CN117224713A - 212 Use of Pb-DOTATATE in preparation of medicine for treating somatostatin receptor positive gastrointestinal pancreatic neuroendocrine tumor - Google Patents

Abstract

The present application discloses the use of a ²¹² Pb derivative of a somatostatin analog in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the ²¹² Pb derivative of the somatostatin analog The derivative is ²¹² Pb‑DOTATATE. The present application also provides the use of a ²¹² Pb derivative of a somatostatin analog derivative in preparing a medicament for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The present application also provides a composition for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. For the purposes described in this application, after intravenous injection of ²¹² Pb-DOTATATE into AR42J tumor-bearing mice, it was found that it has better anti-tumor efficacy than ¹⁷⁷ Lu.

Description

Use of 212Pb-DOTATATE in the preparation of drugs for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors

Technical Field

The present application relates to the field of medicine, and in particular to a use of ²¹² Pb-DOTATATE in the preparation of a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors.

Background Art

Neuroendocrine tumors originate from the neuroendocrine system and mainly occur in the stomach, intestines, and pancreas. Although it is a rare disease with an incidence of approximately 5.25 cases per 100,000 people, it is the second most common gastrointestinal malignancy and its incidence continues to rise. The symptoms and signs of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are not obvious, and the clinical manifestations are varied, making it easy for clinicians to misdiagnose and miss diagnoses, resulting in late discovery of most patients. When diagnosed, they have often reached local spread and/or distant metastasis, and the opportunity for radical surgery is lost. Subsequent treatment options are extremely limited, and the 5-year survival rate of patients is only 35%. Therefore, innovative therapies have become a life-saving straw for these patients.

Peptide receptor radionuclide therapy (PRRT) has been used to treat somatostatin receptor (SSTR)-positive NETs for more than 30 years. The earliest drug used was ¹¹¹ In-DTPA-octreotide, a cell-internalized SSTR receptor agonist. Although this compound can effectively relieve symptoms, it cannot meet the treatment needs due to the low energy of ¹¹¹ In. In addition, complications such as leukemia and myelodysplastic syndrome have also occurred in patients receiving treatment. In order to overcome these problems, ⁹⁰ Y-DOTATOC and ⁹⁰ Y-DOTATATE were successively proposed in the late 1990s. Compared with ¹¹¹ In, ⁹⁰ Y emits pure β rays, with a range of 1.2 cm in tissue and a maximum energy of 2284 KeV, but it is not recommended for continued use due to its nephrotoxicity and hematotoxicity. In contrast, the safer ¹⁷⁷ Lu is more suitable for smaller lesions and is used to treat GEP-NETs. As a relatively safe radioactive metal, research related to ¹⁷⁷ Lu has become the mainstream of PRRT. ¹⁷⁷ Lu-DOTATATE, a therapeutic product for GEP-NETs, was launched in the United States in 2018 under the trade name Lutathera. This is the first time that a radiotherapy drug has been approved for the treatment of this indication, which is a milestone. This approval is based on two key Phase III clinical trials. The results showed that some patients treated with Lutathera had tumors that shrank or completely disappeared, and the progression-free survival time was extended by 19.9 months compared with the control group. The risk of disease progression or death was reduced by 79%, with good safety, and significantly improved the health-related quality of life for these patients. Although the use of Lutathera treatment has achieved unprecedented achievements, the Lutathera treatment method still cannot meet people's requirements for patients' survival time and risk of death.

Summary of the invention

The purpose of the present application is to provide a use of ²¹² Pb-DOTATATE in gastroenteropancreatic neuroendocrine tumors (NETs) expressing somatostatin receptors (SSTRs). After intravenous injection of ²¹² Pb-DOTATATE into AR42J tumor-bearing mice, it was found that it has better anti-tumor efficacy than ¹⁷⁷ Lu.

The specific technical solutions of this application are as follows:

1. Use of a ²¹² Pb derivative of a somatostatin analogue in treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the ²¹² Pb derivative of a somatostatin analogue is ²¹² Pb-DOTATATE.

2. Use of a ²¹² Pb derivative of a somatostatin analogue derivative in the preparation of a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the ²¹² Pb derivative of the somatostatin analogue is ²¹² Pb-DOTATATE.

3. The use according to item 1 or 2, wherein the single dose of ^{the 212} Pb-DOTATATE is 1 μCi to 100 mCi per kg of subject body weight; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi to 100 mCi per kg of subject body weight per time.

4. The use according to item 1 or 2, wherein the single dose of the ²¹² Pb-DOTATATE is 1 μCi-10 mCi/kg body weight of the subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi to 10 mCi/kg body weight of the subject/time.

5. The use according to item 1 or 2, wherein the single dose of the ²¹² Pb-DOTATATE is 250 μCi-500 mCi/each subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 250 μCi-500 mCi/each subject/time.

6. The use according to item 1 or 2, wherein the single administration volume of the ²¹² Pb-DOTATATE is 1 mL-30 mL; or a single dose of the drug containing ²¹² Pb-DOTATATE can be provided to the subject at 1 mL-30 mL/subject/time, or

The administration concentration of the ²¹² Pb-DOTATATE is 1-30 mCi/mL.

7. The use according to item 1 or 2, wherein the administration frequency of the ²¹² Pb-DOTATATE is once every 3-16 weeks.

8. The use according to item 1 or 2, wherein the total dosage of ²¹² Pb-DOTATATE is 0.1 mCi-2Ci.

9. The use according to item 1 or 2, wherein the total administration volume of the ²¹² Pb-DOTATATE is 1 mL-300 mL.

10. The use according to item 1 or 2, wherein the ²¹² Pb-DOTATATE is administered by intravenous injection.

11. A composition for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the composition comprises a ²¹² Pb derivative of a somatostatin analog, and the ²¹² Pb derivative of a somatostatin analog is ²¹² Pb-DOTATATE.

