Treatment method for thyroid cancer using a radiolabeled truncated Evans Blue degenerated fibroblast activation protein inhibitor

Abstract

The present invention discloses a method for treating thyroid cancer using a radiolabeled cleavage-type Evans Blue degenerated fibroblast-activating protein inhibitor, said drug having excellent safety and tolerance in patients with thyroid cancer and having a very excellent therapeutic prospect in the treatment of thyroid cancer.

Description

Technology Field

[0001] The present invention relates to the field of radiopharmaceuticals, and more specifically, to a method for treating thyroid cancer using a radiolabeled cleavage-type Evans Blue degenerated fibroblast activation protein inhibitor. Background Technology

[0002] Thyroid cancer is a malignant tumor originating from thyroid follicular epithelium or follicular radicular epithelial cells, and it is also the most common malignant tumor in the head and neck region. In recent years, the incidence of thyroid cancer has been rapidly increasing worldwide. According to the "IARC Biennial Report 2020-2021" published by the International Agency for Research on Cancer (IARC) under the World Health Organization (WHO), there were approximately 580,000 new cases of thyroid cancer worldwide in 2020, ranking 11th in incidence among all cancers, and it is predicted that thyroid cancer will become the fourth most common cancer by around 2030. Based on differences in tumor origin and differentiation, thyroid cancer can be classified into papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid cancer (ATC). PTC and FTC are collectively referred to as differentiated thyroid carcinoma (DTC), with PTC being the most common, accounting for approximately 90% of all thyroid cancers. These different pathological types of thyroid cancer exhibit distinct differences in terms of pathogenesis, biological behavior, histological morphology, clinical manifestations, treatment methods, and prognosis.Although most DTC patients have a good prognosis after standardized treatment, distant metastasis still occurs in about 23% of patients. Among patients with distant metastasis, about one-third undergo degenerative changes in the morphology and function of tumor cells during the natural course or treatment, leading to a loss of iodine enrichment ability and ultimately progressing to radiooiodine refractory-differentiated thyroid cancer (RAIR-DTC). The survival time of RAIR-DTC patients is significantly shortened compared to DTC patients with good iodine uptake, with an average survival of only 3 to 5 years and a 10-year survival rate of approximately 10%. Tyrosine kinase inhibitors (TKIs) are currently the standard treatment strategy for metastatic RAIR-TC in the advanced stage (mRAIR-TC); however, there are significant challenges in clinical treatment for patients whose disease continues to progress even after TKI therapy.

[0003] Cancer-associated fibroblasts (CAFs) are a population of stromal cells characterized by cellular origin, phenotype, and functional heterogeneity, and are the most important components of the tumor microenvironment (TME). CAFs activated through various pathways can promote tumor growth, angiogenesis, invasion and metastasis, extracellular matrix (ECM) reorganization, and even chemotherapy resistance. Fibroblast activation protein-α (FAP) is abnormally expressed in cancer-associated fibroblasts within the tumor microenvironment and is recognized as a potentially important target for tumor imaging and therapy. In recent years, various radionuclide-labeled quinoline FAP inhibitors (FAPIs) have been developed and are being successfully used for imaging FAP-positive tumors as well as for radioligand therapy (RLT) of targeted tumors. Directly modifying the structure of FAPIs to enhance tumor uptake and retention while reducing accumulation in non-target tissues is the optimal approach for developing therapeutic radiopharmaceuticals. Unfortunately, however, quinoline-based FAPI probes, including FAPI-02, FAPI-04, and FAPI-46, exhibit characteristics of rapid blood clearance and poor tumor retention in animal models and subjects, significantly limiting their further application as diagnostic and therapeutic probes. Evans Blue (EB) is a promising albumin-binding group; after a target molecule binds to an EB derivative, the blood circulation time is significantly extended, thereby improving drug retention time in the tumor. Recently, some EB-modified FAPI (EB-FAPI) radiopharmaceuticals have demonstrated more pronounced antitumor effects than FAPI-04 / 46 in preclinical studies (Wen et al. Theranostics. 2022;12(1):422-433; Millul et al. Eur J Nucl Med Mol Imaging. 2023;50(10):3050-3061.).However, as all related studies are currently in the preclinical research phase, there is a significant unmet clinical demand in the field of renal cell carcinoma diagnostic imaging not only in China but also globally.

[0004] Chinese patent publication number CN114369084A discloses a radiolabeled cleavable Evans Blue-denatured fibroblast-activated protein inhibitor. The radiolabeled cleavable Evans Blue-denatured fibroblast-activated protein inhibitor provided by said patent has a significantly extended circulating half-life and can improve tumor uptake concentration and retention time, performance capabilities that are currently not possessed by other FAPI imaging agents. Further preclinical animal and clinical studies are expected to lead to widespread application in radionuclide therapy and imaging of tumors with high expression of fibroblast-activated protein, which is further advancing exploration in the treatment of thyroid cancer.

[0005] In actual environments, the radiolabeled cleavage-type Evans Blue-denaturing fibroblast activation protein inhibitor provided by the present invention (particularly 177 Lu-EB-FAPI, in the present invention 177 It was found that Lu-LNC1004 (also known as Lu-LNC1004) demonstrates excellent safety and therapeutic potential in the treatment of thyroid cancer patients (particularly mRAIR-TC patients whose cancer has progressed after TKI treatment), and thus has a very promising prospect for therapeutic application.

[0006] Specifically, the present invention provides a method for treating thyroid cancer comprising the step of administering a therapeutically effective amount of a radiolabeled truncated Evans Blue fibroblast-activating protein inhibitor to a patient suffering from thyroid cancer, wherein the structure of the radiolabeled truncated Evans Blue fibroblast-activating protein inhibitor consists of a truncated Evans Blue fibroblast-activating protein inhibitor and a radionuclide, and the truncated Evans Blue fibroblast-activating protein inhibitor is a compound whose structure is represented by formula (I) or a tautomer, meso, racemic mixture, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof.

[0007]

[0008] In addition, the above radionuclides are C-11, N-13, O-15, F-18, Na-24, P-32, P-33, K-42, Sc-43, Sc-44, Sc-47, Cr-51, Mn-51, Fe-52, Mn-52, Mn-52m, Co-55, Co-57, Fe-59, Co-60, Cu-62, Cu-64, Cu-67, Ga-67, Ga-68, As-72, Br-75, Se-75, Br-76, As-77, Rb-82m, Sr-83, Y-86, Y-88, Zr-89, Sr-89, In-90, Y-90, Tc-94, Mo-99, Tc-99m, Pd-103, Rh-105, Ru-106, Pd-109, In-110, In-111, Ag-111, I-120, I-123, I-124, I-125, I-131, Sm-153, Gd-154, Gd-155, Gd-156, Gd-157, Gd-158, Tb-161, Dy-165, Dy-166, Ho-166, Er-169, Yb-169, Lu-177, Yb-177, Re-186, Re-188, Re-189, Ir-192, Ir-194, Au-198, It is selected from any one of Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, and Th-227.

