A Induces Growth Inhibition in PDAC Cellular Models

[0395] In Examples 2 and 3, Compound A is [177Lu]Lu-Compound 2.

[0396] Cell Culture

[0397] The Capan-2 (CAPAN2) cell line was obtained from ATCC. The PK-1 (PK1) cell line was obtained from RIKEN. All cells were maintained at 37 °C in a humidified 5% CO2 incubator. Capan-2 (HTB-80, ATCC) cells were cultured in McCoy’s 5A (#l-18F01-I, BioConcept) supplemented with 10% FCS (#2-0-lF30-I, Bio concept), 2 mM L-glutamine (#5-10K50-H, BioConcept). PK-1 (RCB1972, RIKEN) were cultured in RPMI 1640 (#l-41F01-I, BioConcept) supplemented with 10% FCS (#2-0-lF30-I, BioConcept), 2 mM L-glutamine (#5-10K50-H, BioConcept), 1 mM sodium pyruvate (#5-60F00-H, BioConcept) and 10 mM HEPES (#5-31F00-H, BioConcept). All media were supplemented with Penicillin-Streptomycin 1% (#4-01F00-H, BioConcept).

[0398] Cells were passaged by washing first with Dulbecco’s PBS without Ca2+ / Mg2+ (#3-05F29-I, BioConcept), trypsinizing with TrypLE™ Express (#12605-010, Gibco), centrifuging in the respective culture media, and splitting cells into fresh media.

[0399] Cell Viability Assay

[0400] To assess in vitro growth inhibition, cell viability measuring assays were conducted as follows:

[0401] On Dav 1, cells were trypsinized, resuspended in the respective media and counted using a TC20 cell counter from Bio-Rad. 2’000 or 500 cells / well for Capan-2 and PK-1 respectively were seeded in 100 microliters growth medium into white clear-bottom 96- well plates (Greiner Cat# 655098). Cells were incubated overnight at 37°C in a humidified 5% CO2 atmosphere.PAT059981

[0402] On Dav 2. cells were treated in triplicate with the combination partner at indicated concentrations, using a D300 Digital Dispenser (TECAN). The final concentration of DMSO was normalized to the highest-class value in all wells. Subsequently, cells were treated with Compound A at the indicated concentration by manual pipetting. Cells were incubated overnight at 37°C in a humidified 5% CO2 atmosphere.

[0403] On Dav 5. Compound A-treated media was removed by carefully pipetting and adding 100 microliters of fresh medium. The combination partners were then dispensed again as on Day 2. Cells were incubated at 37°C in a humidified 5% CO2 atmosphere during the extent of the experiment.

[0404] On Dav 12 (10 days after Compound A treatment), cell viability was assessed using CellTiter-Glo® Luminescent Cell Viability Assay (Promega, #G7573) reconstituted according to manufacturer’s instructions. Plates and CellTiter Gio (CTG) reagent were equilibrated at room temperature. Then, 50uL of CTG was added to each well, plates were shaken for 2 min in a plate shaker and incubated for 10 minutes at room temperature. Plates were measured using the Infinite M Plex Multimode Microplate Reader (TECAN) using a luminescence setting with 500 millisecond integration time and no attenuation.

[0405] The data was analyzed by calculating the % of growth inhibition for each condition and represented using Prism-GraphPad.

[0406] Analysis

[0407] In the CAPAN2 PDAC model, the growth inhibition of single agent treatments (Figure 1 or “FIG. 1”) was enhanced when Compound A was combined with either gemcitabine or paclitaxel in vitro. Furthermore, an even greater increase in growth inhibition was observed when Compound A was combined with the standard of care treatment regimen, gemcitabine and paclitaxel.

[0408] In the PK1 PDAC cell model, a slight increase in growth inhibition was observed when Compound A was combined with 5-FU, irinotecan or 5-FU + Irinotecan (active backbone of FOLFIRI). (See Figure 2 or “FIG. 2”). Similar effects were observed when testing the combination of Compound A with 5-FU, oxaliplatin, or 5-FU + oxaliplatin (active backbone of FOLFOX) in the same model (Figure 3 or “FIG. 3”). These results suggest that Compound A may have a minor effect when combined with these treatments in inhibiting PDAC cell growth.PAT059981

[0409] Interestingly, the combination of Compound A with 5-FU + irinotecan + oxaliplatin (FOLFIRINOX treatment regimen) demonstrated the strongest effect in inhibiting cell growth in the PK1 PDAC cell model (Figure 4 or “FIG. 4”).