In this application, DOTATATE can achieve ²¹² Pb labeling, and after labeling, the radiochemical purity (hereinafter referred to as RCP) can reach 98.68% after being tested by Radio-iTLC. After ²¹² Pb-DOTATATE is placed at 2-8°C for 2 hours, the RCP can reach 98.05%, and the in vitro stability meets the test requirements. Moreover, experiments have shown that ²¹² Pb-DOTATATE has better anti-tumor efficacy than the same dose of ¹⁷⁷ Lu-PSMA-617.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a curve showing the weight change over time of the experimental animals of the present application;

FIG. 2 is a curve showing the change of tumor volume over time in the experimental animals of the present application.

DETAILED DESCRIPTION

The present application is described in detail below. Although specific embodiments of the present application are shown, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

It should be noted that certain words are used in the specification and claims to refer to specific components. Those skilled in the art should understand that technicians may use different nouns to refer to the same component. This specification and claims do not use the difference in nouns as a way to distinguish components, but use the functional differences of components as the criterion for distinction. As mentioned throughout the specification and claims, "including" or "comprising" are open-ended terms and should be interpreted as "including but not limited to". The subsequent description of the specification is a preferred embodiment of the present application, but the description is based on the general principles of the specification and is not intended to limit the scope of the present application. The scope of protection of the present application shall be determined by the attached claims.

The present application provides a use of a ²¹² Pb derivative of a somatostatin analog in treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The ²¹² Pb derivative of a somatostatin analog is ²¹² Pb-DOTATATE.

The present application provides a use of a ²¹² Pb derivative of a somatostatin analog derivative in the preparation of a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors.

²¹² Pb and ²¹² Bi are a pair of parent and daughter radionuclides. The parent ²¹² Pb can obtain the daughter ²¹² Bi through β decay, which can undergo two-way decay and emit α and β particles in the process. ²¹² Bi has a shorter half-life of only 1.0h, while ²¹² Pb has a half-life of 10.6h, so the application of the parent can make up for the disadvantage of the shorter life of the daughter. There is no report that 212Pb-DOTATATE can be used to treat SSTR-positive GEP-NETs.

DOTATATE is a DOTA-conjugated peptide that can be radionuclide-labeled for use in SPECT imaging and PRRT. The peptide sequence of DOTATATE is:

DOTA-D-Phe-Cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr-OH.

DOTATATE can be prepared by any preparation method in the prior art, as long as its function can be achieved. Preferably, the preparation of DOTATATE refers to CN111944015A.

DOTATATE is the precursor of ²¹² Pb-DOTATATE. ²¹² Pb-DOTATATE can be obtained by chelating DOTATATE with ²¹² Pb.

²¹² Pb-DOTATATE is a somatostatin-2 receptor analog that has a high affinity for the somatostatin-2 receptor and works by binding to cells with somatostatin receptors that may be present on certain tumors. After binding to the receptor, the drug enters the cell and damages the tumor cell through radiation.

Specifically, the molecular formula of the ²¹² Pb-DOTATATE is ²¹² Pb-C ₆₅ H ₉₀ N ₁₄ O ₁₉ S ₂ , and its structural formula is shown in the following formula I:

In this application, neuroendocrine tumors are tumors originating from neuroendocrine cells. Neuroendocrine cells are a large class of cells in the body that have a neuroendocrine phenotype and can produce a variety of hormones. According to the latest naming regulations for neuroendocrine tumors by WHO in 2010, "Neuroendocrine neoplasm (NEN)" refers to all tumors originating from neuroendocrine cells, among which highly differentiated neuroendocrine tumors are named Neuroendocrine tumor (NET, neuroendocrine tumor), and poorly differentiated neuroendocrine tumors are named Neuroendocrine carcinoma (NEC, neuroendocrine cancer). Neuroendocrine cells are distributed throughout the body, so neuroendocrine tumors can occur anywhere in the body, but the most common are neuroendocrine tumors of the digestive system such as the stomach, intestines, and pancreas, accounting for about 2/3 of all neuroendocrine tumors. Neuroendocrine tumors that occur in the digestive system of the stomach, intestines, and pancreas are gastroenteropancreatic neuroendocrine tumors (GEP-NENs).

In the present application, the term medicine generally refers to a medicine suitable for being applied to a patient, for example, a medicine applied to a human patient. In addition, the medicine may also include one or more (pharmaceutically effective) carriers, stabilizers, excipients, diluents, solubilizers, surfactants, emulsifiers and/or preservatives. In the application, the acceptable ingredients of the medicine may be nontoxic to the recipient at the dosage and concentration used. The form of the medicine of the present application may not be limited to liquid, frozen and lyophilized compositions.

In this application, treatment refers to therapeutic treatment and preventive or prophylactic measures, the purpose of which is to prevent, slow down, improve and stop undesirable physiological changes or disorders, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, alleviation or disappearance (whether partial or complete), extension of the expected survival period when not receiving treatment, etc. Patients in need of treatment include patients who already have a disease or disorder, patients who are susceptible to a disease or disorder, or patients who need to prevent the disease or disorder, and patients who can or are expected to benefit from the administration of ²¹² Pb-DOTATATE disclosed in this application for detection, diagnostic procedures and/or treatment.

In this application, an agent refers to a chemical compound, a mixture of chemical compounds, a biological macromolecule or an extract made from biological material.

In this application, a pharmaceutical agent or drug refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.