[0009] In some preferred embodiments, the radionuclide is C-11, and in other preferred embodiments, the radionuclide is N-13, and in other preferred embodiments, the radionuclide is O-15, and in other preferred embodiments, the radionuclide is F-18, and in other preferred embodiments, the radionuclide is Na-24, and in other preferred embodiments, the radionuclide is P-32, and in other preferred embodiments, the radionuclide is P-33, and in other preferred embodiments, the radionuclide is K-42, and in other preferred embodiments, the radionuclide is Sc-43, and in other preferred embodiments, the radionuclide is Sc-44, and in other preferred embodiments, the radionuclide is Sc-47, and in other preferred embodiments, the radionuclide is Cr-51, and in other preferred embodiments, the radionuclide is Mn-51, and in other preferred embodiments, the radionuclide is Fe-52, and in other preferred embodiments, the radionuclide is Mn-52, and other In a preferred embodiment, the radionuclide is Mn-52m, and in another preferred embodiment, the radionuclide is Co-55, and in another preferred embodiment, the radionuclide is Co-57, and in another preferred embodiment, the radionuclide is Fe-59, and in another preferred embodiment, the radionuclide is Co-60, and in another preferred embodiment, the radionuclide is Cu-62, and in another preferred embodiment, the radionuclide is Cu-64, and in another preferred embodiment, the radionuclide is Cu-67, and in another preferred embodiment, the radionuclide is Ga-67, and in another preferred embodiment, the radionuclide is Ga-68, and in another preferred embodiment, the radionuclide is As-72, and in another preferred embodiment, the radionuclide is Br-75, and in another preferred embodiment, the radionuclide is Se-75, and in another preferred embodiment,The above radionuclide is Br-76, and in another preferred embodiment, the radionuclide is As-77, and in another preferred embodiment, the radionuclide is Rb-82m, and in another preferred embodiment, the radionuclide is Sr-83, and in another preferred embodiment, the radionuclide is Y-86, and in another preferred embodiment, the radionuclide is Y-88, and in another preferred embodiment, the radionuclide is Zr-89, and in another preferred embodiment, the radionuclide is Sr-89, and in another preferred embodiment, the radionuclide is In-90, and in another preferred embodiment, the radionuclide is Y-90, and in another preferred embodiment, the radionuclide is Tc-94, and in another preferred embodiment, the radionuclide is Mo-99, and in another preferred embodiment, the radionuclide is Tc-99m, and in another preferred embodiment, the radionuclide is Pd-103, and in another preferred embodiment, the radionuclide is Rh-105, and in another preferred embodiment, the radionuclide is Ru-106, in another preferred embodiment, the radionuclide is Pd-109, in another preferred embodiment, the radionuclide is In-110, in another preferred embodiment, the radionuclide is In-111, in another preferred embodiment, the radionuclide is Ag-111, in another preferred embodiment, the radionuclide is I-120, in another preferred embodiment, the radionuclide is I-123, in another preferred embodiment, the radionuclide is I-124, in another preferred embodiment, the radionuclide is I-125, in another preferred embodiment, the radionuclide is I-131, in another preferred embodiment, the radionuclide is Xe-133, in another preferred embodiment, the radionuclide is Cs-137, in another preferred embodiment, the radionuclide is Pr-142, and in another preferred embodiment,The above radionuclide is Pr-143, and in another preferred embodiment, the radionuclide is Tb-149, and in another preferred embodiment, the radionuclide is Tb-151, and in another preferred embodiment, the radionuclide is Gd-152, and in another preferred embodiment, the radionuclide is Gd-153, and in another preferred embodiment, the radionuclide is Sm-153, and in another preferred embodiment, the radionuclide is Gd-154, and in another preferred embodiment, the radionuclide is Gd-155, and in another preferred embodiment, the radionuclide is Gd-156, and in another preferred embodiment, the radionuclide is Gd-157, and in another preferred embodiment, the radionuclide is Gd-158, and in another preferred embodiment, the radionuclide is Tb-161, and in another preferred embodiment, the radionuclide is Dy-165, and in another preferred embodiment, the radionuclide is Dy-166, and in other In a preferred embodiment, the radionuclide is Ho-166, and in another preferred embodiment, the radionuclide is Er-169, and in another preferred embodiment, the radionuclide is Yb-169, and in another preferred embodiment, the radionuclide is Lu-177, and in another preferred embodiment, the radionuclide is Yb-177, and in another preferred embodiment, the radionuclide is Re-186, and in another preferred embodiment, the radionuclide is Re-188, and in another preferred embodiment, the radionuclide is Re-189, and in another preferred embodiment, the radionuclide is Ir-192, and in another preferred embodiment, the radionuclide is Ir-194, and in another preferred embodiment, the radionuclide is Au-198, and in another preferred embodiment, the radionuclide is Au-199, and in another preferred embodiment, the radionuclide is At-211, and in another preferred embodiment, the radionuclide is Pb-211,In another preferred embodiment, the radionuclide is Bi-212, in another preferred embodiment, the radionuclide is Pb-212, in another preferred embodiment, the radionuclide is Bi-213, in another preferred embodiment, the radionuclide is Ra-223, in another preferred embodiment, the radionuclide is Ac-225, in another preferred embodiment, the radionuclide is Fm-255, in another preferred embodiment, the radionuclide is Th-226, and in another preferred embodiment, the radionuclide is Th-227.

[0010] In some specific embodiments, the radionuclide is 177 It is Lu.

[0011] In addition, the radiolabeled cleavage-type Evans Blue denaturing fibroblast-activating protein inhibitor is a compound whose structure is represented by formula (II) or its tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

[0012]

[0013] Depending on the origin and differentiation of the tumor, the thyroid cancer is selected from one or more of papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), poorly differentiated thyroid carcinoma (PDTC), anaplastic thyroid cancer (ATC), and differentiated thyroid carcinoma (DTC).

[0014] According to the histological classification of thyroid tumors, the above-mentioned thyroid cancer is a primary epithelial tumor, a primary non-epithelial tumor, or a secondary tumor.

[0015] Furthermore, the above-mentioned thyroid cancer is radioiodine refractory differentiated thyroid cancer (RAIR-TC), and the definition of radioiodine refractory differentiated thyroid cancer (RAIR-TC) may be referenced in the “Common Opinion on Diagnosis, Treatment, and Management of Radioiodine Refractory Differentiated Thyroid Cancer” (2019 edition) or other standards / common opinions / guidelines.

[0016] Furthermore, the aforementioned thyroid cancer is metastatic RAIR-TC (mRAIR-TC) in the disease progression stage.

[0017] Furthermore, the patient is a mammal.

[0018] Furthermore, the above mammal is preferably a human.

[0019] Furthermore, the above human is an adult or a child.

[0020] Preferably, the age group of the children may follow the age group recommendations of ICH (International Council for Harmonization) E11: preterm newborns, full-term newborns (0 to 27 days), infants (28 days to 23 months), children (2 to 11 years) and adolescents [12 to 16 to 18 years (depending on the region)], or the age group in clinical studies may be comprehensively considered by combining drug characteristics with the developmental physiology and pharmacology of the pediatric population.

[0021] Furthermore, the patient has either used or has not used any treatment methods related to thyroid cancer.

[0022] Furthermore, the above-mentioned thyroid cancer-related treatment means is 131I treatment, surgical treatment, radiation therapy, molecular targeted therapy, chemotherapy, immunotherapy, targeted therapy, tyrosine kinase inhibitor (TKI) treatment, and one or more of traditional Chinese medicine treatments, but not limited thereto.

[0023] In some preferred embodiments, the patient 131 I. The patient has received treatment, and in another preferred embodiment, the patient has received surgical treatment related to thyroid cancer, in another preferred embodiment, the patient has received radiation therapy related to thyroid cancer, in another preferred embodiment, the patient has received molecular targeted therapy related to thyroid cancer, in another preferred embodiment, the patient has received chemotherapy related to thyroid cancer, in another preferred embodiment, the patient has received immunotherapy related to thyroid cancer, in another preferred embodiment, the patient has received targeted therapy related to thyroid cancer, in another preferred embodiment, the patient has received TKI treatment related to thyroid cancer, and in another preferred embodiment, the patient has received Traditional Chinese Medicine treatment related to thyroid cancer. In another preferred embodiment, the patient has received any combination of any of the above treatment methods. As can be understood, the above thyroid cancer-related treatment means are treatment methods commonly used in the current art or treatment means / plans known to a person skilled in the art, and exemplary thyroid cancer-related treatment means / plans include, but are not limited to, those exemplified in the 'Guidelines for the Treatment of Thyroid Cancer' (2022 edition).

