Method for treating thyroid cancer by using fibroblast activation protein inhibitor modified with radiolabeled truncated evans blue

Abstract

Disclosed is a method for treating thyroid cancer by using a fibroblast activation protein inhibitor modified with radiolabeled truncated Evans blue. The drug demonstrates good safety and tolerability in thyroid cancer patients, offering excellent therapeutic prospects in the treatment of thyroid cancer.

Description

Method for treating thyroid cancer using radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor Technical Field

[0001] The present invention relates to the field of radiopharmaceuticals, and in particular to a method for treating thyroid cancer by utilizing a radioactively labeled truncated Evans blue-modified fibroblast activation protein inhibitor. Background Art

[0002] Thyroid cancer is a malignant tumor that originates from the follicular or parafollicular epithelial cells of the thyroid gland and is the most common malignant tumor of the head and neck. In recent years, the incidence of thyroid cancer has increased rapidly worldwide. According to the "IARC Biennial Report 2020-2021" released by the International Agency for Research on Cancer (IARC), an agency of the World Health Organization (WHO), approximately 580,000 new cases of thyroid cancer were diagnosed worldwide in 2020, ranking it 11th among all cancers in incidence. It is projected to become the fourth most common cancer in incidence around 2030. Based on tumor origin and differentiation, thyroid cancer can be divided 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). PTC is the most common, accounting for approximately 90% of all thyroid cancers. Different pathological types of thyroid cancer exhibit significant differences in their pathogenesis, biological behavior, histological morphology, clinical manifestations, treatment, and prognosis. Most DTC patients have a good prognosis after standardized treatment, but approximately 23% still develop distant metastases. Approximately one-third of these patients with distant metastases experience degenerative changes in tumor cell morphology and function during the natural course of the disease or during treatment, resulting in a loss of iodine uptake and ultimately developing iodine-refractory DTC (RAIR-DTC). The survival of patients with RAIR-DTC is significantly shorter than that of patients with good iodine uptake, with an average survival of only 3-5 years and a 10-year survival rate of approximately 10%. Tyrosine kinase inhibitors (TKIs) are currently the standard treatment strategy for metastatic RAIR-TC (mRAIR-TC) with advanced disease. However, for patients whose disease progresses despite TKI therapy, clinical treatment presents significant challenges.

[0003] Cancer-associated fibroblasts (CAFs), a stromal cell population with diverse cell origins, phenotypes, and functions, are a crucial component of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion, and metastasis, as well as extracellular matrix (ECM) remodeling and even chemoresistance. Fibroblast activation protein-α (FAP), aberrantly expressed in cancer-associated fibroblasts within the tumor microenvironment, has been recognized as a potential target for tumor imaging and therapy. In recent years, various radionuclide-labeled quinoline FAP inhibitors (FAPIs) have been developed and, while being used for imaging FAP-positive tumors, have also been successfully used in tumor-targeted radioligand therapy (RLT). Directly modifying the structure of FAPIs to enhance tumor uptake and retention while minimizing their accumulation in non-target tissues is an optimal approach for developing therapeutic radiopharmaceuticals. Unfortunately, quinoline FAPI probes, including FAPI-02, FAPI-04, and FAPI-46, have shown rapid blood clearance and poor tumor retention in animal models and subjects, which greatly limits their further application as diagnostic and therapeutic probes. Evans blue (EB) is a promising albumin-binding group. After the targeting molecule is coupled with an EB derivative, its blood circulation time is significantly prolonged, thereby increasing the drug's retention time in the tumor. Recently, some EB-modified FAPI (EB-FAPI) radiopharmaceuticals have shown more significant tumor inhibition 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.), but related studies are currently in the preclinical research stage. Therefore, there is a huge unmet clinical need in the field of renal cell carcinoma diagnostic imaging, both in China and globally.

[0004] Chinese patent publication number CN114369084A discloses a radiolabeled, truncated Evans blue-modified fibroblast activation protein inhibitor. This patented radiolabeled, truncated Evans blue-modified fibroblast activation protein inhibitor exhibits a significantly prolonged circulation half-life and enhanced tumor uptake, enrichment, and retention—performance not currently possessed by other FAPI imaging agents. Further preclinical animal and clinical studies have demonstrated its potential for application in radionuclide therapy and imaging of tumors with high FAPI expression, further advancing its application in the treatment of thyroid cancer.

[0005] Summary of the Invention

[0006] In the real world, it is surprising to find that the radiolabeled truncated Evans blue modified fibroblast activation protein inhibitor provided by the present invention (especially 177 Lu-EB-FAPI, the present invention is also called 177 Lu-LNC1004) has shown good safety performance and therapeutic potential in the treatment of thyroid cancer patients (especially those with mRAIR-TC progression after TKIs treatment), and has great therapeutic application prospects.