In the present application, subjects or patients or treatment objects include but are not limited to humans and animals that can suffer from cancer, or any disease that can be directly or indirectly related to cancer. Research subjects include mammals. Such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, rats, rabbits, mice and transgenic non-human animals. Specifically, subjects or patients or treatment objects include companion animals, such as dogs, cats, rabbits and rats. Specifically, subjects or patients or treatment objects include livestock, such as cattle, pigs, sheep, goats and rabbits. Specifically, subjects or patients or treatment objects include purebred or show animals, such as horses, pigs, cattle and rabbits. Specifically, subjects or patients or treatment objects are humans, for example, humans who have or may have a risk of cancer.

In the present application, the single administration dose of the ²¹² Pb-DOTATATE is 1 μCi to 100 mCi/kg subject body weight; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi to 100 mCi/kg subject body weight/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 0.05-100 mCi/kg body weight of the subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 0.05-100 mCi/kg body weight of the subject/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 0.1-100 mCi/kg body weight of the subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 0.1-100 mCi/kg body weight of the subject/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 1 μCi to 80 mCi/kg of subject body weight; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi to 80 mCi/kg of subject body weight/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 1 μCi to 60 mCi/kg of subject body weight; or a single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi to 60 mCi/kg of subject body weight/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 1 μCi-40 mCi/kg subject body weight; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi-40 mCi/kg subject body weight/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 1 μCi-20 mCi/kg subject body weight; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi-20 mCi/kg subject body weight/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 1 μCi-10 mCi/kg subject body weight; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1 μCi-10 mCi/kg subject body weight/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 1-10 mCi/kg body weight of the subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 1-10 mCi/kg body weight of the subject/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 5-10 mCi/kg body weight of the subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 5-10 mCi/kg body weight of the subject/time.

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 0.01-0.15 mCi/kg body weight of the subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 0.01-0.15 mCi/kg body weight of the subject/time.

Specifically, ^{the 212} The single administration dose of Pb-DOTATATE can be 1 μCi/kg of subject weight, 0.01 mCi/kg of subject weight, 0.05 mCi/kg of subject weight, 0.1 mCi/kg of subject weight, 0.15 mCi/kg of subject weight, 0.2 mCi/kg of subject weight, 0.3 mCi/kg of subject weight, 0.4 mCi/kg of subject weight, 0.5 mCi/kg of subject weight, 0.6 mCi/kg of subject weight, 0.7 mCi/kg of subject weight, 0.8 mCi/kg of subject weight, 0.9 mCi/kg of subject weight, 1 mCi/kg of subject weight, 1.5 mCi/kg of subject weight, 2 mCi/kg of subject weight, 3 mCi/kg of subject weight, 4 mCi/kg of subject weight, 5 mCi/kg of subject weight, 6 mCi/kg of subject weight , 7mCi/kg subject body weight, 8mCi/kg subject body weight, 9mCi/kg subject body weight, 10mCi/kg subject body weight, 15mCi/kg subject body weight, 20mCi/kg subject body weight, 25mCi/kg subject body weight, 30mCi/kg subject body weight, 35mCi/kg subject body weight, 40mCi/kg subject body weight, 45mCi/kg subject body weight, 50mCi/kg subject body weight, 55mCi/kg subject body weight, 60mCi/kg subject body weight, 65mCi/kg subject body weight, 70mCi/kg subject body weight, 75mCi/kg subject body weight, 80mCi/kg subject body weight, 85mCi/kg subject body weight, 90mCi/kg subject body weight, 95mCi/kg subject body weight, 100mCi/kg subject body weight.

In the present application, the single dose of ²¹² Pb-DOTATATE is 50 μCi-500 mCi/each subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 50 μCi-500 mCi/each subject/time. (The subject's weight is 50 kg)

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 250 μCi-500 mCi/per subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 250 μCi-500 mCi/per subject/time. (The subject's weight is 50 kg)

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 50 μCi-100 mCi/per subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 50 μCi-100 mCi/per subject/time. (The subject's weight is 50 kg)

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 50 μCi-200 mCi/per subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 50 μCi-200 mCi/per subject/time. (The subject's weight is 50 kg)

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 50 μCi-300 mCi/per subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 50 μCi-300 mCi/per subject/time. (The subject's weight is 50 kg)

In some embodiments, the single dose of ²¹² Pb-DOTATATE is 50 μCi-400 mCi/per subject; or the single dose of the drug containing ²¹² Pb-DOTATATE can be 50 μCi-400 mCi/per subject/time. (The subject's weight is 50 kg)

Specifically, the subject is 50 kg, and the single administration dose of the ²¹² Pb-DOTATATE is 50 μCi/each subject, 100 μCi/each subject, 150 μCi/each subject, 200 μCi/each subject, 250 μCi/each subject, 300 μCi/each subject, 350 μCi/each subject, 400 μCi/each subject, 450 μCi/each subject, 500 μCi/each subject, 600 μCi/each subject, 700 μCi/each subject, 800 μCi/each subject, 900 μCi/each subject, 1000 μCi/each subject, 1100 μCi/each subject, 1200 μCi/each subject, 1300 μCi/each subject, 1400 μCi/each subject, 1500 μCi/each subject, 1600 μCi/each subject, 1700 μCi/each subject, 1800 μCi/each subject, 1900 μCi/each subject, 2000 μCi/each subject, 212 0 μCi/each subject, 800 μCi/each subject, 900 μCi/each subject, 1 mCi/each subject, 10 mCi/each subject, 50 mCi/each subject, 100 mCi/each subject, 150 mCi/each subject, 200 mCi/each subject, 250 mCi/each subject, 300 mCi/each subject, 350 mCi/each subject or 400 mCi/each subject.