[0024] In some preferred embodiments, exemplary surgical treatments include, but are not limited to, resection of the affected adenolobum and isthmus, extended isthmus, total thyroidectomy and other resections of the affected structural organs.

[0025] In some preferred embodiments, exemplary tyrosine kinase inhibitors (TKIs) include, but are not limited to, Sorafenib, Lenvatinib, Apatinib, Donafenil, Anlotinib, Surufatinib, cabozantinib, Ponatinib, Defactinib, Motesanib, Axitinib, Vandetanib, Sunitinib, Pazopanib, etc.

[0026] Furthermore, the method of administration of the radiolabeled cleavage-type Evans Blue denatured fibroblast activation protein inhibitor according to the present invention is intravenous injection, subcutaneous injection, or intramuscular injection.

[0027] Furthermore, the effective dose of the radiolabeled truncated Evans Blue-denatured fibroblast-activating protein inhibitor is 1.82 to 7.4 GBq / cycle (e.g., 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3, 3.01, 3.02, 3.03, 3.04, 3.05, 3.06, 3.07, 3.08, 3.09, 3.1, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.2, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.3, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.4, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.5, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.58, 3.59, 3.6, 3.61, 3.62, 3.63, 3.64, 3.65, 3.66, 3.67, 3.68, 3.69, 3.7, 3.71, 3.72, 3.73, 3.74, 3.75, 3.76, 3.77, 3.78, 3.79, 3.8, 3.81, 3.82, 3.83, 3.84, 3.85, 3.86, 3.87, 3.88, 3.89, 3.9, 3.91, 3.92, 3.93, 3.94, 3.95, 3.96, 3.97, 3.98, 3.99, 4, 4.01, 4.02, 4.03, 4.04, 4.05, 4.06, 4.07, 4.08, 4.09, 4.1, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.2, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 4.3, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.4, 4.41, 4.42, 4.43, 4.44, 4.45, 4.46, 4.47, 4.48, 4.49, 4.5, 4.51, 4.52, 4.53, 4.54, 4.55, 4.56, 4.57, 4.58, 4.59, 4.6, 4.61, 4.62, 4.63, 4.64, 4.65, 4.66, 4.67, 4.68, 4.69, 4.7, 4.71, 4.72, 4.73, 4.74, 4.75, 4.76, 4.77, 4.78, 4.79, 4.8, 4.81, 4.82, 4.83, 4.84, 4.85, 4.86, 4.87, 4.88, 4.89, 4.9, 4.91, 4.92, 4.93, 4.94, 4.95, 4.96, 4.97, 4.98, 4.99, 5, 5.01, 5.02, 5.03, 5.04, 5.05, 5.06, 5.07, 5.08, 5.09, 5.1, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.2, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.3, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.4, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.49, 5.5, 5.51, 5.52, 5.53, 5.54, 5.55, 5.56, 5.57, 5.58, 5.59, 5.6, 5.61, 5.62, 5.63, 5.64, 5.65, 5.66, 5.67, 5.68, 5.69, 5.7, 5.71, 5.72, 5.73, 5.74, 5.75, 5.76, 5.77, 5.78, 5.79, 5.8, 5.81, 5.82, 5.83, 5.84, 5.85, 5.86, 5.87, 5.88, 5.89, 5.9, 5.91, 5.92, 5.93, 5.94, 5.95, 5.96, 5.97, 5.98, 5.99, 6, 6.01, 6.02, 6.03, 6.04, 6.05, 6.06, 6.07, 6.08, 6.09, 6.1, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16, 6.17, 6.18, 6.19, 6.2, 6.21, 6.22, 6.23, 6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.3, 6.31, 6.32, 6.33, 6.34, 6.35, 6.36, 6.37, 6.38, 6.39, 6.4, 6.41, 6.42, 6.43, 6.44, 6.45, 6.46, 6.47, 6.48, 6.49, 6.5, 6.51, 6.52, 6.53, 6.54, 6.55, 6.56, 6.57, 6.58, 6.59, 6.6, 6.61, 6.62, 6.63, 6.64, 6.65, 6.66, 6.67, 6.68, 6.69, 6.7, 6.71, 6.72, 6.73, 6.74, 6.75, 6.76, 6.77, 6.78, 6.79, 6.8, 6.81, 6.82, 6.83, 6.84, 6.85, 6.86, 6.87, 6.88, 6.89, 6.9, 6.91, 6.92, 6.93, 6.94, 6.95, 6.96, 6.97, 6.98, 6.99, 7, 7.01, 7.02, 7.03, 7.04, 7.05, 7.06, 7.07, 7.08, 7.09, 7.1, 7.11, 7.12, 7.13, 7.14, 7.15, 7.16, 7.17, 7.18, 7.19, 7.2, 7.21, 7.22, 7.23, 7.24, 7.25, 7.26, 7.27, 7.28, 7.29, 7.3, 7.31, 7.32, 7.33, 7.34, 7.35, 7.36, 7.37, 7.38, 7.39, 7.4 GBq / cycle or selected from the interval of any one of the above values.

[0028] In some preferred embodiments, the effective dose of the radiolabeled cleavage-type Evans Blue denaturing fibroblast activation protein inhibitor is 2.22 GB / cycle.

[0029] The effective dose of the above-mentioned radiolabeled cleavage-type Evans Blue denaturing fibroblast activation protein inhibitor is 3.33 GB / cycle.

[0030] The effective dose of the above-mentioned radiolabeled cleavage-type Evans Blue denaturing fibroblast activation protein inhibitor is 4.44 GB / cycle.

[0031] Furthermore, the administration cycle of the radiolabeled cleavage-type Evans Blue-denatured fibroblast-activating protein inhibitor is 1 to 52 cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 cycles).

[0032] Furthermore, the administration interval between each administration cycle is 7 to 84 days (e.g., intervals 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, It is 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 days.

[0033] Furthermore, the administration interval between each administration cycle may be 1 to 12 weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks).

[0034] The present invention further provides a drug composition for treating thyroid cancer comprising a radiolabeled cleavage Evans Blue degenerated fibroblast activating protein inhibitor or a cleavage Evans Blue degenerated fibroblast activating protein inhibitor according to any one of the above claims, wherein the thyroid cancer is preferably as described in the aforementioned limitation and is not described again herein.

[0035] Furthermore, the above drug composition further comprises pharmaceutically acceptable carriers, excipients, diluents, and / or additives.

[0036] The present invention provides a combination drug composition for treating thyroid cancer comprising a truncated Evans Blue degenerated fibroblast activating protein inhibitor according to any one of the above, a radiolabeled truncated Evans Blue degenerated fibroblast activating protein inhibitor, or a drug composition according to any one of the above.

[0037] Furthermore, since the above combination drug composition may further include other drugs and these drugs can be arbitrarily selected and adjusted in combination with the patient's condition during the clinical process according to current medical means, it can be understood that the selection of other drugs among the combination drug compositions should not be considered a limitation to the present invention, provided that the truncated Evans Blue degenerated fibroblast activating protein inhibitor or the radiolabeled truncated Evans Blue degenerated fibroblast activating protein inhibitor provided by the present invention or the drug composition according to any one of the above claims has a therapeutic prospect for patients with thyroid cancer.

