Method for confirming therapeutic effect by radioactive therapeutic agent

Abstract

To provide a method for confirming a therapeutic effect by a radioactive therapeutic agent.SOLUTION: A method for confirming a therapeutic effect by a radioactive therapeutic agent comprises: a procedure 1 for using a Zr marker probe before therapy, for acquiring a PET image; a procedure 2 for generating an administration plan related to a dose and a dosage number of ann Ac marker probe being the radioactive therapeutic agent, on the basis of a vivo distribution of the Zr marker probe indicated by the PET image acquired in the procedure 1; a procedure 3 for administering simultaneously, the Zr marker probe and the Ac marker probe, for acquiring a PET image A in administration initial stage; a procedure 4 for, acquiring a PET image B after elapse of a prescribed number of days after administration of the Ac marker probe; a procedure 5 for comparing the PET image A with the PET image B, for determining whether a therapeutic effect is sufficient or insufficient, on the basis of a decrement of Zr-89: a procedure 6 for reducing the dose of the Ac marker probe when the therapeutic effect can be achieved, and correcting the administration plan so as to increase the dose of the Ac marker probe, when the therapeutic effect is insufficient, on the basis of a result in the procedure 5.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for confirming the therapeutic effect of a radioactive therapeutic agent. [Background technology]

[0002] In cancer treatment, various tests and diagnoses are performed before starting treatment to determine the treatment method. In recent years, a technique called "theranostics" (combining diagnosis and treatment) has been developed.

[0003] Theranostics makes it possible to visualize the state of the lesion based on the pharmacokinetics of drugs labeled with diagnostic RI and optimize the dosage of drugs labeled with therapeutic RI, and is therefore expected to lead to the realization of personalized medicine.

[0004] PET-CT examination is generally performed as a means for detecting the distribution of diagnostic RI-labeled drugs and therapeutic RI-labeled drugs in the human body. In a PET-CT examination, a PET (Positron Emission Computed Tomography) device is used in combination with a CT (Computed Tomography) device, and a molecular imaging technique is used to visualize the location and size of a tumor in clear images, enabling more detailed analysis.

[0005] Molecular imaging is a technique for visualizing the amount of proteins in a living body, the expression level of enzyme activity genes, etc. in vivo, and is applied in various fields such as pathological elucidation, clinical testing, and pharmacological evaluation. Specifically, it is a method in which a compound (hereinafter also referred to as a "probe") that specifically binds to a molecule in the body is labeled with a positron-emitting nuclide, and its spatial distribution is measured outside the body using positron emission tomography (PET).

[0006] In PET examinations, the following positron-emitting nuclides (positron isotopes) are used as markers. F-18: Half-life: 109.8 minutes C-11: Half-life: 20.4 minutes N-13: Half-life: 9.97 minutes O-15: Half-life: 2.04 minutes Of these, F-18 has a half-life of 109.8 minutes, which is longer than other positron isotopes, making it possible to synthesize it in a relatively complex manner, and it is widely used as a positron isotope. A representative PET drug using F-18 is 2-Deoxy-2-[ 18 F]fluoro-D-glucose ( 18 FDG) is used in a wide range of fields, including brain function, cardiac function, and malignant tumor diagnosis. As other positron isotopes for PET examination, Ga-68 (see, for example, Patent Document 1) and Zr-89 (see, for example, Patent Document 2) have been proposed.

[0007] In Non-Patent Document 1, a PET probe ( 18 We report the results of a simulation in which radiation diagnosis is performed using a fluorine-containing fluoride-containing solution (F-NKO-035 injection) and radiation therapy is performed by changing the nuclide to an alpha-ray source (At-211). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] JP 2022-133357 A [Patent Document 2] JP 2019-112309 A [Non-patent literature]

[0009] [Non-Patent Document 1] Press release by the Japan Atomic Energy Agency and Osaka University, "Enabling dose assessment of alpha-particle nuclear medicine therapy that reflects the individual characteristics of each patient," January 14, 2021 (https: / / www.rcnp.osaka-u.ac.jp / RCNPhome / ja / news / pr_2021jan14.pdf) Summary of the Invention [Problem to be solved by the invention]

[0010] The above-mentioned Non-Patent Document 1 shows that radiodiagnosis using F-18 (half-life: 109.8 minutes) and radiotherapy using At-211 (half-life: 7.2 hours) are performed in cancer treatment. Figure 1 is a figure published in Non-Patent Document 1, and the image showing the therapeutic effect was created on the assumption that the distribution of the diagnostic nuclide F-18 in the body is the same as that of the therapeutic nuclide At-211 in the body. However, a problem with the conventional technology is that the dosage of the radioactive therapeutic drug determined at the start of treatment is not changed over the course of treatment, which may result in excessive side effects due to overdosing or insufficient therapeutic effects due to underdosing.