[0410] Example 3: In vivo Efficacy of Compound A in Combination with Standard of Care (SoC)

[0411] Abraxane + Gemcitabine in a PDAC Patient Derived Xenograft

[0412] ST4454 (PDAC patient derived xenograft):

[0413] Antitumor in vivo efficacy studies were performed in NMRI mice bearing a subcutaneous ST4454 PDX. Mice were subcutaneously implanted with a PDX (Patient derived xenograft) fragment into the right flank. The studies were typically performed when tumors were approximately 100-200 mm3in volume. Compound A was radiolabeled as described in the radiochemistry section (see Example 1). Animals were administered with an activity of 37 MBq / lnmol per animal every week for a total of six weeks. The efficacy was evaluated by tumor growth monitoring, as shown in Figure 5 (“FIG. 5”) and Figure 6 (“FIG. 6”).

[0414] NMRI mice bearing ST4454 PDAC xenografts were treated with either Compound A alone, Abraxane (nab-paclitaxel) + gemcitabine or the combination of Compound A + Abraxane + gemcitabine. While Abraxane + gemcitabine or Compound A alone induced a modest tumor growth inhibition, combination with the two resulted in full tumor regression which was sustained over the course of the study. (See Figures 5 and 6). Figure 6 indicates the same experiment as in Figure 5, recorded after a higher number of study days.

[0415] Overall, the combination of Compound A with standard PDAC treatments such as gemcitabine + Abraxane (paclitaxel) or FOLRINOX demonstrates strong potential for enhancing growth inhibition in PDAC cells.

[0416] Table of Abbreviations

[0417] Abbreviation Description

[0418] PDAC Pancreatic Ductal Adenocarcinoma

[0419] 5-FU 5-Fluorouracil

[0420] CO2 Carbon Dioxide

[0421] FCS Fetal calf serumPAT059981

[0422] Abbreviation Description

[0423] PDX Patient derived xenograft

[0424] FOLFIRI Folinic acid (leucovorin), 5-FU, irinotecan

[0425] FOLFOX Folinic acid (leucovorin), 5-FU, oxaliplatin

[0426] FOLFIRINOX Folinic acid (leucovorin), 5-FU, irinotecan, oxaliplatin

[0427] CTG CellTiter-Glo®

[0428] DMSO Dimethyl sulfoxide

[0429] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

PAT059981CLAIMS1. A method of treating a cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of:(a) a fibroblast activation protein (FAP) -targeting radiotherapeutic agent, or a pharmaceutically acceptable salt thereof;wherein the FAP-targeting radiotherapeutic agent does not comprise any C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

2. The method of claim 1, wherein the FAP-targeting radiotherapeutic agent comprises a cyclized peptide ligand.

3. The method of claim 1 or 2, wherein the FAP-targeting radiotherapeutic agent comprises177LU.

4. The method of any one of claims 1-3, wherein the FAP-targeting radiotherapeutic agentor a pharmaceutically acceptable salt or solvate thereof.PAT0599815. The method of any one of claims 1-3, wherein the FAP-targeting radiotherapeutic agentor a pharmaceutically acceptable salt or solvate thereof.

6. The method of any one of claims 1-5, wherein the antimetabolite agent is an antimetabolite-antineoplastic agent.

7. The method of any one of claims 1 -6, wherein the antimetabolite agent is a nucleoside metabolic inhibitor.

8. The method of claim 7, wherein the nucleoside metabolic inhibitor is 5 -fluorouracil (5-FU).

9. The method of any one of claims 1-8, wherein the antineoplastic agent comprises one or more of a taxane antineoplastic agent, a Topoisomerase I inhibitor, and / or a platinum-containing antineoplastic agent.