[0038] The present invention further provides a reagent kit for treating thyroid cancer comprising a radiolabeled cleavage Evans Blue degenerated fibroblast activating protein inhibitor or a cleavage Evans Blue degenerated fibroblast activating protein inhibitor according to any one of the above claims, wherein the thyroid cancer is preferably as described in the aforementioned limitation and is not described again herein.

[0039] The present invention further provides the application of a radiolabeled truncated Evans Blue degenerated fibroblast activation protein inhibitor in the manufacture of drugs for the treatment of thyroid cancer.

[0040] Furthermore, the structure of the radiolabeled truncated Evans Blue fibroblast-activated protein inhibitor consists of the truncated Evans Blue fibroblast-activated protein inhibitor and a radionuclide, and the truncated Evans Blue fibroblast-activated protein inhibitor is a compound whose structure is represented by formula (I) or its tautomer, meso, racemic mixture, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

[0041]

[0042] Likewise, the above-mentioned thyroid cancer is preferably as described in the aforementioned limitation and is not described again herein.

[0043] Furthermore, the above radionuclides are C-11, N-13, O-15, F-18, Na-24, P-32, P-33, K-42, Sc-43, Sc-44, Sc-47, Cr-51, Mn-51, Fe-52, Mn-52, Mn-52m, Co-55, Co-57, Fe-59, Co-60, Cu-62, Cu-64, Cu-67, Ga-67, Ga-68, As-72, Br-75, Se-75, Br-76, As-77, Rb-82m, Sr-83, Y-86, Y-88, Zr-89, Sr-89, In-90, Y-90, Tc-94, Mo-99, Tc-99m, Pd-103, Rh-105, Ru-106, Pd-109, In-110, In-111, Ag-111, I-120, I-123, I-124, I-125, I-131, Sm-153, Gd-154, Gd-155, Gd-156, Gd-157, Gd-158, Tb-161, Dy-165, Dy-166, Ho-166, Er-169, Yb-169, Lu-177, Yb-177, Re-186, Re-188, Re-189, Ir-192, Ir-194, Au-198, It is selected from any one of Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, and Th-227.

[0044] Furthermore, the radiolabeled cleavage-type Evans Blue denaturing fibroblast-activating protein inhibitor is a compound whose structure is represented by formula (II) or its tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

[0045]

[0046] The present invention is the first to provide a cleavage-type Evans Blue-denatured fibroblast-activating protein inhibitor (particularly177 Lu-LNC1004) has excellent safety and tolerability in thyroid cancer patients, and since early data related to tumor response are encouraging, the above-mentioned truncated Evans Blue degenerated fibroblast activating protein inhibitor (especially 177 It was proven that Lu-LNC1004) demonstrates excellent therapeutic prospects in terms of thyroid cancer treatment. Brief explanation of the drawing

[0047] Fig. 1 is 177 These are the results of normal organ biodistribution and dose measurement (absorption percentage %) in patients treated with Lu-LNC1004. Figure 2 is 177 These are the results of normal organ biodistribution and dose measurement (effective half-life, unit h) in patients treated with Lu-LNC1004. Fig. 3 is 177 These are the results of normal organ biodistribution and dose measurement (retention time, unit h) in patients treated with Lu-LNC1004. Fig. 4 is 177 Exposure situations at 1m and 3m in three dose groups, 4-168 hours after Lu-LNC1004 treatment. Specific details for implementing the invention

[0048] [definition]

[0049] Before describing the invention in detail, it should be understood that the invention is not limited to the specific methods, methods, and reagents described herein, and that they may vary. Furthermore, it should be understood that the terms used herein are merely for the purpose of describing specific embodiments and are not intended to limit the scope of the invention, and that the scope of the invention is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art.

[0050] Preferably, the terms used herein follow the definitions in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", edited by Leuenberger, HGW, Nagel, B. and Klbl, Hb (1995), Helvetica Chimica Acta, CH-4010, Basel, Switzerland.

[0051] Unless otherwise required by the context, the word “comprising” and variations such as “comprising” and “containing” in the entire specification and the following claims shall be understood to implicitly include the described integers, steps, materials, components or ingredients, compositions, etc., or groups of integers, steps, materials, components or ingredients, compositions, or groups of integers, steps, materials, components or ingredients, compositions, or groups of integers, steps, materials, components or ingredients, compositions. The same aspects of the invention will be defined in more detail in the following paragraphs. Each aspect defined in this way may be combined with one or more other aspects unless explicitly indicated otherwise. In particular, the described optional, preferred, or advantageous features may be combined with one or more other described optional, preferred, or advantageous features.

[0052] Some documents are cited in the entirety of this specification. Regardless of whether they are cited above or below, every document cited herein (including but not limited to all patents, patent applications, scientific publications, literature, articles, news promotions, manufacturer manuals, operating instructions, etc.) is incorporated into the text in its entirety by reference. Nothing in the text shall be construed as an acknowledgment that the present invention cannot have rights prior to such disclosures of the prior art. Some documents cited in the text are identified as "incorporated by reference." In the event that a definition or teaching of such incorporated reference conflicts with a definition or teaching described in this specification, the present specification shall prevail.

[0053] The elements of the present invention are described below. These elements are listed with specific embodiments. However, it should be understood that they may be combined in any manner and any number to form other embodiments. The various described embodiments and preferred embodiments should not be construed as limiting the present invention only to the clearly described embodiments. This description should be understood as supporting and encompassing any method of combining the clearly described embodiments with any number of disclosed and / or preferred elements. Furthermore, unless otherwise indicated in the context, any permutation and combination of all elements described in this application are deemed to be disclosed in the specification of this application.

[0054] The term "thyroid cancer" as used in this invention refers to a malignant tumor originating from thyroid follicular epithelium or follicular radicular epithelial cells. Signs of thyroid cancer are primarily thyroid enlargement or nodules; the nodules are irregular in shape, adhere to surrounding tissues to become fixed, gradually enlarge, have a hard texture, and have indistinct boundaries. Initially, they may move up and down with swallowing movements, but in later stages, they are mostly immobile. If accompanied by cervical lymph node metastasis, cervical lymph node enlargement may be palpable.

[0055] According to the present invention, "therapeutic effective dose" or "effective dosage" refers to the total amount of each active ingredient sufficient to produce a meaningful patient benefit. When applied to an individual active ingredient administered alone, this term refers to the said ingredient alone. When applied to a combination, this term refers to the combined amount of active ingredients (regardless of whether administered in combination, sequentially, or simultaneously) that produce a therapeutic effect.

[0056] The term “treatment” according to the present invention means: (i) suppressing a disease, disease, or condition, i.e., preventing its progression; and (ii) alleviating a disease, disease, or condition, i.e., causing the disease, disease, and / or condition to disappear. In some embodiments, the present invention also includes using a compound according to any disclosed embodiment to prevent the occurrence of a disease, disease, or condition in a patient who may be susceptible to such disease, disease, and / or condition but has not yet been diagnosed with such disease, disease, and / or condition.

[0057] "Pharmaceuticalally acceptable" according to the present invention means a compound or agent that is compatible with the compound of the present invention and does not interfere with or substantially reduce its diagnostic or therapeutic activity. The pharmaceutically acceptable carrier preferably has sufficiently high purity and sufficiently low toxicity to be suitable for administration to a subject (patient) to be treated.