[0011] An object of the present invention is to provide a method for confirming the therapeutic effect of a radioactive therapeutic drug in a patient's body in near real time. [Means for solving the problem]

[0012] The present invention is as described below. (1) A method for confirming the therapeutic effect of a radioactive therapeutic agent, comprising: A probe is labeled with Zr-89 to obtain a Zr-labeled probe as a radioactive diagnostic drug; The probe is labeled with Ac-225 to obtain an Ac-labeled probe as the radioactive therapeutic agent; A method for confirming the therapeutic effect of the radioactive therapeutic drug by carrying out at least the following steps using the Zr-labeled probe and the Ac-labeled probe. Step 1: Before treatment, a PET image is obtained using the Zr-labeled probe. Step 2: Based on the distribution of the Zr-labeled probe in the body shown in the PET images obtained in step 1, an administration plan is made regarding the dosage and number of administrations of the Ac-labeled probe. Step 3: The Zr-labeled probe and the Ac-labeled probe are administered simultaneously, and a PET image A is obtained at an early stage after administration. Step 4: After administration of the Ac-labeled probe, a PET image B is obtained after a predetermined number of days have passed. Step 5: Compare PET image A with PET image B, and if the attenuation rate of Zr-89 is large, it is determined that the therapeutic effect is sufficient, and if the attenuation rate of Zr-89 is small, it is determined that the therapeutic effect is insufficient. Step 6: Based on the results of step 5, modify the administration plan to reduce the dosage of the Ac-labeled probe if the therapeutic effect is sufficient, or to increase the dosage of the Ac-labeled probe if the therapeutic effect is insufficient. (2) The method for confirming the therapeutic effect of a radioactive therapeutic drug according to (1) above, wherein the probe is a protein, a peptide, or a low molecular weight organic compound. Effect of the Invention

[0013] According to the present invention, it is possible to confirm the therapeutic effect of a radiopharmaceutical agent inside a patient's body in near real time. [Brief description of the drawings]

[0014] [Figure 1] The images are diagnostic images taken using a conventional method and images that simulate the effects of treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The details of the present invention are described below. First, the procedure for conventional internal therapy using radioactive nuclides will be described. In conventional internal therapy using radioactive nuclides, treatment is carried out in the following steps. Step 1: Perform a PET diagnosis in advance. Step 2: Treatment is carried out with several doses of therapeutic radionuclide. Step 3: PET diagnosis is performed after treatment. The dosage of the radioactive drug was determined according to body weight.

[0016] In the present invention, Zr-89 is used as the radionuclide of the radiodiagnostic agent, and Ac-225 is used as the radionuclide of the radiotherapeutic agent. Radioactive diagnostic agents (imaging agents) can be obtained by labeling compounds (probes) that specifically bind to biological molecules with Zr-89. Radioactive therapeutic drugs can also be obtained by labeling compounds (probes) that specifically bind to biological molecules with Ac-225. As the probe, an appropriate one can be selected depending on the tissue to be treated. Specifically, a protein, a peptide, or a low molecular weight organic compound is used. In the present invention, the same probe is used as the labeled probe for both the radioactive diagnostic drug and the radioactive therapeutic drug.

[0017] Zr-89 is a positron-emitting nuclide and is known to be a useful radioisotope for medical imaging, and its half-life is approximately 3 days (78.4 hours). Ac-225 is an alpha-emitter and is considered the most promising therapeutic radionuclide, with a half-life of approximately 10 days (9.92 days).

[0018] The present invention is characterized by combining a radioactive diagnostic agent consisting of a probe labeled with Zr-89, which has a half-life of approximately 3 days, with a radioactive therapeutic agent consisting of a probe labeled with Ac-225, which has a half-life of approximately 10 days, and administering Zr-89 and Ac-225 simultaneously during treatment.

[0019] The method of the present invention for confirming the therapeutic effect of a radioactive therapeutic drug includes at least the following steps: Step 1: Using the Zr-labeled probe, a PET image is obtained using the Zr-labeled probe before treatment. Step 2: Based on the distribution of the Zr-labeled probe in the body shown in the PET images obtained in step 1, an administration plan is made regarding the dosage and number of administrations of the Ac-labeled probe. Step 3: The Zr-labeled probe and the Ac-labeled probe are administered simultaneously, and a PET image A is obtained at an early stage after administration. Step 4: After administration of the Ac-labeled probe, a PET image B is obtained after a predetermined number of days have passed. Step 5: Compare PET image A with PET image B, and if the attenuation rate of Zr-89 is large, it is determined that the therapeutic effect is sufficient, and if the attenuation rate of Zr-89 is small, it is determined that the therapeutic effect is insufficient. Step 6: Based on the results of step 5, modify the administration plan to reduce the dosage of the Ac-labeled probe if the therapeutic effect is sufficient, or to increase the dosage of the Ac-labeled probe if the therapeutic effect is insufficient.