[0007] Specifically, the present invention provides a method for treating thyroid cancer, comprising administering a therapeutically effective amount of a radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor to a patient suffering from thyroid cancer, wherein the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor comprises a truncated Evans blue-modified fibroblast activation protein inhibitor and a radionuclide, and the truncated Evans blue-modified fibroblast activation protein inhibitor is a compound represented by formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

[0008] Furthermore, the radionuclide is selected from 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, ln-9 0. 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, Au-198, Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, Th-227.

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

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

[0011] Furthermore, the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is a compound having a structure as shown in formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

[0012] According to the differences in tumor origin and differentiation, the above-mentioned 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).

[0013] According to the histological classification of thyroid tumors, the above-mentioned thyroid cancers are primary epithelial tumors, primary non-epithelial tumors or secondary tumors.

[0014] Furthermore, the thyroid cancer is iodine-refractory differentiated thyroid cancer (RAIR-TC), and the definition of iodine-refractory thyroid cancer (RAIR-TC) can refer to the "Consensus on the Diagnosis, Treatment and Management of Iodine-Refractory Differentiated Thyroid Cancer" (2019 edition) or other standards / consensus / guidelines.

[0015] Furthermore, the thyroid cancer is metastatic RAIR-TC (mRAIR-TC) in the advanced stage of the disease.

[0016] Furthermore, the patient is a mammal.

[0017] Furthermore, the mammal is preferably a human.

[0018] Furthermore, the human being is an adult or a child.

[0019] Preferably, the age stratification of children can be based on the age stratification recommendations in ICH (International Council for Harmonization) E11: premature newborns, full-term newborns (0-27 days), infants (28 days to 23 months), children (2-11 years old) and adolescents [12 to 16-18 years old (depending on different regions)], or the age stratification in clinical research can be comprehensively considered in combination with drug characteristics and developmental physiology and pharmacology of pediatric populations.

[0020] Furthermore, the patient may or may not have received thyroid cancer-related treatments in the past.

[0021] Furthermore, the aforementioned thyroid cancer-related treatments include but are not limited to the following: 131 One or more of I therapy, surgical treatment, radiotherapy, molecular targeted therapy, chemotherapy, immunotherapy, targeted therapy, tyrosine kinase inhibitor (TKI) treatment, and traditional Chinese medicine treatment.

[0022] In some preferred embodiments, the patient has previously received 131 I treatment; in other preferred embodiments, the patient has previously received thyroid cancer-related surgical treatment; in other preferred embodiments, the patient has previously received thyroid cancer-related radiotherapy; in other preferred embodiments, the patient has previously received thyroid cancer-related molecular targeted therapy; in other preferred embodiments, the patient has previously received thyroid cancer-related chemotherapy; in other preferred embodiments, the patient has previously received thyroid cancer-related immunotherapy; in other preferred embodiments, the patient has previously received thyroid cancer-related targeted therapy; in other preferred embodiments, the patient has previously received thyroid cancer-related TKI treatment; in other preferred embodiments, the patient has previously received thyroid cancer-related traditional Chinese medicine treatment. In other preferred embodiments, the patient has previously received any combination of any of the above-mentioned treatment methods. It is understandable that the above-mentioned thyroid cancer-related treatment methods are the commonly used treatment methods in the prior art or those treatment methods / schemes known to those skilled in the art. Exemplary thyroid cancer-related treatment methods / schemes include but are not limited to those exemplified in the "Guidelines for the Diagnosis and Treatment of Thyroid Cancer" (2022 edition).

[0023] In some preferred embodiments, exemplary surgical treatments include, but are not limited to, ipsilateral lobectomy and isthmus resection, extended isthmus resection, total thyroidectomy, and resection of other affected structures and organs.

[0024] 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, and the like.

[0025] Furthermore, the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor of the present invention is administered by intravenous injection, subcutaneous injection, or intramuscular injection.

[0026] Furthermore, the effective dosage of the radiolabeled truncated Evans blue modified fibroblast activation protein inhibitor is 1.82-7.4 GBq / cycle (such as 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 7, 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, 3.7474、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, 7.1 7.2, 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 an interval selected from any of the above values).

[0027] In some preferred embodiments, the effective dosage of the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is 2.22 GBq / cycle.

[0028] The effective dosage of the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is 3.33 GBq / cycle.

[0029] The effective dosage of the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is 4.44 GBq / cycle.

[0030] Furthermore, the administration cycle of the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is 1-52 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).

[0031] Furthermore, the dosing interval between each dosing cycle is 7-84 days (e.g., 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, 2, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 days).

[0032] Furthermore, the dosing interval between each dosing cycle can also be 1-12 weeks (such as 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks).

[0033] The present invention also provides a pharmaceutical composition for treating thyroid cancer, which comprises the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor or the truncated Evans blue-modified fibroblast activation protein inhibitor described above, wherein the thyroid cancer is preferably as described in the above definition and will not be repeated here.

[0034] Furthermore, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent and / or additive.

[0035] The present invention also provides a combination pharmaceutical composition for treating thyroid cancer, wherein the combination pharmaceutical composition comprises any of the above-mentioned truncated Evans blue-modified fibroblast activation protein inhibitors, the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitors, or any of the above-mentioned pharmaceutical compositions.