[0058] The “pharmaceuticalally acceptable salt” according to the present invention can be prepared by conventional methods, for example, by reacting any free base and / or acid of the dual target compound according to the present invention with at least a stoichiometric amount of the desired hydrochloric acid or base. The pharmaceutically acceptable salt of the present invention comprises salts having inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts having organic bases. Suitable organic bases include N-methyl-D-glucarmine, benzathine penicillin, diethanolamine, ethanolamine, and tris(hydroxymethyl)aminomethane. The pharmaceutically acceptable salt according to the present invention also comprises salts derived from organic or inorganic acids (e.g., trifluoroacetate). Suitable anions include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, ethylenedisulfonate, esylate, fumarate, glucoheptonate, gluconate, glucuronate, hypochlorite, hydroiodide, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, methanesulfonate, methyl bromide, methylsulfate, naphthalenesulfonate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, toluenesulfonate, and triethyliodide.

[0059] According to the present invention, “patient” generally includes human and non-human animals, preferably mammals (e.g., non-human primates including marmosets, tamarins, spider monkeys, owl monkeys, bervet monkeys, squirrel monkeys and baboons, macaques, chimpanzees, orangutans, gorillas; cattle; horses; sheep; pigs; chickens; cats; dogs; mice; rats; rabbits; guinea pigs, etc.), and includes chimeras and transgenic animals and disease models. In the context of the present invention, the term “patient” preferably refers to a non-human primate or a human, most preferably a human.

[0060] The term “drug composition” according to the present invention means a mixture of one or more compounds according to the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components (e.g., physiologically / pharmaceutically acceptable carriers and excipients). The purpose of the drug composition is to exert biological activity by facilitating the administration of the compounds to a living organism and the absorption of the active components. As can be understood, the drug composition may also include necessary pharmaceutically acceptable carriers, excipients, diluents, and / or additives, and said “carriers, excipients, diluents, and / or additives” may each exhibit different functional actions, and a person skilled in the art may generally select suitable pharmaceutically acceptable carriers, diluents, and / or additives based on the formulation of the drug composition / formulation. This includes, but is not limited to, fillers, expansion agents, carriers, disintegrants, binders, lubricants, flow aids, coating agents, solvents and co-solvents, buffers, preservatives, aids, antioxidants, wetting agents, defoaming agents, thickeners, sweeteners, flavorings and humectants.

[0061] Drug compositions (or formulations) containing the compounds provided by the present invention may be in any suitable form. For example, they may be in the form of a solution or powder, may be prepared as injectable suspensions with or without a diluent, and may include additional components, including but not limited to pharmacologically acceptable carriers. Pharmacologically acceptable carriers may include but not limited to saline solution, water, lactic acid, mannitol, or combinations thereof. The excipients described in the present invention facilitate the processing of the dual-target compounds and / or dimeric radioactive compounds provided by the present invention into medicinal formulations. Suitable formulations depend on the selected route of administration. Further details regarding the carriers, excipients, diluents, and / or additives described herein refer, for example, Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; This can be seen in Liberman, HA and Lachman, L. eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), and the disclosures of these literature or the recognition and definitions of the prior art are incorporated into the text by citation.

[0062] "according to the present invention" 177 "Lu-LNC1004" is obtained by referring to the manufacturing method disclosed in publication number CN114369084A. In some specific embodiments, the " 177A compound not labeled with the radionuclide "Lu-LNC1004" (or referred to as LNC1004, and a method of preparation disclosed in Publication No. CN114369084A may also be referenced) is a compound having the following structure or its tautomer, meso, racemic mixture, enantiomer, diastereomer, or pharmaceutically acceptable salt;

[0063]

[0064] In other specific embodiments, the above " 177 Lu-LNC1004" is based on LNC1004 177 Lu is a radioactive label; and in another specific embodiment, the " 177 "Lu-LNC1004" is a compound having the following structure or its tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or pharmaceutically acceptable salt.

[0065]

[0066] [Specific Implementation]

[0067] The following describes embodiments of the present invention in detail with reference to the examples, but those skilled in the art will understand that the following examples are intended to illustrate the present invention and do not limit the scope of the present invention.

[0068] This embodiment is a single-center, open-label, non-randomized, first human dose-increasing study discovered by researchers in a real-world setting.

[0069] [Inclusion Criteria]

[0070] (1) Adult patients (over 18 years of age) with histologically confirmed metastatic thyroid cancer (including DTC, MTC and ATC), who have previously 131 I Patients with pathological subtypes of DTC diagnosed as mRAIR-DTC based on treatment results;

[0071] (2) Unresectable tumor;

[0072] (3) Disease progression after TKI treatment; and

[0073] (4) 68 Tumor lesions showing increased radiotracer uptake in Ga-FAPI-46 PET / CT (defined as maximum standardized uptake ≥10 in more than 50% of the tumor lesion).

[0074] [Exclusion Criteria]

[0075] (1) Serum creatinine level >150 μmol / L;

[0076] (2) Hemoglobin level <8.0 g / dL;

[0077] (3) White blood cell count <2.0X10 9 / L;

[0078] (4) Platelet count <50X10 9 / L;

[0079] (5) Total bilirubin levels exceeding 3 times the upper limit of the normal range, serum albumin levels <2.0 g / dL;

[0080] (6) Including heart failure, carcinoid heart valve disease, severe allergy or radiocontrast allergy;

[0081] (7) Claustrophobia;

[0082] (8) Pregnancy or breastfeeding.

[0083] [Research Plan and Administration Plan]

[0084] Adopting a traditional 3+3 dose escalation design, the initial dose was set at 2.22 GBq (60 mCi), and the dose for each group was subsequently increased by 50% until dose-limiting toxicity (DLT) was observed. Initially, the first dose group (2.22 GBq / cycle) included 3 patients. If none of the 3 patients in a cohort exhibited DLT, 3 additional patients were recruited for the next higher dose level. If 1 of the 3 patients exhibited DLT at a specific dose level, 3 additional patients were enrolled at the same dose level. The maximum tolerated dose (MTD) is the highest dose at which DLT occurs in 1 in 6 patients or fewer. Adverse events (AEs) were classified using the Common Criteria for Adverse Events, 5th Edition (CTCAE 5.0). DLT 177 It was defined as AE≥3 (G3) associated with Lu-LNC1004.

[0085] The patient 177 No fasting, special diet, or other special preparations were required on the day of injecting Lu-LNC1004. Prior to treatment, the patient took 4 mg of ondansetron to prevent nausea and vomiting. 177 Received intravenous fluid replacement (1 liter of 0.9% normal saline) 30 minutes before Lu treatment. Radiopharmaceutical 177 Lu-LNC1004 was diluted with 100 ml of 0.9% normal saline and administered slowly via intravenous infusion over 20 to 30 minutes. The patient's symptoms and vital signs were monitored before, during, and after treatment. The treatment plan consisted of up to two cycles, with a time interval of six weeks between cycles.

[0086] [Primary and Secondary Endpoints]

[0087] The primary endpoint is in mRAIR-TC patients 177 The objective was to evaluate the safety and MTD of Lu-LNC1004. Secondary endpoints were dose measurement and 177 It was an initial confirmation of the efficacy of Lu-LNC1004.