In the present application, the single administration volume of the ²¹² Pb-DOTATATE is 1 mL-30 mL; or a single dose of the drug containing ²¹² Pb-DOTATATE can be provided to the subject at 1 mL-30 mL/subject/time.

Specifically, the single administration volume of ^the12Pb -DOTATATE may be 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 11ml, 12ml, 13ml, 14ml, 15ml, 16ml, 17ml, 18ml, 19ml, 20ml, 21ml, 22ml, 23ml, 24ml, 25ml, 26ml, 27ml, 28ml, 29ml or 30ml.

In the present application, the administration concentration of the ²¹² Pb-DOTATATE is 1-30 mCi/mL.

Specifically, ^{the 212} Pb-DOTATATE may be administered at a concentration of 1 mCi/mL, 2 mCi/mL, 3 mCi/mL, 4 mCi/mL, 5 mCi/mL, 6 mCi/mL, 7 mCi/mL, 8 mCi/mL, 9 mCi/mL, 10 mCi/mL, 11 mCi/mL, 12 mCi/mL, 13 mCi/mL, 14 mCi/mL, 15 mCi/mL, 16 mCi/mL, 17 mCi/mL, 18 mCi/mL, 19 mCi/mL, 20 mCi/mL, 21 mCi/mL, 22 mCi/mL, 23 mCi/mL, 24 mCi/mL, 25 mCi/mL, 26 mCi/mL, 27 mCi/mL, 28 mCi/mL, 29 mCi/mL, or 30 mCi/mL.

In the present application, the administration frequency of the ²¹² Pb-DOTATATE is once every 3-16 weeks.

Specifically, the administration frequency of the ²¹² Pb-DOTATATE can be once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks or once every 16 weeks.

In the present application, the total dose of ²¹² Pb-DOTATATE administered is 0.1 mCi-2 Ci (total dose for humans), or the total dose of ²¹² Pb-DOTATATE administered is 1 μCi-1 mCi (total dose for animals).

Specifically, the total dosage of the ²¹² Pb-DOTATATE can be 1 μCi, 5 μCi, 10 μCi, 100 μCi, 1 mCi, 10 mCi, 50 mCi, 100 mCi, 200 mCi, 300 mCi, 400 mCi, 500 mCi, 600 mCi, 700 mCi, 800 mCi, 900 mCi, 1000 mCi, 1100 mCi, 1200 mCi, 1300 mCi, 1400 mCi, 1500 mCi, 1600 mCi, 1700 mCi, 1800 mCi, 1900 mCi or 2000 mCi. (The total dosage here is the total dosage after multiple administrations, for example, the total dosage of 4 administrations)

The dosage of the ²¹² Pb-DOTATATE should be based on the actual situation of the subject, combined with the dosage, dosage volume, dosage concentration and total dosage, to implement a dosage regimen suitable for the subject.

In the present application, the total administration volume of the ²¹² Pb-DOTATATE is 1 ml-300 ml.

Specifically, the total administration volume of the ²¹² Pb-DOTATATE can be 1ml, 5ml, 10ml, 15ml, 20ml, 25ml, 30ml, 35ml, 40ml, 45ml, 50ml, 55ml, 60ml, 65ml, 70ml, 75ml, 80ml, 85ml, 90ml, 95ml, 100ml, 110ml, 120ml, 130ml, 140ml, 150ml, 160ml, 170ml, 180ml, 190ml, 200ml, 210ml, 220ml, 230ml, 240ml, 250ml, 260ml, 270ml, 280ml, 290ml or 300ml.

The administration volume of the ²¹² Pb-DOTATATE can be appropriately administered according to the actual conditions of the subject and the dosage.

In some embodiments, the dosage for neuroendocrine tumor patients is 200 mCi every 8 weeks, the volume of each administration is 20 mL, the concentration is 10 mCi/mL, the total number of administrations is 4 times, and the total dosage is 800 mCi.

In the present application, the composition, drug or agent may be administered by intraperitoneal injection, intravenous injection, oral administration or skin application. Specifically, the dosage to the subject varies according to the administration route, symptoms, patient age, etc., and can be determined by the clinician.

In some embodiments, the ²¹² Pb-DOTATATE is administered by intravenous injection.

In the present application, pharmaceutically acceptable carriers or excipients may be added to the drug or reagent containing ²¹² Pb-DOTATATE.

Specifically, the drug or agent can be prepared in the following form: the protein synthesis inhibitor or the composition containing the same is mixed with a pharmaceutically acceptable carrier, for example, to obtain an oral preparation, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules, microcapsules), granules, powders, lozenges, syrups, emulsions, suspensions, films (e.g., orally disintegrating films), etc., parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops), external preparations (e.g., skin preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pills, nasal drops, respiratory preparations (inhalants), eye drops, etc. In addition, these preparations can be used as controlled release preparations (e.g., sustained release microcapsules), such as immediate release preparations, sustained release preparations, etc. Such preparations can be obtained by the preparation methods conventionally used in the art.

Specifically, examples of the above-mentioned pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinyl pyrrolidone, etc.), lubricants (e.g., magnesium stearate, calcium stearate, talc, etc.), disintegrants (e.g., carboxymethyl cellulose calcium, talc, etc.), diluents (e.g., water for injection, saline, etc.), additives (e.g., stabilizers, preservatives, colorants, flavorings, dissolution aids, emulsifiers, buffers, isotonic agents, etc.), and the like.