[0036] Furthermore, the combination pharmaceutical composition also contains other drugs, which can be selected and adjusted according to current medical methods and the patient's condition during the clinical process. Therefore, it can be understood that, based on the premise that the truncated Evans blue-modified fibroblast activation protein inhibitor or the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor provided by the present invention or the pharmaceutical composition described in any of the above items has therapeutic prospects for thyroid cancer patients, the selection of other drugs in the combination pharmaceutical composition should not be regarded as a limitation of the present invention.

[0037] The present invention also provides a kit for treating thyroid cancer, which comprises the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor or the truncated Evans blue-modified fibroblast activation protein inhibitor described above, wherein the thyroid cancer is preferably as described in the above definition and will not be repeated here.

[0038] The present invention also provides a use of a radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor in the preparation of a medicine for treating thyroid cancer.

[0039] Furthermore, the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor structure consists of a truncated Evans blue-modified fibroblast activation protein inhibitor and a radionuclide, and the truncated Evans blue-modified fibroblast activation protein inhibitor is a compound represented by formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

[0040] Similarly, the thyroid cancer is preferably as described above, and will not be repeated here.

[0041] Furthermore, the radionuclide is selected from 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, ln-9 0. 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, Au-198, Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, Th-227.

[0042] Furthermore, the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is a compound having a structure as shown in formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

[0043] The present invention first proves that the truncated Evans blue modified fibroblast activation protein inhibitor provided by the present invention (especially 177 Lu-LNC1004) has a good safety and tolerability profile in patients with thyroid cancer, and preliminary data on tumor response are encouraging, suggesting that the truncated Evans blue-modified fibroblast activation protein inhibitor (especially 177 Lu-LNC1004) will have excellent therapeutic prospects in the treatment of thyroid cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1177 Biodistribution and dose determination results (% absorption) of normal organs in patients treated with Lu-LNC1004;

[0045] Figure 2 177 Biodistribution and dose determination results of normal organs in patients treated with Lu-LNC1004 (effective half-life, in hours);

[0046] Figure 3 177 Biodistribution and dose determination results of normal organs of patients treated with Lu-LNC1004 (residence time, in hours);

[0047] Figure 4 shows 177 Exposure of the three dose groups at 1m and 3m from 4 to 168h after Lu-LNC1004 treatment. DETAILED DESCRIPTION

[0048]

definition

[0049] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as they may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0050] Preferably, the terms used herein are defined in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, HGW, Nagel, B. and Klb1, Hb, eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

[0051] Unless the context requires otherwise, throughout the specification and the claims that follow, the word "comprise" and variations such as "comprising" and "containing" will be understood to implicitly include the integers, steps, materials, components, or ingredients, compositions, etc., or groups of integers, steps, materials, components, or ingredients, compositions, but not to exclude any other integers, steps, materials, components, or ingredients, compositions, or groups of integers, steps, materials, components, or ingredients, compositions. In the following paragraphs, the same aspects of the invention will be defined in more detail. Each aspect so defined can be combined with any other one or more aspects unless there is a clear indication to the contrary. In particular, any feature that is optional, preferred or advantageous can be combined with any other one or more features that are optional, preferred or advantageous.

[0052] Some documents are cited throughout this specification. Each document cited herein (including but not limited to all patents, patent applications, scientific publications, documents, articles, press releases, manufacturer's instructions, operating instructions, etc.) is incorporated herein by reference in its entirety, whether above or below. Nothing herein shall be construed as an admission that the present invention is not entitled to such disclosures as prior inventions. Certain documents cited herein are identified as "incorporated by reference." In the event that the definitions or teachings in such incorporated references conflict with the definitions or teachings described in this specification, the text of this specification shall prevail.

[0053] The elements of the present invention are described below. These elements are listed together with specific embodiments. However, it should be understood that they can be combined in any manner and in any number to form other embodiments. The various described embodiments and preferred embodiments should not be interpreted as limiting the present invention to only the embodiments clearly described. This description should be understood to support and encompass solutions that combine the clearly described embodiments with any number of disclosed and / or preferred elements. In addition, it should be understood that any arrangement and combination of all elements described in this application are disclosed in the specification of this application, unless the context indicates otherwise.

[0054] The term "thyroid cancer," as used herein, refers to a malignant tumor that originates in the follicular or parafollicular epithelium of the thyroid gland. Symptoms of thyroid cancer include enlarged thyroid glands or nodules. These nodules are irregular in shape, adherent to surrounding tissues, and gradually increase in size. They are firm and have ill-defined borders. Initially, they may move up and down with swallowing, but later on, they often become immobile. If cervical lymph node metastasis is present, palpation of the cervical lymph nodes may be performed.

[0055] As used herein, a "therapeutically effective amount" or "effectively administered amount" refers to the total amount of each active ingredient sufficient to demonstrate a meaningful patient benefit. When applied to an individual active ingredient administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to the combined amount of the active ingredients (whether administered in combination, serially or simultaneously) that results in a therapeutic effect.