[0088] [Patient Information and Treatment History]

[0089] A total of 12 patients were enrolled, of whom 3 patients received a dose of 2.28±0.10 GBq (Group A: Patients 1-3), 6 patients received a dose of 3.50±0.09 GBq (Group B: Patients 4-9), and 3 patients received a dose of 4.80±0.28 GBq (Group C: Patients 10-12). Specific patient information and treatment history are as follows:

[0090] Patient 1 : 52 years old, male, pathology subtype PTC (BRAFV600E+), treatment history: total thyroidectomy, 131 I Treatment (3 courses, cumulative dose 20.35 GBq), TKI treatment (Sorafenib), 125 I particle implantation;

[0091] Patient 2 : 53 years old, female, pathology subtype PTC, treatment history: total thyroidectomy (and cervical lymph node dissection, tracheostomy), 131 I Treatment (2 courses, cumulative dose 16.65 GBq), TKI treatment (Sorafenib);

[0092] Patient 3 : 58 years old, male, pathology subtype PTC, treatment history: total thyroidectomy, 131 I Treatment (4 courses, cumulative dose 25.90 GBq), TKI treatment (Anlotinib);

[0093] Patient 4 : 35 years old, male, pathology subtype PTC (BRAF V600E-), treatment history: total thyroidectomy (and cervical lymph node dissection, tumor resection and right clavicle internal fixation), 131 I Treatment (4 courses, cumulative dose 24.05 GBq), TKI treatment (Apatinib, Anlotinib);

[0094] Patient 5: 42 years old, male, pathology subtype PTC, treatment history: total thyroidectomy (and tumor resection and vertebral fixation), 131 I Treatment (6 courses, cumulative dose 59.20 GBq), TKI therapy (Lenvatinib), external beam radiation therapy (EBRT);

[0095] Patient 6 : 55 years old, female, pathology subtype MTC (BRAF V600E-, RET-), treatment history: total thyroidectomy, TKI treatment (Anlotinib), 131 I have no treatment experience;

[0096] Patient 7 : 48 years old, female, pathology subtype FTC, treatment history: total thyroidectomy (and tumor resection and vertebral fixation), 131 I Treatment (5 courses, cumulative dose 44.40 GBq), TKI treatment (Sorafenib);

[0097] Patient 8 : 72 years old, female, pathology subtype: primary tumor PTC, mediastinal lymph node metastasis ATC, treatment history: total thyroidectomy (and endobronchial stent insertion), TKI treatment (Anlotinib), 131 I have no treatment experience;

[0098] Patient 9 : 32 years old, female, pathology subtype PTC, treatment history: total thyroidectomy (and cervical lymph node dissection), 131 I Treatment (5 courses, cumulative dose 37.00 GBq), TKI treatment (Sorafenib);

[0099] Patient 10 : 56 years old, female, pathology subtype PTC, treatment history: total thyroidectomy (and cervical lymph node dissection), 131 I Treatment (2 courses, cumulative dose 7.40 GBq), TKI treatment (Sorafenib);

[0100] Patient 11 : 64 years old, female, pathology subtype PTC, treatment history: total thyroidectomy, 131I Treatment (2 courses, cumulative dose 12.95 GBq), TKI treatment (Sorafenib);

[0101] Patient 12 : 33 years old, female, Pathology PTC, Treatment history: Total thyroidectomy, 131 I Treatment (4 courses, cumulative dose 29.60 GBq), TKI treatment (Anlotinib).

[0102] [Safety Assessment]

[0103] In Patient 4, swelling appeared in the superficial cervical lymph nodes and clavicular metastatic lesions one hour after injection; the swelling persisted for several days and disappeared on the seventh day, after which hemorrhage and necrosis occurred in the clavicular lesions. In Patients 5 and 6, pain symptoms at the bone metastatic lesions worsened on the second day after treatment; Patient 5 took a non-steroidal anti-inflammatory drug, and pain symptoms persisted for six days but gradually subsided thereafter. Transient fatigue symptoms also occurred in Patients 2 and 4. Other than these, no life-threatening adverse events (AEs) were observed. Notably, Patient 8 reported improvements in self-reported physical strength and quality of life after treatment. Additionally, hematotoxicity was observed in all three groups (A, B, and C), but all were reversible after treatment, and no hepatotoxicity or nephrotoxicity was observed in the patients.

[0104] [Full Body Scan]

[0105] 1 hour after administration, 177 The blood pool uptake of Lu-LNC1004 was relatively high, and it showed strong signals in the cardiac region and major blood vessels. In normal organs 177 Lu-LNC1004 showed increased uptake in the liver, spleen, and kidneys, and was excreted into the bladder via the kidneys. 1 hour after administration 177 The tumor uptake status of Lu-LNC1004 was clearly observed. In addition to increased blood circulation activity, 177 The in vivo biodistribution pattern of Lu-LNC1004 is prior to treatment 68It was identical to Ga-FAPI PET / CT. In addition, in the analysis of whole-body and SPECT / CT scans after treatment, all patients in the delayed image 7 days after injection 177 Lu-LNC1004 demonstrated clear uptake and retention in tumor lesions.

[0106] [Capacity Measurement Evaluation]

[0107] 177 Dosthetic parameters after Lu-LNC1004 administration, specifically the percentage of absorption in the systemic, blood pool, liver, kidney, and metastatic sites, effective half-life, retention time, and mean absorbed dose, were measured. According to the results, within 1 hour 177 The systemic absorption rate of Lu-LNC1004 was 100%, and the curves declined at an almost constant rate. Additionally, the blood pool and liver curves initially showed rapid flushing from the first scan up to 24 hours after administration, followed by a slower decline. The kidneys 177 The initial uptake and washout rates for Lu-LNC1004 decreased slowly. 177 The effective half-lives of Lu-LNC1004 in the systemic, blood pool, liver, and kidneys were 90.20±7.68 hours, 74.35±6.28 hours, 82.73±6.64 hours, and 101.00±6.40 hours, respectively. 177 Refer to Figures 1 and 2 for the kinetics and effective half-life of Lu-LNC1004 in the salivary glands, pancreas, spleen, and bladder.

[0108] Retention time represents the total number of decays occurring within the integration time of a unit dose activity. 177The residence times of Lu-LNC1004 in the whole body, blood pool, liver, and kidney were 123.65±13.85 hours, 6.37±2.36 hours, 5.52±1.89 hours, and 2.43±0.98 hours, respectively. Based on these kinetic parameters, the average absorbed doses in the whole body, heart wall, red bone marrow, liver, and kidney were calculated to be 0.17±0.02 mSv / MBq, 0.82±0.38 mSv / MBq, 0.11±0.03 mSv / MBq, 0.29±0.13 mSv / MBq, and 1.32±0.69 mSv / MBq, respectively. 177 The whole-body effective dose of Lu-LNC1004 was 0.17±0.04 mSv / MBq. For the residence time and average absorbed dose of other organs, refer to Figure 3 and Table 1.

[0109] Table 1. 177 Absorbed dose after intravenous administration of Lu-LNC1004

[0110]

[0111] In the case of tumor lesions, the initial stage of all metastatic lesions 177 The uptake rate of Lu-LNC1004 was 0.33% [0.22-0.70%], and the uptake rate of bone metastatic lesions (0.30% [0.22-0.71%]) was slightly lower than that of lymph node metastatic lesions (0.37% [0.26-0.70%]) and other metastatic lesions (0.37% [0.16-1.38%]). The lavage rate of metastatic lesions decreased slowly and was similar to the lavage rate of the kidneys. 177 The effective half-life of Lu-LNC1004 in all metastatic lesions was 92.46±9.66h, and the effective half-life in bone metastatic lesions (98.82±11.89h) was slightly longer than in lymph node metastatic lesions (91.77±9.27h) and other metastatic lesions (87.77±5.12h). 177The residence time of Lu-LNC1004 in metastatic lesions (0.42h [0.29-0.99h]) was shorter than that of the organs mentioned above, but the average absorbed dose (8.50±12.36Gy / GBq) was the highest (range 1.32-58.72Gy / GBq). Specifically, the residence times in the bone, lymph nodes, and other metastatic lesions were 0.62 h [0.38-2.73 h], 0.39 h [0.25-0.93 h], and 0.36 h [0.18-1.17 h], respectively, and the average absorbed dose was 5.12 ± 2.50 Gy / GBq (range 2.31-7.62 Gy / GBq), 5.95 ± 6.80 Gy / GBq (range 1.32-25.03 Gy / GBq), and 15.27 ± 20.52 Gy / GBq (range 2.10-58.72 Gy / GBq).