The present application provides a composition for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the composition comprises a ²¹² Pb derivative of a somatostatin analog, and the ²¹² Pb derivative of a somatostatin analog is ²¹² Pb-DOTATATE.

In the present application, after a single intravenous injection of different doses of ²¹² Pb-DOTATATE, DOTATATE or ¹⁷⁷ Lu-DOTATATE was given to AR42J tumor-bearing mice, the weight of the five groups of animals showed an overall trend of first increasing, then decreasing, and then increasing during the test period, and the weight of the five groups of animals increased by about 6.9-12.5% at the end of the test. During the test period, the tumor volume of the animals in the low-dose group (G1), the blank control group (G4) and the ¹⁷⁷ Lu-DOTATATE control group (G5) showed an overall trend of continuous increase from D0 to D35; the tumor volume of the animals in the medium-dose group (G2) showed an overall trend of gradual increase from D0 to D6, the tumor volume showed a trend of continuous decrease from D7 to D14, and the tumor volume gradually increased from D15 to D35; the tumor volume of the animals in the high-dose group (G3) showed an overall trend of gradual increase from D0 to D3, the tumor volume showed a trend of continuous decrease from D4 to D27, and the tumor volume slightly increased from D28 to D35. At the end of the test, the T/C of the low-dose group (G1) was 81.7% (>40%), which was statistically different from the control group (G4) (P<0.05), and the anti-tumor efficacy of the low-dose group was poor; the relative tumor proliferation rate T/C of the medium-dose group (G2) was 48.9% (>40%), which was statistically different from the control group (G4) (P<0.05), and the overall judgment was that the anti-tumor effect of the medium-dose group was certain. The relative tumor proliferation rate T/C of the high-dose group (G3) was 6.4% (<40%), and there was a statistical difference (P<0.05) compared with the control group (G4), and the anti-tumor efficacy of the high-dose group was judged to be effective. The relative tumor proliferation rate T/C of the control group (G5) was 99.2% (>40%), which was not statistically different from the blank control group (G4) (P>0.05), and the anti-tumor effect of the control group was judged to be ineffective. At the end of the test, the tumor volume and weight of G3 animals were significantly lower than those of other groups; the TGI _TW of G1, G2, G3 and G5 were 17.6%, 50.5%, 93.0% and 3.3% respectively, and the tumor growth inhibition rate of G3 was significantly higher than that of G1, G2 and G5. The human dose was calculated based on the surface area of animals and humans and the experience of nuclear medicine use.

Example

The present application provides a general and/or specific description of the materials and test methods used in the experiments. In the following examples, unless otherwise specified, % means wt%, i.e., weight percentage. The reagents or instruments used without indicating the manufacturer are all conventional reagent products that can be obtained commercially.

All experimental operations in this application strictly comply with the "Technical Guidelines for Non-clinical Research of Cytotoxic Anti-tumor Drugs" issued by the China Food and Drug Administration and the standard experimental operating procedures (SOP) of Midu (Nanjing) Biotechnology Co., Ltd.

Example 1

Preparation method of ²¹² Pb-DOTATATE:

18-70 nanomolar DOTATATE aqueous solution (1 mg/ml) was added to the pre-treated solution of ²¹² Pb (1 MBq, 1 ml). After that, 2 M Na ₂ CO ₃ was added to the mixture to increase the pH value to 4.5-6.5.

The final volume of the label ²¹² Pb is 1 ml. The container with the reaction mixture is placed in a thermostat at a temperature of (90±2)° C. The synthesis reaction is interrupted by cooling the mixture of the container and water at a temperature of 15° C.

The preparation of DOTATATE refers to CN111944015A.

The labeling of ¹⁷⁷ Lu-DOTATATE refers to CN112584875A.

Example 2

2.1 Animal selection

According to the requirements of the Technical Guidelines for Nonclinical Studies of Cytotoxic Anti-tumor Drugs, AR42J ectopic tumor-bearing BALB/c-nude mice were selected as the experimental animal model for tissue distribution experiments. The number of animals used is the minimum value to ensure the scientific validity and statistical significance of the data. Currently, there is no effective non-in vivo experiment to replace it. The experimental results of this application will provide important information for its non-clinical and clinical studies.

2.2 Basic information of animals

A total of 40 AR42J tumor-bearing mice (8 spare animals from the same batch were prepared) were used in this experiment. All of them were male and were modeled by Yikang (Beijing) Pharmaceutical Technology Co., Ltd. The tumor-bearing mice had small cell lung cancer. BALB/c-nude mice were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd. The experimental animal production license number is SCXK (Beijing) 2019-0010, and the experimental animal quality certificate number is 110324211106533021. Each animal has a unique ear tag identification number. The weight of the enrolled animals at the time of administration was 19.9-24.5g, and the tumor volume was 88.4-301.1mm3.

2.3 Animal management

After the AR42J tumor-bearing mice arrived at the SPF-level barrier animal room of Midu (Nanjing) Biotechnology Co., Ltd., they were transferred to polycarbonate/polysulfone feeding boxes. Each cage housed 1 to 5 animals of the same sex and quarantined according to the relevant SOP of Midu. Healthy animals that passed the quarantine were selected before the experiment to enter the experiment. The animals were free to eat and drink water during the feeding period. The measured temperature and humidity of the environmental conditions met the set requirements throughout the experiment (room temperature 20℃～26℃, relative humidity 40%～70%). The temperature and humidity monitoring records are kept in the Midu archives. The lighting is set to alternate between light and dark for 12 hours. Due to the needs of the experimental operation, there is sometimes a short lighting period at night. Experimental Animal Use License: SYXK (Beijing) 2019-0028 (Yikang), SYXK (Su) 2020-0016.

