Application of a humanized DKK-1 monoclonal antibody in the preparation of drugs to improve sarcopenia

Abstract

This invention discloses the application of a humanized DKK-1 monoclonal antibody in the preparation of a drug for improving sarcopenia, wherein the light and heavy chains of the humanized DKK-1 monoclonal antibody are shown in SEQ ID NO. 1-2. Animal experiments have demonstrated that the humanized DKK-1 monoclonal antibody of this invention can effectively improve grip strength and increase body weight in aging mice, providing a new treatment option for improving sarcopenia.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of a humanized DKK-1 monoclonal antibody in the preparation of a drug to improve sarcopenia. Background Technology

[0002] Sarcopenia is an age-related syndrome characterized by progressive loss of skeletal muscle mass and function, severely impacting the quality of life and independence of older adults. Skeletal muscle atrophy is primarily caused by excessive breakdown of muscle protein, which is usually accompanied by reduced protein synthesis, resulting in decreased skeletal muscle mass and dysfunction. This leads to a decline in patients' quality of life and increases morbidity and mortality. Epidemiological data shows that the global prevalence of sarcopenia is 6-12%, with a prevalence of 14-33% in people aged 65 and older. Epidemiological surveys of sarcopenia in the Chinese population show a prevalence of 8.9-38.8% among elderly people in the community, with a significant increase in prevalence with age, reaching as high as 67.1% in those aged 80 and older. Currently, clinical interventions for sarcopenia are mainly limited to nutritional and exercise interventions, lacking effective pharmacological interventions.

[0003] Reported DKK-1 antibodies mainly include: DKN-01, BHQ-880, DKK1-A2, RH2-18, and Hetero-DS. Among them, DKN-01 is a humanized anti-DKK-1 IgG4 monoclonal antibody developed by Leap Therapeutics for the treatment of various tumors, such as cholangiocarcinoma, endometrial cancer, gastric cancer, esophageal cancer, liver cancer, ovarian cancer, and prostate cancer, and is currently in Phase II clinical trials. BHQ-880 can be used to treat multiple myeloma and osteosarcoma. DKK1-A2 recognizes the DKK1 P20 peptide and is used to treat hematologic malignancies and solid tumors. RH2-18 can treat postmenopausal osteoporosis. Hetero-DS can treat postmenopausal osteoporosis and fractures. In the applicant's prior authorized Chinese invention patent CN119318703B, the application of a humanized DKK-1 monoclonal antibody in the preparation of a drug for treating Alzheimer's disease is disclosed. Animal experiments have confirmed that the humanized DKK-1 monoclonal antibody can prolong the survival time of Alzheimer's mice, improve the cognitive level of Alzheimer's mice, improve the memory ability of Alzheimer's mice, and lower blood sugar, indicating that the humanized DKK-1 monoclonal antibody has the effect of treating Alzheimer's disease and can alleviate the symptoms of senile dementia.

[0004] As can be seen from the above, current research on DKK-1 antibodies mainly focuses on the treatment of fractures, osteoporosis, cancer, and Alzheimer's disease, while research on sarcopenia and related conditions is rarely reported. However, the inventors of this application, through further research, discovered that the aforementioned humanized DKK-1 monoclonal antibody also has a certain effect on improving sarcopenia, thus completing this invention. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides an application of a humanized DKK-1 monoclonal antibody in the preparation of a drug to improve sarcopenia, and specifically provides the following technical solution: This invention provides the use of a humanized DKK-1 monoclonal antibody in the preparation of a drug for improving sarcopenia, wherein the light and heavy chains of the humanized DKK-1 monoclonal antibody are as shown in SEQ ID NO.1-2.

[0006] In a preferred embodiment of the invention, the application is for the elderly.

[0007] In a preferred embodiment of the invention, the application includes improving grip strength and / or improving body weight.

[0008] In a preferred embodiment of the present invention, the drug is an injectable preparation.

[0009] In a preferred embodiment of the present invention, the drug is an injectable preparation for subcutaneous injection.