[0056] As used herein, "treating" refers to: (i) inhibiting a disease, disorder, or condition, i.e., preventing its development; and (ii) alleviating a disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition. In some embodiments, the present invention also encompasses the use of a compound according to any of the disclosed embodiments for preventing the onset of a disease, disorder, or condition in a patient who may be susceptible to the disease, disorder, and / or condition but has not yet been diagnosed with the disease, disorder, and / or condition.

[0057] The term "pharmaceutically acceptable" as used herein refers to a compound or agent that is compatible with the compounds of the present invention and does not interfere with and / or substantially reduce the diagnostic or therapeutic activity thereof. Pharmaceutically acceptable carriers preferably have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the subject (patient) to be treated.

[0058] The "pharmaceutically acceptable salts" of the present invention can be prepared by conventional methods, such as by reacting any free base and / or acid of the dual-targeted compound of the present invention with at least a stoichiometric amount of a desired salt-forming acid or base, respectively. Pharmaceutically acceptable salts of the present invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, benzathine penicillin, diethanolamine, ethanolamine, and tromethamine. Pharmaceutically acceptable salts according to the present invention also include salts derived from organic or inorganic acids (such as trifluoroacetate). Suitable anions include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, edisylate, etopoate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, methanesulfonate, methylbromide, methylsulfate, naphthenate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, toluenesulfonate, and triethiodide.

[0059] The "patient" described herein generally includes humans and non-human animals, and preferably includes mammals (e.g., non-human primates, including marmosets, tamarins, spider monkeys, owl monkeys, vervet monkeys, squirrel monkeys, and baboons, macaques, chimpanzees, orangutans, gorillas; cows; horses; sheep; pigs; chickens; cats; dogs; mice; rats; rabbits; guinea pigs, etc.), including chimeric 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 "pharmaceutical composition" as used herein refers to a mixture of one or more compounds according to the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components (such as physiologically / pharmaceutically acceptable carriers and excipients). The purpose of a pharmaceutical composition is to promote the administration of the compound to an organism and the absorption of the active ingredient, thereby exerting biological activity. It is understood that the pharmaceutical composition may also contain necessary, pharmaceutically acceptable carriers, excipients, diluents and / or additives, and the "carriers, excipients, diluents and / or additives" and each component may exhibit different functional effects. Those skilled in the art can generally select appropriate pharmaceutically acceptable carriers, diluents and / or additives based on the formulation of the pharmaceutical composition / preparation, including but not limited to fillers, bulking agents, carriers, disintegrants, binders, lubricants, glidants, coatings, solvents and cosolvents, buffers, preservatives, adjuvants, antioxidants, wetting agents, defoaming agents, thickeners, sweeteners, flavorings and moisturizers, etc.

[0061] The pharmaceutical composition (or preparation) containing the compound provided by the invention can be in any suitable form. For example, it can be a solution or powder form, with or without a diluent to prepare an injectable suspension, and can include additional ingredients, including but not limited to a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier can be saline, water, lactic acid, mannitol or a combination thereof (including but not limited to). The excipient of the present invention promotes that the dual-targeted compound provided by the invention and / or the heterodimer radioactive compound are processed into a pharmaceutically acceptable preparation. Appropriate preparation depends on the selected route of administration. Additional details regarding the carriers, excipients, diluents and / or additives described herein can be found, for example, in 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; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), the disclosures of which or the prior art recognition and definitions of which are incorporated herein by reference.

[0062] The present invention involves the 177 Lu-LNC1004" is prepared with reference to the preparation disclosed in publication number CN114369084A. In some specific embodiments, the " 177 The compound “Lu-LNC1004” that is not labeled with a radionuclide (or referred to as LNC1004, which can also be prepared by referring to the preparation disclosed in Publication No. CN114369084A) is a compound having the following structure or its tautomers, mesoforms, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof:

[0063] In other specific embodiments, the “ 177 Lu-LNC1004" is based on LNC1004 177 Lu radioactive label; in other specific embodiments, the " 177Lu-LNC1004" is a compound having the following structure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof:

[0064] [Specific embodiment]

[0065] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0066] This example is a single-center, open-label, non-randomized, first-in-human dose-escalation study discovered by researchers in a real-world setting.

[0067] Inclusion criteria

[0068] (1) Adult patients (over 18 years old) with histologically confirmed metastatic thyroid cancer (including DTC, MTC, and ATC) who have 131 I. Patients with the pathological subtype of DTC diagnosed as mRAIR-DTC after treatment;

[0069] (2) unresectable tumors;

[0070] (3) disease progression after TKIs treatment; and

[0071] (4) 68 Ga-FAPI-46 PET / CT showed tumor lesions with increased radiotracer uptake (defined as a maximum standardized uptake value ≥ 10 in more than 50% of tumor lesions).