[0112] Refer to Figure 4 for the radiation emission curves. The average radiation doses of the three groups recorded 4 hours after treatment at a distance of 1 m from the patient were 5.95±0.32 μSv / h (Group A), 10.53±2.22 μSv / h (Group B), and 14.77±2.84 μSv / h (Group C), respectively. The average radiation doses of the three groups within 4 hours at a distance of 3 m from the patient were 1.38±0.16 μSv / h (Group A), 2.02±0.15 μSv / h (Group B), and 2.72±0.28 μSv / h (Group C), respectively. As time passed, the radiation emission curve gradually decreased, and the average radiation doses at 1m and 3m for the three groups 48 hours after administration were 4.22±0.42μSv / h (Group A), 7.00±1.34μSv / h (Group B), and 9.91±1.42μSv / h (Group C), and 1.09±0.18μSv / h (Group A), 1.46±0.19μSv / h (Group B), and 1.95±0.15μSv / h (Group C), respectively.

[0113] [Treatment Effect]

[0114] Six weeks after the end of the second cycle, all patients were evaluated according to the clinical efficacy evaluation index for solid tumors (RECIST 1.1). As a result, partial responses were observed in three patients (patients 4, 5, and 6), the condition of the other seven patients stabilized, and the ORR and DCR were 25% (3 / 12) and 83% (10 / 12), respectively. In patient 4, the target lesions in the right clavicle, ribs, and lymph nodes clearly shrank after two cycles. Notably, obstructive pneumonia caused by enlargement of the left hilar lymph node metastatic lesion was alleviated. In patient 5, both the target lesion of the liver metastasis and the non-target lesion of the pleural effusion disappeared, and the sum of the longest diameters (SLD) of the target lesions of the bone and lung metastases also decreased.

[0115] [conclusion]

[0116] This prospective study is the first of its kind in mRAIR-TC patients whose disease progressed after TKI treatment. 177 The feasibility of Lu-LNC1004 RLT was proven, and data from its first use in humans showed good safety with almost no serious AEs.

[0117] until now 131 I has always been the most common adjuvant therapy for metastatic DTC, but patients with advanced DTC 131 New resistance or tolerance to I develops. In addition, medullary and anaplastic thyroid cancers are due to a lack of iodine metabolism-related gene expression. 131 Patients are unable to respond to I regimen. Although mRAIR-TC TKI therapy has experienced rapid advancements over the past decade, tolerability remains a major obstacle to improving prognosis. Currently, there are no other treatment options available for patients with advanced cancer who have exhausted or rejected existing treatment plans. In this study, 68 According to data from mRAIR-TC patients selected by Ga-FAPI-46 PET / CT, 177 Lu-LNC1004 is 131It can demonstrate a favorable therapeutic effect in patients who are still in the disease progression phase even after I therapy and / or TKI treatment and / or other therapeutic means, which 177 This explains that Lu-LNC1004 is a potential treatment for mRAIR-TC. Furthermore, despite the fact that patients in this study received only two cycles of treatment and the follow-up period being limited, control of radiological disease was observed in 83% of patients, and simultaneously, signs of tumor response were present, which 177 It was superior to the efficacy of Lu-FAPI-46 (see Assadi M, Rekabpour SJ, Jafari E, Divband G, Nikkholgh B, Amini H, et al. Feasibility and therapeutic potential of 177Lu-fibroblast activation protein inhibitor-46 for patients with relapsed or refractory cancers: a preliminary study. Clin Nucl Med 2021;46(11):e523-e30.). Overall, this study 177 The initial response of Lu-LNC1004 to tumors was previously 177 Studies using Lu-FAP-2286 on various adenocarcinoma patients and 90 It was superior to studies using Y-FAPI-46 in patients with advanced sarcoma (see Fendler WP, Pabst KM, Kessler L, Fragoso Costa P, Ferdinandus J, Weber M, et al. Safety and efficacy of 90Y-FAPI-46 radioligand therapy in patients with advanced sarcoma and other cancer entities. Clin Cancer Res 2022;28(19):4346-53.).

[0118] Previous studies have used the therapeutic radionuclide label FAPI-46 for FAP-targeted radionuclide therapy in various advanced cancers; however, the in vivo half-life of the radiotherapy drug is not sufficiently long, which may result in insufficient absorption and retention by the tumor. As confirmed in this experiment, 177 The effective half-life of Lu-LNC1004 (whole body) is 90.20±7.68h, and 177 It was longer than the effective half-life of Lu-FAP-2286 (35.00±9.00h) (Baum RP, Schuchardt C, Singh A, Chantadisai M, Robiller FC, Zhang J, et al. Feasibility, biodistribution, and preliminary dosimetry in peptide-targeted radionuclide therapy of diverse adenocarcinomas using (177) See Lu-FAP-2286: first-in-humans results. J Nucl Med 2022;63(3):415-23.). Therefore 177 The whole-body radiation dose of Lu-LNC1004 reached 0.17±0.04 mSv / MBq, 177 It was 6.54 times that of Lu-FAPI-46. Also 177 Despite a slight increase in the distribution of Lu-LNC1004 in the liver and kidneys, each 177 Although it was 2.13 times and 1.49 times that of Lu-FAPI-46 (Assadi M, Rekabpour SJ, Jafari E, Divband G, Nikkholgh B, Amini H, et al. Feasibility and therapeutic potential of 177(See Lu-fibroblast activation protein inhibitor-46 for patients with relapsed or refractory cancers: a preliminary study. Clin Nucl Med 2021;46(11):e523-e30.), and not a single patient showed hepatotoxicity or nephrotoxicity. This indicates that the increased radiation dose due to prolonged blood circulation time is acceptable.

[0119] In addition, the average radiation dose at 1m and 3m 4 hours after treatment for the three groups of patients in this study 131 It was lower than I treatment and also lower than the Nuclear Regulatory Commission's release criteria (see Nuclear Regulatory Commission 2019 Regulatory Guide 8.39: Release of Patients Administered Radioactive Materials [cited 2023 Feb 21]). of 2.22 GBq and 3.33 GBq doses 177 For patients treated with Lu-LNC1004, the radiation dose at 1 m was less than 9 μSv / h 4 hours after administration, and the patient 177 Lu-PSMA-617 and 177It was lower than the discharge criteria when receiving Lu-DOTATATE treatment (Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol 2018;19(6):825-33 and Hope TA, Abbott A, Colucci K, Bushnell DL, Gardner L, Graham WS, et al. Although the radiation dose at 1m in the 4.99 GBq group was higher than this threshold within 4 hours after treatment, it was sufficient to reduce the radiation dose to below 9 μSv / h within 48 hours. While the duration varies, generally, 3 days 177 It is considered sufficient to resume public activities after exposure to Lu-LNC1004.

[0120] In summary, the present invention is the first 177 Lu-LNC1004 demonstrated the safety and feasibility of dose escalation therapy for RLT thyroid cancer patients (using mRAIR-TC patients as an example). Overall, all patients 177 Lu-LNC1004 tolerated high-dose radiation to the mRAIR-TC lesion well. Initial data regarding tumor response are encouraging, and in mRAIR-TC treatment 177 Lu-LNC1004 supports the potential therapeutic role of RLT.