[0020] The reasons for taking the above steps are explained below. For example, the present invention will be described with reference to the application of the method to cancer patients. When the diagnostic radionuclide Zr-89 and the therapeutic radionuclide Ac-225 are administered simultaneously to a patient, they kill cancer cells over time. The affinity of the radioactive diagnostic agent to the killed cancer cells weakens, and the radioactive diagnostic agent leaves the cancer cells. As Zr-89 leaves the cancer cells, the dose of positrons emitted from the cancer cells decreases, and the degree of this decrease in positrons is an index for evaluating the effectiveness of the treatment.

[0021] Therefore, by comparing a PET image taken immediately after administration of the therapeutic nuclide with a PET image taken a predetermined number of days (eg, 1 to 3 days) after administration, the therapeutic effect of Ac-225 can be confirmed. Conventionally, F-18 has been used as a radioactive diagnostic drug, but because it has a short half-life, it can only be used for diagnosis before administration, and it has not been possible to compare the distribution of the radioactive diagnostic drug and the radioactive therapeutic drug in the body a certain number of days after administration.

[0022] In contrast, in the present invention, Zr-89, which has a long half-life, is used as the PET radioactive diagnostic agent, so that the radioactive diagnostic agent can have enough time to be distributed in the body, compared to PET diagnosis using a short half-life such as F-18. Specifically, from the viewpoint of metabolism of substances in the body, PET imaging is performed about one day after administration of the radioactive diagnostic agent, and the therapeutic effect of the radioactive therapeutic agent can be confirmed.

[0023] In this way, by checking the therapeutic effect of internal therapy at the time of treatment and adjusting the dosage of the radioactive therapeutic drug from the next treatment onwards, it is possible to maximize the therapeutic effect on the patient, reduce unnecessary radiation exposure, and minimize side effects.

[0024] In the method of the present invention for confirming the therapeutic effect of a radioactive therapeutic drug, a radioactive diagnostic agent is basically administered simultaneously with the first administration of the radioactive therapeutic drug to confirm the therapeutic effect. However, a radioactive diagnostic agent may be administered simultaneously with each administration of the radioactive therapeutic drug from the second administration onwards to confirm the therapeutic effect. However, as long as treatment with the same drug is continued, it is expected that the second and subsequent administrations of the radioactive therapeutic drug will have the same effect as the first administration, so there is little merit in simultaneously administering a radioactive diagnostic drug to confirm the therapeutic effect when the second or subsequent administrations of the radioactive therapeutic drug are administered.

[0025] A method of irradiating a yttrium (Y) target with a proton beam is known as a method for producing radioactive zirconium (Zr-89). In the production method using a proton beam, a minute amount of radioactive zirconium in the order of tens to hundreds of nanograms (ng) is produced in hundreds of milligrams (mg) of yttrium. The yttrium is dissolved, and the yttrium and Zr-89 are separated and purified using a Zr adsorption resin.

[0026] A method for binding Zr-89 to a probe is described in US Pat. No. 5,399,633. Ac-225 can also be bound to the probe in the same manner as Zr-89.

Claims

1. A method for confirming the therapeutic effect of a radioactive therapeutic agent, comprising: A Zr-labeled probe obtained by labeling a probe with Zr-89 is used as a radioactive diagnostic drug; The probe is labeled with Ac-225 to obtain an Ac-labeled probe as the radioactive therapeutic agent; A method for confirming the therapeutic effect of the radioactive therapeutic drug by carrying out at least the following steps using the Zr-labeled probe and the Ac-labeled probe. Step 1: Obtain a PET image with the Zr-labeled probe before treatment. Step 2: Based on the distribution of the Zr-labeled probe in the body shown in the PET images obtained in step 1, an administration plan is made regarding the dosage and number of administrations of the Ac-labeled probe. Step 3: The Zr-labeled probe and the Ac-labeled probe are administered simultaneously, and a PET image A is obtained at an early stage of administration. Step 4: A PET image B is obtained a predetermined number of days after administration of the Ac-labeled probe. Step 5: Compare PET image A with PET image B, and if the attenuation rate of Zr-89 is large, it is determined that the therapeutic effect is sufficient, and if the attenuation rate of Zr-89 is small, it is determined that the therapeutic effect is insufficient. Step 6: Based on the results of step 5, the administration plan is revised so that the dosage of the Ac-labeled probe is reduced if the therapeutic effect is sufficient, and is increased if the therapeutic effect is insufficient.

2. The method for confirming the therapeutic effect of a radioactive therapeutic drug according to claim 1, wherein the probe is a protein, a peptide, or a low molecular weight organic compound.

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