[0010] In a preferred embodiment of the present invention, the drug further includes other pharmaceutical excipients or the drug is a lyophilized powder injection.

[0011] Beneficial effects: Animal experiments have demonstrated that the humanized DKK-1 monoclonal antibody of this invention can effectively improve grip strength and increase body weight in aging mice, providing a new treatment option for improving sarcopenia. Attached Figure Description

[0012] Figure 1 These are the statistical results of grip strength in the treatment group and the control group mice. This indicates a significant difference (P < 0.05).

[0013] Figure 2 These are the statistical results of the body weight of mice in the treatment group and the control group. This indicates a significant difference (P < 0.05).

[0014] Figure 3 This is the result of HE staining. Detailed Implementation

[0015] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0016] Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art. Unless otherwise specified, the materials, reagents, etc. used in the following embodiments are all commercially available.

[0017] Example 1: Preparation of DKK-1 monoclonal antibody The preparation and bioactivity verification of the humanized DKK-1 monoclonal antibody are described in prior art patent 202410979827.5 (application number) and are incorporated herein by reference. Specifically, the light and heavy chain amino acid sequences of the DKK-1 monoclonal antibody used in this embodiment are as follows: Light chain sequence (SEQ ID NO.1): DIQMTQSPSSSLSASVGDRVTITCRASQGISNYLNWYQQKPGKAPKLLISYTSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYSKLPLTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Heavy chain sequence (SEQ ID NO.2): EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSSISTGGTTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVSEIYWPMDFWGQGT LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG Example 2: Validation of the effect of humanized DKK-1 monoclonal antibody in improving sarcopenia To evaluate the effect of DKK-1 monoclonal antibody on muscle function, a natural aging sarcopenia model was established using 18-month-old male C57BL / 6 mice. The mice were randomly divided into two groups (n=8 per group): the experimental group received weekly subcutaneous injections of DKK-1 monoclonal antibody (25 mg / kg, diluted in 100 μL PBS), while the control group received an equal volume of PBS subcutaneously.

[0018] Treatment with DKK-1 monoclonal antibody (25 mg / kg) once weekly for three months significantly improved muscle function in aging mice. Specific assessments are as follows: Figure 1 As shown in the figure, the experimental results showed that the limb grip strength of the mice in the treatment group was significantly enhanced, and their weight also showed healthy growth.

[0019] In addition, the gastrocnemius muscle of mice was stained with hematoxylin and eosin (HE), and the staining results were as follows: Figure 3 As shown in the figure, the average cross-sectional area of ​​muscle fibers in DKK-1 monoclonal antibody-treated sarcopenic mice was larger than that in the sarcopenic control group, indicating that the muscles of the DKK-1 monoclonal antibody-treated mice were more developed. Furthermore, the muscle fiber tears in DKK-1 monoclonal antibody-treated sarcopenic mice were less than those in the control group, and the muscle structure of the DKK-1 monoclonal antibody-treated mice was more intact; additionally, in the areas where muscle tissue lesions occurred, cell nuclei aggregated. It can be seen that "intracellular translocation" and nuclear aggregation exist in the muscle tissue of sarcopenic mice. Figure 3(As indicated by the arrow), and after treatment with DKK-1 monoclonal antibody, the nuclear translocation phenomenon disappeared significantly.

[0020] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. The use of a humanized DKK-1 monoclonal antibody in the preparation of a medicament for improving sarcopenia, wherein the light and heavy chains of the humanized DKK-1 monoclonal antibody are as shown in SEQ ID NO.1-2.

2. The application according to claim 1, wherein the application is for the elderly.

3. The application according to claim 1, wherein the application includes improving grip strength and / or improving body weight.

4. The application according to claim 1, wherein the drug is an injectable preparation.

5. The application according to claim 4, wherein the drug is an injectable preparation for subcutaneous injection.

6. In the application according to claim 4, the drug further includes other pharmaceutical excipients or the drug is a lyophilized powder for injection.

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