10. The method of any one of claims 1-9, wherein the antineoplastic agent comprises one or more of nab-paclitaxel, gemcitabine, irinotecan, and / or oxaliplatin.

11. The method of any one of claims 1-10, wherein the B vitamin analog is leucovorin.PAT05998112. The method of any one of claims 1-11, wherein the chemotherapy comprises an antimetabolite agent and an antineoplastic agent.

13. The method of any one of claims 1-12, wherein the chemotherapy comprises an antimetabolite agent and a taxane antineoplastic agent.

14. The method of any one of claims 1-12, wherein the chemotherapy comprises gemcitabine and nab-paclitaxel.

15. The method of any one of claims 1-10 or 12, wherein the chemotherapy comprises an antimetabolite-antineoplastic agent and at least one antineoplastic agent.

16. The method of any one of claims 1-10, 12, or 15, wherein the chemotherapy comprises 5-FU and irinotecan.

17. The method of any one of claims 1-10, 12, or 15, wherein the chemotherapy comprises 5-FU and oxaliplatin.

18. The method of any one of claims 1-17, wherein the chemotherapy comprises an additional antineoplastic agent.

19. The method of any one of claims 1-18, wherein the chemotherapy comprises an antimetabolite-antineoplastic agent and two antineoplastic agents.

20. The method of any one of claims 1-8, 12, or 15-19, wherein the chemotherapy comprises a nucleoside metabolic inhibitor, a Topoisomerase I inhibitor, and a platinum-containing antineoplastic agent.

21. The method of any one of claims 1-8, 12, or 15-20, wherein the chemotherapy comprises 5-FU, irinotecan, and oxaliplatin.PAT05998122. The method of any one of claims 1-21, wherein the chemotherapy comprises one or more of nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin.

23. The method of any one of claims 1-22, wherein the chemotherapy comprises two or more of nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin.

24. The method of any one of claims 1-23, wherein the chemotherapy comprises 5-FU and one or more of leucovorin, irinotecan, and oxaliplatin.

25. The method of any one of claims 1-24, wherein the chemotherapy comprises:(1) 5-FU; and(2) irinotecan and / or oxaliplatin.

26. The method of any one of claims 1-24, wherein the chemotherapy comprises:(1) 5-FU;(2) leucovorin; and(3) irinotecan and / or oxaliplatin.

27. The method of any one of claims 1-25, wherein the chemotherapy comprises 5-FU, irinotecan, and oxaliplatin.

28. The method of any one of claims 1-27, wherein the chemotherapy comprises 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin.

29. The method of any one of claims 1 -28, wherein the chemotherapy is administered to the subject prior to administration of the FAP-targeting radiotherapeutic agent.

30. The method of any one of claims 1-29, wherein the chemotherapy is administered on a 14-day cycle.

31. The method of claim 30, wherein the chemotherapy is administered on a 14-day cycle, and wherein:PAT059981i) oxaliplatin is administered on the first day of the 14-day cycle;ii) leucovorin is administered on the first day of the 14-day cycle;iii) irinotecan is administered on the first day of the 14-day cycle; andiv) 5-fluorouracil is administered on the first and second day of the 14-day cycle.

32. The method of any one of claims 1-11 or 15-31, wherein the oxaliplatin is administered intravenously at a dose from about 60 mg / m2to about 100 mg / m2.

33. The method of any one of claims 1-11 or 15-32, wherein the oxaliplatin is administered intravenously at a dose of about 65 mg / m2.

34. The method of any one of claims 1-11 or 15-32, wherein the oxaliplatin is administered intravenously at a dose of about 85 mg / m2.

35. The method of any one of claims 1-11 or 15-34, wherein the leucovorin is administered intravenously at a dose from about 150 mg / m2to about 500 mg / m2.

36. The method of any one of claims 1-11 or 15-35, wherein the leucovorin is administered intravenously at a dose of about 200 mg / m2.

37. The method of any one of claims 1-11 or 15-35, wherein the leucovorin is administered intravenously at a dose of about 400 mg / m2.

38. The method of any one of claims 1-11 or 15-37, wherein the irinotecan is administered intravenously at a dose from about 100 mg / m2to about 200 mg / m2.