[0121] The foregoing description is merely a preferred embodiment and serves only as an example and does not limit the combination of features necessary for carrying out the invention. The provided title is not intended to limit various embodiments of the invention. Terms such as "comprising," "containing," and "comprising" are not intended to be limiting. Furthermore, unless otherwise noted, the plural form is included where no modifier is used, and "or" and "or" mean "and / or." Unless otherwise defined in the text, the meaning of all technical and scientific terms used in the text is the same as commonly understood by a person skilled in the art.

[0122] All disclosures and patents mentioned in this application are incorporated herein by reference. Various modifications and variations of the methods and compositions described in this invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described through specific preferred embodiments, the invention is not unduly limited to these specific embodiments. It is intended for those skilled in the art that various variations of the described modes for carrying out the invention are within the scope of the following claims.

Claims

Claim 1 A method for treating thyroid cancer, comprising the step of administering a therapeutically effective amount of a radiolabeled cleavage Evans Blue fibroblast-activating protein inhibitor to a patient suffering from thyroid cancer, wherein the structure of the radiolabeled cleavage Evans Blue fibroblast-activating protein inhibitor consists of a cleavage Evans Blue fibroblast-activating protein inhibitor and a radionuclide, and wherein the cleavage Evans Blue fibroblast-activating protein inhibitor is a compound whose structure is represented by formula (I) or a tautomer, meso, racemic mixture, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof. Claim 2 In claim 1, the radioactive nuclides are C-11, N-13, O-15, F-18, Na-24, P-32, P-33, K-42, Sc-43, Sc-44, Sc-47, Cr-51, Mn-51, Fe-52, Mn-52, Mn-52m, Co-55, Co-57, Fe-59, Co-60, Cu-62, Cu-64, Cu-67, Ga-67, Ga-68, As-72, Br-75, Se-75, Br-76, As-77, Rb-82m, Sr-83, Y-86, Y-88, Zr-89, Sr-89, In-90, Y-90, Tc-94, Mo-99, Tc-99m, Pd-103, Rh-105, Ru-106, Pd-109, In-110, In-111, Ag-111, I-120, I-123, I-124, I-125, I-131, Sm-153, Gd-154, Gd-155, Gd-156, Gd-157, Gd-158, Tb-161, Dy-165, Dy-166, Ho-166, Er-169, Yb-169, Lu-177, Yb-177, Re-186, Re-188, Re-189, Ir-192, Ir-194, Au-198, A method characterized by being selected from any one of Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, and Th-227. Claim 3 A method according to any one of claims 1 to 2, wherein the radiolabeled cleavage-type Evans Blue-denatured fibroblast-activating protein inhibitor is a compound whose structure is represented by formula (II) or a tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof. Claim 4 A method according to any one of claims 1 to 3, wherein the thyroid cancer is selected from one or more of papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), poorly differentiated thyroid carcinoma (PDTC), anaplastic thyroid cancer (ATC), and differentiated thyroid carcinoma (DTC). Claim 5 A method characterized in that, in any one of claims 1 to 4, the thyroid cancer is a primary epithelial tumor, a primary non-epithelial tumor, or a secondary tumor. Claim 6 A method characterized in that, in any one of claims 1 to 5, the thyroid cancer is iodine-refractory thyroid cancer (RAIR-TC), and preferably, the thyroid cancer is metastatic RAIR-TC (mRAIR-TC) in the disease progression stage. Claim 7 A method characterized in that, in any one of claims 1 to 6, the patient is a mammal. Claim 8 A method according to claim 7, wherein the mammal is preferably a human. Claim 9 A method according to claim 8, characterized in that the human being is an adult or a child. Claim 10 A method characterized in that, in any one of claims 1 to 9, the method of administration is intravenous injection, subcutaneous injection, or intramuscular injection. Claim 11 A method characterized in that, in any one of claims 1 to 10, the patient has used or has not used a treatment means related to thyroid cancer. Claim 12 In Clause 11, the above-mentioned thyroid cancer-related treatment means is 131 A method characterized by including, but not limited to, one or more of I treatment, surgical treatment, radiation therapy, molecular targeted therapy, chemotherapy, immunotherapy, targeted therapy, tyrosine kinase inhibitor (TKI) treatment, and traditional Chinese medicine treatment. Claim 13 A method according to any one of claims 1 to 12, characterized in that the effective dose of the radiolabeled cleavage-type Evans Blue-denatured fibroblast-activating protein inhibitor is 1.82 to 7.4 GBq / cycle. Claim 14 A method according to claim 13, characterized in that the administration cycle of the radiolabeled cleavage-type Evans Blue-denatured fibroblast-activating protein inhibitor is 1 to 52 cycles. Claim 15 A method according to claim 14, characterized in that the administration interval between each administration cycle is 7 to 84 days, and preferably, the administration interval between each administration cycle is 1 to 12 weeks. Claim 16 A pharmaceutical composition for treating thyroid cancer, characterized by comprising a radiolabeled truncated Evans Blue-denatured fibroblast-activating protein inhibitor or a truncated Evans Blue-denatured fibroblast-activating protein inhibitor according to any one of claims 1 to 3. Claim 17 A pharmaceutical composition according to claim 16, characterized in that the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent and / or additive. Claim 18 A combination drug composition for the treatment of thyroid cancer, characterized by comprising a truncated Evans Blue-denatured fibroblast-activating protein inhibitor according to any one of claims 1 to 3, a radiolabeled truncated Evans Blue-denatured fibroblast-activating protein inhibitor, or a pharmaceutical composition according to any one of claims 16 to 17. Claim 19 A reagent kit for treating thyroid cancer, characterized by comprising a radiolabeled truncated Evans Blue-denatured fibroblast-activating protein inhibitor or a truncated Evans Blue-denatured fibroblast-activating protein inhibitor according to any one of claims 1 to 3. Claim 20 Application of a radiolabeled truncated Evans Blue fibroblast-activated protein inhibitor in the manufacture of a drug for treating thyroid cancer, wherein the structure of the radiolabeled truncated Evans Blue fibroblast-activated protein inhibitor consists of a truncated Evans Blue fibroblast-activated protein inhibitor and a radionuclide, and wherein the truncated Evans Blue fibroblast-activated protein inhibitor is a compound whose structure is represented by formula (I) or a tautomer, meso, racemic mixture, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof. Claim 21 In paragraph 20, the above radionuclides are C-11, N-13, O-15, F-18, Na-24, P-32, P-33, K-42, Sc-43, Sc-44, Sc-47, Cr-51, Mn-51, Fe-52, Mn-52, Mn-52m, Co-55, Co-57, Fe-59, Co-60, Cu-62, Cu-64, Cu-67, Ga-67, Ga-68, As-72, Br-75, Se-75, Br-76, As-77, Rb-82m, Sr-83, Y-86, Y-88, Zr-89, Sr-89, In-90, Y-90, Tc-94, Mo-99, Tc-99m, Pd-103, Rh-105, Ru-106, Pd-109, In-110, In-111, Ag-111, I-120, I-123, I-124, I-125, I-131, Xe-133, Cs-137, Pr-142, Pr-143, Tb-149, Tb-151, Gd-152, Gd-153, Sm-153, Gd-154, Gd-155, Gd-156, Gd-157, Gd-158, Tb-161, Dy-165, Dy-166, Ho-166, Er-169, Yb-169, Lu-177, Yb-177, Re-186, Re-188, Re-189, Ir-192, Ir-194, An application characterized by being selected from any one of Au-198, Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, and Th-227. Claim 22 An application according to any one of claims 20 to 21, wherein the radiolabeled cleavage-type Evans Blue-denatured fibroblast-activating protein inhibitor is a compound whose structure is represented by formula (II) or a tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof.

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