[0072]

Exclusion criteria

[0073] (1) Serum creatinine level >150 μmol / L;

[0074] (2) hemoglobin level <8.0 g / dL;

[0075] (3) White blood cell count <2.0×10 9 / L;

[0076] (4) Platelet count <50×10 9 / L;

[0077] (5) total bilirubin level >3 times the upper limit of the normal range and serum albumin level <2.0 g / dL;

[0078] (6) cardiac insufficiency, including carcinoid valvular heart disease, severe allergy, or allergy to radiocontrast agents;

[0079] (7) Claustrophobia;

[0080] (8) Pregnancy or breastfeeding.

[0081] Study plan and dosing regimen

[0082] A classic 3+3 dose-escalation design was used, with the initial dose set at 2.22GBq (60mCi), followed by a 50% dose increase in each group until dose-limiting toxicity (DLT) was observed. Initially, the first-dose group (2.22GBq / cycle) included three patients. If none of the three patients in a cohort experienced DLT (dose-limiting toxicity), three more patients were recruited at the next higher dose level. If one of the three patients experienced DLT at a certain dose level, three more patients were enrolled at the same dose level. The highest dose at which no more than one of the six patients experienced DLT was the maximum tolerated dose (MTD). Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, 5th edition (CTCAE 5.0). DLT was defined as any adverse event related to 177 Lu-LNC1004-related AEs ≥ Grade 3 (G3).

[0083] Patient injection 177 No fasting, special diet, or other special preparation is required on the day of Lu-LNC1004. 4 mg of ondansetron is taken before treatment to prevent nausea and vomiting. 177 Lu received intravenous fluids (1 liter of 0.9% saline) 30 minutes before treatment. 177 Lu-LNC1004 was diluted in 100 ml of 0.9% saline and administered slowly over 20-30 minutes via intravenous infusion. Patients' symptoms and vital signs were monitored before, during, and after treatment. Treatment was planned for a maximum of two cycles, with a six-week interval between cycles.

[0084] Primary and Secondary End Points

[0085] The primary endpoint was to assess 177 Safety and MTD of Lu-LNC1004 in patients with mRAIR-TC. Secondary endpoints were dose determination and 177 Preliminary efficacy of Lu-LNC1004.

[0086] Patient information and previous treatment history

[0087] 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 previous treatment history are as follows:

[0088] Patient 1: 52 years old, male, pathological subtype PTC (BRAFV600E + ), previously received: total thyroidectomy, 131 I treatment (3 courses, cumulative dose of 20.35 GBq), TKI treatment (Sorafenib), and 125 I seed implantation;

[0089] Patient 2: 53 years old, female, case subtype is PTC, previously received: total thyroidectomy (with neck lymph node dissection, tracheotomy), 131 I treatment (2 courses, cumulative dose of 16.65 GBq), TKI treatment (Sorafenib);

[0090] Patient 3: 58 years old, male, case subtype is PTC, previously received: total thyroidectomy, 131 I treatment (4 courses, cumulative dose of 25.90 GBq), TKI treatment (Anlotinib);

[0091] Patient 4: 35 years old, male, case subtype PTC (BRAF V600E - ), who had previously undergone: total thyroidectomy (with neck lymph node dissection, tumor resection and right clavicle internal fixation), 131 I treatment (4 courses, cumulative dose of 24.05 GBq), TKI treatment (Apatinib, Anlotinib);

[0092] Patient 5: 42 years old, male, case subtype is PTC, previously received: total thyroidectomy (with tumor resection and vertebral fixation), 131 I treatment (6 courses, cumulative dose of 59.20 GBq), TKI treatment (Lenvatinib), and external beam radiotherapy (EBRT);

[0093] Patient 6: 55 years old, female, case subtype MTC (BRAF V600E - ,RET - ), previously received: total thyroidectomy, TKI treatment (Anlotinib), not received 131 I treatment;

[0094] Patient 7: 48 years old, female, case subtype is FTC, previously received: total thyroidectomy (with tumor resection and vertebral fixation), 131 I treatment (5 courses, cumulative dose of 44.40 GBq), TKI treatment (Sorafenib);

[0095] Patient 8: 72 years old, female, case subtype: primary tumor is PTC, mediastinal lymph node metastasis is ATC, previous treatment: total thyroidectomy (and endobronchial stent placement), TKI treatment (Anlotinib), no treatment 131 I treatment;

[0096] Patient 9: 32 years old, female, case subtype is PTC, previously received: total thyroidectomy (and neck lymph node dissection), 131 I treatment (5 courses, cumulative dose of 37.00 GBq), TKI treatment (Sorafenib);

[0097] Patient 10: 56 years old, female, case subtype is PTC, previously received: total thyroidectomy (and neck lymph node dissection), 131 I treatment (2 courses, cumulative dose of 7.40 GBq), TKI treatment (Sorafenib);

[0098] Patient 11: 64-year-old female, case subtype PTC, previously received: total thyroidectomy, 131I treatment (2 courses, cumulative dose of 12.95GBq), TKI treatment (sorafenib);

[0099] Patient 12: 33-year-old female, case subtype PTC, previously received: total thyroidectomy, 131I treatment (4 courses, cumulative dose of 29.60GBq), TKI treatment (Anlotinib);