39. The method of any one of claims 1-11 or 15-38, wherein the irinotecan is administered intravenously at a dose of about 150 mg / m2.

40. The method of any one of claims 1-11 or 15-39, wherein the 5 -fluorouracil is administered intravenously at a dose from about 1000 mg / m2to about 3000 mg / m2.PAT05998141. The method of any one of claims 1-11 or 15-40, wherein the 5 -fluorouracil is administered intravenously at a dose of about 2400 mg / m2.

42. The method of any one of claims 1-14, 18, 22, 23, 29, or 30, wherein the nab-paclitaxel is administered intravenously at a dose from about 50 mg / m2to about 150 mg / m2.

43. The method of any one of claims 1-14, 18, 22, 23, 29, 30, or 42, wherein the gemcitabine is administered intravenously at a dose of about 1000 mg / m2.

44. The method of any one of claims 1-43, wherein the FAP-targeting radiotherapeutic agent is administered intravenously as a single dose once every three weeks ± three days, four weeks ± three days, five weeks ± three days, or six weeks ± three days.

45. The method of claim 44, wherein the single dose is from about 1 GBq to about 20 GBq.

46. The method of any one of claims 1-45, wherein the FAP-targeting radiotherapeutic agent is administered intravenously to achieve a cumulative dose of about 10 GBq to 100 GBq.

47. The method of any one of claims 1-46, further comprising administering a FAP-targeting radioimaging agent prior to administration of the FAP-targeting radiotherapeutic agent.

48. The method of claim 47, wherein the FAP-targeting radioimaging agent comprises68Ga,64Cu, or18F.

49. The method of any one of claims 47-48, wherein the FAP-targeting radioimaging agent is:PAT059981or a pharmaceutically acceptable salt or solvate thereof.

50. The method of any one of claims 1-49, wherein the cancer is selected from bladder cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, endocrine cancer, epithelial cancer, glioblastoma, head and / or neck cancer, mesothelioma, nasopharyngeal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, and sarcoma.

51. The method of any one of claims 1-50, wherein the cancer is pancreatic cancer.

52. The method of any one of claims 1-51, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

53. The method of claim 52, wherein the PDAC is FAP-expressing.PAT05998154. The method of claim 52 or 53, wherein the PDAC is metastatic.

55. The method of any one of claims 1-50, wherein the cancer is lung cancer.

56. The method of any one of claims 1-50 or 55, wherein the lung cancer is small cell lung cancer (NSCLC).

57. The method of any one of claims 1-50, wherein the cancer is breast cancer.

58. A pharmaceutical combination comprising:(a) a fibroblast activation protein (FAP)-targeting radiotherapeutic agent, or a pharmaceutically acceptable salt thereof;wherein the FAP -targeting radiotherapeutic agent does not comprise any C-S bonds; and (b) chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.

59. The pharmaceutical combination of claim 58, wherein the FAP-targeting radiotherapeutic agent comprises a cyclized peptide ligand.

60. The pharmaceutical combination of claim 58 or 59, wherein the FAP-targeting radiotherapeutic agent comprises177Lu.PAT05998161. The pharmaceutical combination of any one of claims 58-60, wherein the FAP-targetingor a pharmaceutically acceptable salt or solvate thereof.

62. The pharmaceutical combination of claim 58, for use in a method of treating a cancer, wherein the method is according to any one of claims 1-57.

63. A FAP-targeting radiotherapeutic agent which is:or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a cancer, according to any one of claims 1-57.

64. The radiotherapeutic agent for use of claim 63, wherein the radiotherapeutic agent is administered in combination with chemotherapy comprising one or more of an antimetabolite agent, an antineoplastic agent, and / or a B vitamin analog.PAT05998165. The radiotherapeutic agent for use of claim 63 or 64, for use in a method of treating a cancer, wherein the method is according to any one of claims 1-57.

66. The radiotherapeutic agent for use of any one of claims 63-65, wherein the cancer is selected from bladder cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, endocrine cancer, epithelial cancer, glioblastoma, head and / or neck cancer, mesothelioma, nasopharyngeal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, and sarcoma.

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