2.4 Dosage regimen trial design

In combination with the requirements of radiation safety and instrument detection, the dosage of ²¹² Pb-DOTATATE, compound (DOTATATE) and ¹⁷⁷ Lu-DOTATATE in this experiment is set as shown in the following table. This experiment is a single dose and intravenous administration. The specific animal grouping and dosing regimen are detailed in Table 1 below.

Table 1

Note a: The control group was given the same amount of DOTATATE as the high-dose group.

i.v. refers to intravenous administration.

Storage method of test substances: Except during administration and analysis, the labeled test substances should be stored at 2-8°C.

Preparation of the test substance: The diluent for administration of ²¹² Pb-DOTATATE was normal saline.

The information of the test substances is shown in Table 2.

Table 2

Unlabeled test substance Labeling of test substances Labeling of test substances Test substance name DOTATATE ²¹² Pb-DOTATATE ¹⁷⁷ Lu-DOTATATE Provided by Beijing Xiantong Biopharmaceutical Technology Co., Ltd. NA NA Production Enterprise NA Midu (Nanjing) Biotechnology Co., Ltd. Midu (Nanjing) Biotechnology Co., Ltd. batch number 190101 L21122401 L21122401 Chemical purity 85.80% NA NA Radiochemical purity NA 100% 100% Molecular weight 1434Da NA NA Physical and chemical properties powder Clear liquid Clear liquid Storage conditions -20℃ Freezer 2～8℃, lead tank 2～8℃, lead tank

2.5 Instruments and reagents

Table 3 Test instruments

Table 4 Test reagents

Reagent name factory batch number Gentisic acid Provided by Xiantong C0210-2-20195-28-01 Pentetic acid Provided by Xiantong 099-PTS-]Z-9-T Normal saline Chenxin Pharmaceutical Co., Ltd. 2002200723 Sterile water for injection Nanjing Gonglu Biotechnology Co., Ltd. SD21010711 acetic acid Sinopharm Chemical Reagent Co., Ltd. 20200408 Sodium acetate VETEC WXBD1272V Sodium hydroxide VETEC WXBD4667V Sodium Chloride Injection Chenxin Pharmaceutical Co., Ltd. 2009010724 Normal saline Sichuan Kelun Pharmaceutical Co., Ltd. A21051105B Sterile water for injection Shandong Hualu SD21041102

Example 3 Quality Control of ²¹² Pb-DOTATATE

In this experiment, Radio-iTLC method was used to control the quality of ²¹² Pb labeled products. A certain amount of ²¹² Pb labeled compound was spotted onto a glass fiber plate, placed in a 0.05M citric acid/sodium citrate (pH=4.0) developing agent for chromatography, and detected by a thin layer scanner to calculate the radiochemical purity (RCP), which should be ≥95%.

In this experiment, a total of 1 batch of ²¹² Pb-DOTATATE was produced, with the batch number L21122401. The results of Radio-iTLC detection showed that the RCP was 98.68%, which met the test requirements. The specific results are shown in Table 5.

Table 5 Quality control results of ²¹² Pb-DOTATATE

batch number L21122401 Characteristics Clarity and transparency pH 4.5 RCP(%) 98.68

Example 4 In vitro stability of ^212Pb -DOTATATE

²¹² Pb-DOTATATE was used as a test sample and stored in a labeled solution system at 2-8°C. The RCP of ²¹² Pb-DOTATATE was detected by Radio-iTLC as its in vitro stability data. At least two detection time points were set. The first detection time point was 0h, which was the purity detection in quality control, and the last detection time point was later than the end of drug administration, specifically 2h after drug administration.

The results of Radio-iTLC detection showed that the RCP of ²¹² Pb-DOTATATE was 98.05% 2 hours after drug delivery (later than the end of drug administration), which met the test requirements. Specific in vitro stability results are shown in Table 6.

Table 6 In vitro stability data of ²¹² Pb-DOTATATE at different time points

Example 5 Animal Dosing, Body Weight, Tumor Volume and Weight

Before administration, the body weight and tumor volume of all animals participating in the experiment were weighed and recorded. Tumor-bearing mice within the appropriate tumor volume range and in good tumor condition were selected and randomly divided into groups according to tumor volume (8 animals per group). During the administration process, the initial radioactive dose, initial dose determination time, injection time, residual radioactive dose, residual dose determination time (groups 1-3, group 5), and the injection time of DOTATATE in group 4 were recorded.

5.1 Actual dosage for animals

The actual dosage of animals is as follows: the planned dosage of G1, G2, and G3 animals is 1μCi/animal, 5μCi/animal, and 10μCi/animal, respectively. After testing and calculation, the actual average dosage is 1.2μCi/animal (G1), 5.2μCi/animal (G2), and 10.5μCi/animal (G3), and the average dosage volume is 5.6mL/kg (G1), 5.5mL/kg (G2), and 5.4mL/kg (G3). G4 is the blank control group, and it is planned to give DOTATATE at the same dose as G3. The actual dosage is about 0.93μg/animal, and the dosage volume is about 5.5mL/kg. G5 is the control group, and it is planned to give ^177Lu -PSMA-617 at the same dose as G5. The actual dosage is about 11.6μCi/animal, and the dosage volume is about 4.9mL/kg. The body weight and actual dosage of each animal are detailed in Tables 7 and 8.

Table 7 Grouping and dosing information of experimental animals in G1 (low dose), G2 (medium dose), G3 (high dose) and G5 (control group)

Table 8 G4 (blank control group) experimental animal grouping and drug administration information

5.2 Animal weight and tumor size monitoring

After the animals were administered the test substance/normal saline, the tumor diameter and body weight were measured twice a week, with at least 2 days between each measurement.