[0100] Safety evaluation

[0101] Patient 4 developed swelling of the superficial cervical lymph nodes and clavicle metastases 1 hour after injection, which persisted for several days and subsided on the 7th day, followed by hemorrhage and necrosis of the clavicle. In patients 5 and 6, the pain symptoms of the bone metastases worsened on the second day after treatment. Patient 5 took nonsteroidal anti-inflammatory drugs, and his pain symptoms persisted for 6 days but then gradually subsided. Patients 2 and 4 also experienced transient fatigue symptoms. Apart from this, no life-threatening adverse events (AEs) were observed. It is worth mentioning that patient 8 showed improvement in self-reported physical fitness and quality of life after treatment. In addition, although blood toxicity was observed in groups A, B, and C, it was reversible after treatment, and no patient experienced hepatotoxicity or nephrotoxicity.

[0102]

Full body scan

[0103] One hour after taking the medicine, 177 Lu-LNC1004 has a relatively high uptake in the blood pool, showing strong signals in the heart region and major blood vessels. 177 Lu-LNC1004 uptake increased in the liver, spleen, and kidneys, and was excreted into the bladder through the kidneys. One hour after administration, 177 Lu-LNC1004 uptake by tumors was clearly observed. In addition to the increased activity in the blood circulation, 177 The in vivo biodistribution pattern of Lu-LNC1004 was similar to that before and after treatment. 68 Ga-FAPI PET / CT was the same. In addition, post-treatment whole-body and SPECT / CT scan analysis showed that all patients had 177 Lu-LNC1004 was clearly taken up and retained in tumor lesions.

[0104] Dosimetry Assessment

[0105] Determined 177 The dosimetric parameters of Lu-LNC1004 after administration, especially the percentage of absorption in the whole body, blood pool, liver, kidney and metastatic sites, effective half-life, residence time and average absorbed dose, were analyzed. 177 The systemic absorption of Lu-LNC1004 was 100%, with the curves decreasing at a nearly constant rate. In addition, the curves for the blood pool and liver showed an initial rapid washout between the first scan and 24 hours after dosing, followed by a slower decline. 177 The initial uptake rate and elution rate of Lu-LNC1004 decreased slowly. 177 The effective half-lives of Lu-LNC1004 in the whole body, blood pool, liver and kidney were 90.20±7.68 hours, 74.35±6.28 hours, 82.73±6.64 hours and 101.00±6.40 hours, respectively. 177 The kinetics and effective half-life of Lu-LNC1004 in the salivary glands, pancreas, spleen, and bladder are shown in Figures 1 and 2.

[0106] Residence time represents the total amount of disintegration that occurs per unit of administered activity during the integrated time. 177The residence times of Lu-LNC1004 in the 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 mean absorbed doses for the body, heart wall, red pulp, liver, and kidney were 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 effective whole-body dose of Lu-LNC1004 was 0.17 ± 0.04 mSv / MBq. The residence times and mean absorbed doses of other organs are shown in Figure 3 and Table 1.

[0107] Table 1 Intravenous administration 177 Absorbed dose after Lu-LNC1004

[0108] In terms of tumor lesions, the initial 177 Lu-LNC1004 uptake was 0.33% [0.22-0.70%], with bone metastases (0.30% [0.22-0.71%]) having slightly lower uptake than lymph node metastases (0.37% [0.26-0.70%]) and other metastases (0.37% [0.16-1.38%]). The washout rate in metastases decreased slowly, similar to that in 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 metastases (98.82±11.89h) was slightly longer than that in lymph node metastases (91.77±9.27h) and other metastases (87.77±5.12h). 177 The residence time of Lu-LNC1004 in metastatic lesions (0.42 h [0.29-0.99 h]) was shorter than that in the above organs, but its average absorbed dose (8.50±12.36 Gy / GBq) was the highest (range, 1.32-58.72 Gy / GBq). Specifically, the residence times in bones, lymph nodes, and other metastases 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 mean absorbed doses were 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).

[0109] The radiation emission curves are shown in Figure 4. At a distance of 1 meter from the patient, the average radiation doses recorded 4 hours after treatment for the three groups 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). At a distance of 3 meters from the patient, the average radiation doses for the three groups over the 4-hour period 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). The radiation emission curves gradually decreased over time, so that 48 hours after administration, the average radiation doses for the three groups at 1 and 3 meters were 4.22 ± 0.42 μSv / h (Group A), 7.00 ± 1.34 μSv / h (Group B), and 2.02 ± 0.15 μSv / h (Group C), respectively. 00±1.34μSv / h(Group B), 9.91±1.42μSv / h(Group C) and 1.09±0.18μSv / h(Group A), 1.46±0.19μSv / h(Group B), 1.95±0.15μSv / h(Group C).