5.3. Treatment of experimental animals

35 days after the experimental animals were given ²¹² Pb-DOTATATE, DOTATATE or ¹⁷⁷ Lu-DOTATATE (D35, the day of administration is D0, the first day of administration is D1, the second day of administration is D2, and so on), all experimental animals were euthanized after measuring the tumor diameter and weighing, and the tumors were removed, photographed and weighed.

5.4. Data collection and result calculation

The relative tumor volume (RTV) and relative tumor proliferation rate (T/C) were calculated based on the tumor diameter measurement data. The tumor mass inhibition rate (TG _TW ) and tumor volume inhibition rate (TG _TV ) were calculated based on the tumor mass and tumor volume, and the tumor growth curve was drawn based on the tumor volume. The calculation formula is as follows:

RTV = _Vt / _V0 ( _Vt is the tumor volume at each measurement, _V0 is the tumor volume measured at _D0 )

T/C = _TRTV / _CRTV * 100% ( _TRTV : RTV of the test group; _CRTV : RTV of the blank control group)

TGI _TW = (1-average tumor weight of the test group/average tumor weight of the blank control group) × 100%

TGI _TV = (1-average tumor volume of the test group/average tumor volume of the blank control group) × 100%

During the experiment, the body weight of the five groups of animals showed an overall trend of first increasing, then decreasing, and then increasing again. At the end of the experiment, the body weight of the five groups of animals increased by about 6.9-12.5%. Specific body weight data are shown in Tables 9-13, and the specific curve of average body weight change over time is shown in Figure 1.

Table 9 Body weight of animals in G1 (low dose) test

Table 10 Body weight of animals in the G2 (medium dose) test

Table 11 Body weight of animals in G3 (high dose) test

Table 12 Body weight of G4 (control group) experimental animals

Table 13 Body weight of G5 (control group) experimental animals

During the experiment, the tumor volume of animals in the low-dose group (G1), blank control group (G4) and comparison group (G5) showed a continuous increasing trend from D ₀ to D ₃₅ ; the tumor volume of animals in the medium-dose group (G2) showed a gradual increasing trend from D ₀ to D ₆ , the tumor volume showed a continuous decreasing trend from D ₇ to D ₁₄ , and the tumor volume increased slightly from D ₁₅ to D ₃₅ ; the tumor volume of animals in the high-dose group (G3) showed a gradual increasing trend from D ₀ to D ₃ , the tumor volume showed a continuous decreasing trend from D ₄ to D ₂₇ , and the tumor volume increased slightly from D ₂₈ to D _35. During the experiment, the tumor volumes of animals in each group from D ₀ to D ₃ were basically the same, and the tumor volumes of each group from D ₆ to D ₃₅ were ranked as G3<G2<G1<G5<G4. At the end point of the experiment, the average tumor volumes of G1, G2, G3, G4 and G5 animals were 1245.1 mm ³ , 634.8 mm ³ , 105.4 mm ³ , 1511.6 mm ³ and 1461.2 mm ³ , respectively. The tumor volume of G3 animals was significantly smaller than that of G4.

During the experiment, the relative tumor proliferation rate T/C of G1, G2, G3 and G5 animals showed a trend of first decreasing and then increasing. G1, G2, G3 and G5 dropped to the minimum value at D ₁₄ , D ₁₇ , D ₃₁ and D ₁₁ , respectively, which were 64.3%, 23.7%, 3.3% and 81.5%. During the experiment, the T/C of G1 animals did not reach the level of ≤40% (T/C was 64.3% (D ₁₄ ) ~ 81.7% (D ₃₅ ) overall), and the variance analysis of tumor volume between G1 and G4 animals at D ₃₅ showed statistical difference (P = 0.05), judging that the anti-tumor drug efficacy of the low-dose group was poor. The T/C of G2 animals from D ₁₁ to D ₃₁ was close to the level of 40%, and the T/C of D ₃₅ was 48.9% (> 40%), judging that the medium-dose group had a certain anti-tumor drug effect. The T/C of G3 animals dropped to 21.0% on D ₁₁ , and continued to drop to 3.3% (D ₃₁ ) from D ₁₁ to D ₃₁ , and slightly increased to 6.4% (D ₃₅ ) from D ₃₂ to D ₃₅ ; the T/C from D ₁₁ to D ₃₅ was lower than 40%, and the tumor volume of G3 and G4 animals was statistically different in the period of D ₁₁ to D ₃₅ (P<0.05), judging that the anti-tumor drug in the high-dose group was effective. The T/C of G5 animals did not reach the level of ≤40% (T/C was 81.5% (D ₁₄ ) to 99.2% (D ₃₅ ) overall), and there was no statistical difference in the tumor volume of G1 and G4 animals in the variance analysis during the experiment (P>0.05), judging that the anti-tumor drug in the low-dose group was ineffective.

During the experiment, the tumor volume inhibition rates of G1, G2, G3 and G5 showed a trend of first increasing and then decreasing, reaching peak values of 35.2%, 76.0%, 96.5% and 20.5% on D ₁₄ , D ₁₇ , D ₃₁ and D _11, respectively; at the end of the experiment, the average tumor weights of G1, G2, G3, G4 and G5 were 2.1913g, 1.5205g, 0.1560g, 2.7726g and 2.6381g, respectively. The tumor weight of G3 animals was significantly lower than that of G4, and was statistically different from that of G4 (P < 0.05). The average tumor weights of G1 and G5 groups were equivalent and had no statistical differences with those of G4 group. The tumor mass inhibition rates (TGI _TW ) of G1, G2, G3 and G5 were 21.0%, 45.2%, 94.4% and 4.9%, respectively, indicating that the tumor growth inhibition rate of G3 was significantly higher than that of G1, G2 and G5.