[0110]

Efficacy

[0111] Six weeks after the end of the second cycle, all patients were evaluated according to the Clinical Response Evaluation Index for Solid Tumors (RECIST1.1). The results showed that three patients (patients 4, 5, and 6) had partial responses, and the other seven patients had stable disease. 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 were significantly reduced after two cycles. It is worth noting that the obstructive pneumonia caused by the enlargement of the left hilar lymph node metastasis was relieved. In patient 5, the target lesions of liver metastases and non-target lesions in the pleural effusion had regressed, and the sum of the longest diameters (SLD) of the target lesions of bone and lung metastases also decreased.

[0112]

in conclusion

[0113] This prospective study demonstrates for the first time 177 The feasibility of Lu-LNC1004RLT in patients with mRAIR-TC whose disease progressed after TKIs was investigated, and first-in-human data showed a favorable safety profile with few serious AEs.

[0114] So far, 131 I has been the most commonly used adjuvant therapy for metastatic DTC. However, patients with advanced DTC may 131 In addition, medullary thyroid cancer and asexual thyroid cancer cannot respond to iodine metabolism due to the lack of expression of iodine metabolism-related genes. 131Although TKIs for the treatment of mRAIR-TC have experienced rapid development in the past decade, drug resistance remains a major obstacle to improving prognosis. Currently, there are no other treatment options for patients with advanced cancer who have exhausted or refused conventional treatment options. 68 Data from mRAIR-TC patients screened with Ga-FAPI-46PET / CT showed that 177 Lu-LNC1004 is based on 131 Patients who are still in the stage of disease progression after I therapy and / or TKIs treatment and / or other treatment methods can still show good treatment effects, which also shows that 177 Lu-LNC1004 is a potential approach for the treatment of mRAIR-TC. In addition, in this trial, although patients received only two treatment cycles and follow-up was limited, 83% of patients were observed to have radiographic disease control and signs of tumor response, which is better than 177 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, the results of this study were 177 Lu-LNC1004's initial tumor response was superior to that of previously used 177 Lu-FAP-2286 is studied and used in patients with various adenocarcinomas. 90 A study of 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.).

[0115] Although previous studies have used the therapeutic radionuclide FAPI-46 for FAP-targeted radionuclide therapy of various advanced cancers, the half-life of the radiotherapy drug in vivo may not be long enough to be adequately absorbed and retained by the tumor. 177 The effective half-life of Lu-LNC1004 (whole body) was 90.20±7.68h, which was longer than 177 The effective half-life of Lu-FAP-2286 is 35.00 ± 9.00 h (see 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) 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 reaches 0.17±0.04mSv / MBq. 177 6.54 times that of Lu-FAPI-46. In addition, although 177 The distribution of Lu-LNC1004 in the liver and kidney was slightly increased, respectively. 177 2.13-fold and 1.49-fold of Lu-FAPI-46 (see Assadi M, Rekabpour SJ, Jafari E, Divband G, Nikkholgh B, Amini H, et al. Feasibility and therapeutic potential of 177 Lu-fibroblast activation protein inhibitor-46 for patients with relapsed or refractory cancers: a preliminary study. Clin Nucl Med 2021; 46(11): e523-e30.), but no patient developed liver or kidney toxicity. This suggests that the increased radiation dose due to prolonged blood circulation time is acceptable.

[0116] In addition, the average radiation dose of the three groups of patients at 1 meter and 3 meters 4 hours after treatment was lower than 131 I treatment, which is also below the Nuclear Regulatory Commission's release standards (see Nuclear Regulatory Commission 2019 Regulatory Guide 8.39: Release of Patients Administered Radioactive Materials[cited 2023Feb 21].). 177 Patients treated with Lu-LNC1004 received less than 9 μSv / h of radiation at 1 meter 4 hours after administration, which is lower than that of patients treated with Lu-LNC1004. 177 Lu-PSMA-617 and 177 Discharge criteria during Lu-DOTATATE treatment (see 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. NANETS / SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-DOTATATE. J Nucl Med 2019;60(7):937-43.). Although the radiation dose at 1 meter in the 4.99 GBq group was higher than this threshold within 4 hours after treatment, 48 hours was sufficient for the radiation dose to drop below 9 μSv / h. Although the length of time varies, it is generally believed that 3 days is sufficient to reduce the radiation dose to below 9 μSv / h. 177 Public activity resumed after Lu-LNC1004 exposure.

[0117] In summary, the present invention demonstrates for the first time 177The safety and feasibility of Lu-LNC1004RLT in patients with thyroid cancer (using mRAIR-TC patients as an example) with dose escalation. Overall, all patients tolerated it well. 177 Lu-LNC1004 high-dose irradiation of mRAIR-TC lesions. Preliminary data on tumor responses are encouraging and support the 177 Potential therapeutic role of Lu-LNC1004RLT in the treatment of mRAIR-TC.

[0118] The above description is merely a preferred embodiment, which is intended to be illustrative and non-limiting of the combinations of features necessary to implement the present invention. The titles provided are not intended to limit the various embodiments of the present invention. Terms such as "comprising," "including," and "including" are not intended to be limiting. In addition, unless otherwise indicated, the absence of a numeral modifier includes the plural form, and "or" and "or" mean "and / or." Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0119] All disclosures and patents mentioned in this application are incorporated herein by reference. Without departing from the scope and spirit of the present invention, multiple modifications and variants of the described method and composition of the present invention will be apparent to those skilled in the art. Although the present invention has been described by specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, those multiple variants of the described pattern that are apparent to those skilled in the relevant art are intended to be included in the scope of the appended claims.