Specific tumor volumes are shown in Tables 14 to 18, RTV data are shown in Tables 19 to 23, T/C and TGI _TV data are shown in Table 24, tumor weight and TGI _TW data are shown in Table 25, the results of variance analysis of tumor volume and tumor weight of each group are shown in Table 26, and the curve of the change of the average tumor volume over time is shown in Figure 2.

Table 14 Tumor volume of G1 (low dose group) experimental animals

Table 15 Tumor volume of G2 (medium dose group) experimental animals

Table 16 Tumor volume of G3 (high dose group) experimental animals

Table 17 Tumor volume of G4 (control group) experimental animals

Table 18 Tumor volume of G5 (control group) experimental animals

Table 19 Relative tumor volume of G1 (low dose group) experimental animals

Table 20 Relative tumor volume of G2 (medium dose) experimental animals

Table 21 Relative tumor volume of G3 (high dose) experimental animals

Table 22 Relative tumor volume of G4 (control group) experimental animals

Table 23 Relative tumor volume of G5 (high dose) experimental animals

Table 24 Relative tumor proliferation rate T/C and tumor volume inhibition rate (TGI _TV ) of G1 (low dose), G2 (medium dose), G3 (high dose) and G5 (control group) experimental animals

Table 25 Tumor mass and tumor mass inhibition rate (TGI _TW ) of experimental animals

Table 26 Statistical results of variance analysis of tumor volume and tumor mass of animals in different groups

Example 6 Observation of Animal Status

Immediately after administration, observe the animals for abnormal reactions. All animals should be observed once a day during the experiment. The observation content includes but is not limited to the animal's mental state, behavioral activities, breathing, secretions, feces, and diet. If an animal dies during the experiment, notify the person in charge of the topic in time, conduct an autopsy observation and take photos, and keep the photos as original data.

During the entire test period, the animals were observed once a day. On D _3, wounds were found on the left foot of the G1-M-03 animal. The wounds had scabs on D ₅ and fell off on D ₁₂ , and the animal returned to normal. On D _4, wounds were found on the feet of G3-M-05 and G3-M-07. The wounds had scabs the next day. The scabs were observed to fall off on D _11. On D _12, wounds were found on the backs of the G1-M-04 and G1-M-05 animals. The wounds on the backs had scabs on D ₁₃ to D ₁₄ , and the animal returned to normal on D _20. On D _23, wounds were found on the backs of the G5-M-02 animal. The wounds had scabs on D ₂₅ and fell off on D _31. The tumor of the G4-M-06 animal was observed to turn black on D ₃₀ , and it continued until the end of the test (D ₃₅ ). No obvious abnormal symptoms were observed in all other animals.

The above is only the preferred embodiment of the present application, and does not limit the present application in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present application without departing from the content of the technical solution of the present application still belongs to the protection scope of the technical solution of the present application.

Claims (11)

1. Somatostatin analogues ²¹² Use of a derivative of Pb in the treatment of somatostatin receptor positive gastrointestinal pancreatic neuroendocrine tumors wherein said somatostatin analogue ²¹² Pb derivatives are ²¹² Pb-DOTATATE。

2. Derivatives of somatostatin analogues ²¹² Use of a derivative of Pb in the manufacture of a medicament for the treatment of somatostatin receptor positive gastrointestinal pancreatic neuroendocrine tumors, wherein the somatostatin analogue ²¹² Pb derivatives are ²¹² Pb-DOTATATE。

3. Use according to claim 1 or 2, wherein the ²¹² The one-time administration dosage of Pb-DOTATATE is 1 mu Ci-100 mCi/kg of the body weight of the subject; or comprises ²¹² The single dose of Pb-DOTATATE drug can be 1 μCi to 100mCi per kg of subject body weight per time。

4. Use according to claim 1 or 2, wherein the ²¹² One dose of Pb-DOTATATE is 1 μCi-10 mCi/kg body weight of the subject; or comprises ²¹² The single dose of Pb-DOTATATE drug can be 1. Mu. Ci to 10mCi per kg of subject body weight per time.

5. Use according to claim 1 or 2, wherein the ²¹² One dose of Pb-DOTATATE is 250. Mu. Ci-500 mCi/each subject; or comprises ²¹² A single dose of Pb-dottate drug can be in the range of 250 μci-500mCi per subject per time.

6. Use according to claim 1 or 2, wherein the ²¹² The volume of one administration of Pb-DOTATATE is 1mL-30mL; or comprises ²¹² A single dose of Pb-DOTATATE drug can be provided to the subject at 1mL-30 mL/subject/time, or

The said ²¹² Pb-DOTATATE was administered at a concentration of 1-30mCi/mL.

7. Use according to claim 1 or 2, wherein the ²¹² The frequency of administration of Pb-DOTATATE was once every 3-16 weeks.

8. Use according to claim 1 or 2, wherein the ²¹² The total dose of Pb-DOTATATE administered was 0.1mCi-2Ci.

9. Use according to claim 1 or 2, wherein the ²¹² The total volume of Pb-DOTATATE administered was 1mL-300mL.

10. Use according to claim 1 or 2, wherein the ²¹² The Pb-DOTATATE is administered by intravenous injection.

11. Gastrointestinal pancreatic neuroendocrine for treatment of somatostatin receptor positiveA composition of a neoplasm, wherein the composition comprises a somatostatin analog ²¹² Derivatives of Pb, the somatostatin analogues ²¹² Pb derivatives are ²¹² Pb-DOTATATE。