Claims

1. A method for treating thyroid cancer, characterized in that: The method comprises administering a therapeutically effective amount of a radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor to a patient suffering from thyroid cancer, wherein the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor structure consists of a truncated Evans blue-modified fibroblast activation protein inhibitor and a radionuclide, and the truncated Evans blue-modified fibroblast activation protein inhibitor is a compound having a structure as shown in formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof:

2. The method according to claim 1, characterized in that The radioactive nuclide is selected from 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, ln-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, G d-153, Sm-153, Gd-154, Gd-155, Gd-156, Gd-157, Gd-158, Tb-161, Dy-165, Dy-166, Ho-166, Any one of Er-169, Yb-169, Lu-177, Yb-177, Re-186, Re-188, Re-189, Ir-192, Ir-194, Au-198, Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, Th-227.

3. The method according to any one of claims 1 to 2, characterized in that: The radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is a compound having a structure as shown in formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof:

4. The method according to any one of claims 1 to 3, characterized in that: 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).

5. The method according to any one of claims 1 to 4, characterized in that: The thyroid cancer is a primary epithelial tumor, a primary non-epithelial tumor or a secondary tumor.

6. The method according to any one of claims 1 to 5, characterized in that: The thyroid cancer is iodine-refractory thyroid cancer (RAIR-TC); preferably, the thyroid cancer is metastatic RAIR-TC (mRAIR-TC) in the advanced stage of the disease.

7. The method according to any one of claims 1 to 6, characterized in that: The patient is a mammal.

8. The method according to claim 7, characterized in that The mammal is preferably a human.

9. The method according to claim 8, characterized in that The human being is an adult or a child.

10. The method according to any one of claims 1 to 9, characterized in that: The administration method is intravenous injection, subcutaneous injection, or intramuscular injection.

11. The method according to any one of claims 1 to 10, characterized in that: The patients may or may not have received thyroid cancer related treatments in the past.

12. The method according to claim 11, characterized in that The thyroid cancer related treatment methods include but are not limited to 131 One or more of I therapy, surgical therapy, radiotherapy, molecular targeted therapy, chemotherapy, immunotherapy, targeted therapy, tyrosine kinase inhibitor (TKI) therapy, and traditional Chinese medicine treatment.

13. The method according to any one of claims 1 to 12, characterized in that: The effective dosage of the radioactively labeled truncated Evans blue-modified fibroblast activation protein inhibitor is 1.82-7.4 GBq / cycle.

14. The method according to claim 13, characterized in that The administration cycle of the radioactively labeled truncated Evans blue-modified fibroblast activation protein inhibitor is 1-52 cycles.

15. The method according to claim 14, characterized in that The dosing interval between each dosing cycle is 7-84 days; preferably, the dosing interval between each dosing cycle is 1-12 weeks.

16. A pharmaceutical composition for treating thyroid cancer, characterized in that: The pharmaceutical composition comprises the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor or the truncated Evans blue-modified fibroblast activation protein inhibitor according to any one of claims 1 to 3.

17. The pharmaceutical composition according to claim 16, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent and / or additive.

18. A combined pharmaceutical composition for treating thyroid cancer, characterized in that: The combined pharmaceutical composition comprises the truncated Evans blue-modified fibroblast activation protein inhibitor described in any one of claims 1-3, the radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor, or the pharmaceutical composition described in any one of claims 16-17.

19. A kit for treating thyroid cancer, characterized in that: The kit comprises the radioactively labeled truncated Evans blue-modified fibroblast activation protein inhibitor or the truncated Evans blue-modified fibroblast activation protein inhibitor according to any one of claims 1 to 3.

20. Use of a radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor in the preparation of a drug for treating thyroid cancer, wherein: The radioactively labeled truncated Evans blue-modified fibroblast activation protein inhibitor structure consists of a truncated Evans blue-modified fibroblast activation protein inhibitor and a radionuclide, and the truncated Evans blue-modified fibroblast activation protein inhibitor is a compound as shown in formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof:

21. The use according to claim 20, characterized in that The radioactive nuclide is selected from 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, ln-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, G d-153, Sm-153, Gd-154, Gd-155, Gd-156, Gd-157, Gd-158, Tb-161, Dy-165, Dy-166, Ho-166, Any one of Er-169, Yb-169, Lu-177, Yb-177, Re-186, Re-188, Re-189, Ir-192, Ir-194, Au-198, Au-199, At-211, Pb-211, Bi-212, Pb-212, Bi-213, Ra-223, Ac-225, Fm-255, Th-226, Th-227.

22. The use according to any one of claims 20-21, characterized in that: The radiolabeled truncated Evans blue-modified fibroblast activation protein inhibitor is a compound having a structure as shown in formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof:

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