CN114939161A - Application of PD-1 antibody in preparation of medicine for treating tendon injury - Google Patents
Application of PD-1 antibody in preparation of medicine for treating tendon injury Download PDFInfo
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- CN114939161A CN114939161A CN202210724451.4A CN202210724451A CN114939161A CN 114939161 A CN114939161 A CN 114939161A CN 202210724451 A CN202210724451 A CN 202210724451A CN 114939161 A CN114939161 A CN 114939161A
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Abstract
The invention belongs to the technical field of medicines, discloses an application method of a PD-1 antibody in preparing a medicine for treating tendon injury, and particularly discloses an application of the PD-1 antibody or an antigen binding fragment derivative thereof in preparing a medicine for preventing and/or treating sports injury. The invention discloses the application of a PD-1 antibody or an antigen binding fragment derivative thereof in preventing and/or treating sports injury for the first time, the PD-1 antibody or the antigen binding fragment derivative thereof can obviously improve the elastic modulus of injured tissues, reduce the calcified volume of the injured tissues, reduce the formation of ectopic ossification of the injured tissues, and achieve the purpose of treating sports injury by inhibiting the formation of calcified tissues of the injured tissues, improving the biomechanical properties of the injured tissues and/or reducing the formation of ectopic ossification of the injured tissues, so that the PD-1 antibody or the antigen binding fragment derivative thereof can be used for preparing medicines for preventing and/or treating sports injury, and is convenient to be applied to clinical and daily health care after tendon injury.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of a PD-1 antibody in preparation of a medicine for treating tendon injury.
Background
The tendon is a dense connective tissue connecting muscles and bones, and transmits contraction force of the muscles to the bones to support body movement. In the case of overuse or age degeneration of tendons, tendon injuries are common in daily life and sports fields because they are acute and chronic injuries of various degrees. Calcification of tendons is a common and serious complication of tendon injury and also a manifestation of chronic functional and structural disorders resulting from tendon injury. The incidence of calcification after achilles tendon rupture surgery is as high as 14% -62%, and symptoms such as pain, tendon weakness, local edema and limited activity can be caused.
At present, the pathogenesis of tendon calcification is not clear, so that no clear medicament for preventing and treating tendon calcification exists. Once formed, the calcification of the tendon cannot be eliminated by conservative treatment methods such as medicines, and can only be relieved by some conservative treatment methods such as local injection of non-steroidal anti-inflammatory drugs, glucocorticoids or local shock wave treatment, and in severe cases, the calcification focus can only be eliminated by surgery, but the effect is limited. The treatment effect of shock wave treatment on tendon calcification is uncertain, although partial research confirms the effectiveness of the treatment, research shows that no obvious beneficial effect exists, the mechanism of shock wave treatment is uncertain, and under the current condition, the treatment method is an option for relieving symptoms unsuitably as a physical treatment method, and a new safer and more effective treatment method is expected to appear in clinic. Although non-steroidal anti-inflammatory drugs and glucocorticoids provide some relief from symptoms and local inflammation in the treatment of calcification in tendons, they may adversely affect the self-healing and homeostasis of the tendons when used as a conservative treatment. Research shows that glucocorticoid can induce tendon cell to generate fibro-cartilage tissue and induce spinal ligament cell to generate osteogenic differentiation, so it is prudent to select glucocorticoid for conservative treatment. After calcification has formed, only analgesic effects can be achieved with non-steroidal anti-inflammatory drugs. Whether non-steroidal anti-inflammatory drugs adversely affect tendon self-healing and homeostasis is controversial. Studies show that the non-steroidal anti-inflammatory drug can inhibit the proliferation and migration of tendon cells in vitro, and animal experiments also find that the non-steroidal anti-inflammatory drug can damage the biomechanical strength of the tendon. Therefore, the development of a drug for preventing and/or treating calcification formation of tendon after tendon injury and improving the biomechanical strength of tendon is a scientific problem to be solved.
Apoptosis receptor (PD-1) antibodies initially serve as an immune checkpoint molecule that down-regulates a variety of immune Cell activities during the immune response to prevent damage to autoimmune tissue, but also thereby impair the killing function of the autoimmune system against tumor cells or pathogens. The PD-1 antibody can improve the immune tolerance of the body caused by tumors or various chronic infections and improve the autoimmune activity by combining with the antibody. At present, the PD-1 antibody is used as an immune check point inhibitor, is applied to diseases such as non-small cell lung cancer, melanoma, head and neck tumors, breast cancer, liver cancer, digestive tract tumors and the like, has good clinical effect, and gradually enters clinical treatment tests of infectious diseases such as HIV, viral hepatitis, septicemia and the like.
The main effects of the PD-1 antibody reported in the prior literature are as follows: (1) treating melanoma, squamous non-small cell lung cancer, Hodgkin lymphoma, hepatocellular carcinoma, and urothelial cancer; (2) treating viral hepatitis; (3) treating sepsis and improving the survival rate of patients. Until now, there is no report that the PD-1 antibody has the effects of preventing the formation of calcification in tendon after tendon injury and improving the biomechanical strength of tendon, and it cannot be inferred from the known properties of PD-1 antibody whether it has the effects of preventing the formation of calcification in tendon after tendon injury and improving the biomechanical strength of tendon.
Disclosure of Invention
The object of the first aspect of the present invention is to provide the use of a PD-1 antibody or an antigen-binding fragment derivative thereof for the preparation of a medicament for the prevention and/or treatment of sports injuries.
The second aspect of the present invention is directed to the use of a PD-1 antibody or an antigen-binding fragment derivative thereof for the manufacture of a medicament for inhibiting the formation of calcification of damaged tissue.
The object of the third aspect of the present invention is to provide the use of a PD-1 antibody or an antigen-binding fragment derivative thereof for the manufacture of a medicament for improving the biomechanical properties of damaged tissue.
The fourth aspect of the present invention is directed to the use of a PD-1 antibody or an antigen-binding fragment derivative thereof for the manufacture of a medicament for inhibiting ectopic ossification after tissue damage.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided the use of PD-1, or an antigen-binding fragment derivative thereof, in the manufacture of a medicament for the prevention and/or treatment of sports injuries.
Preferably, the sports injury comprises at least one of acute injury, chronic injury; further acute injury.
Preferably, the athletic injury comprises at least one of tendon injury, ligament injury; further tendon injury.
Preferably, the tendon injury comprises at least one of rotator cuff injury, biceps brachii longus tendon injury, triceps brachii tendon injury, adductor femoris tendon injury, iliotibial band injury, quadriceps tendon injury, patellar tendon rupture, patellar tendon end disease, achilles tendon injury; further achilles tendon injury.
Preferably, the ligament injury comprises at least one of a ligament injury surrounding an elbow joint, a ligament injury surrounding a knee joint, and a cruciate ligament injury.
Preferably, the antibody or antigen binding fragment thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 Fd, Fv, dAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody.
Preferably, the medicament achieves the purpose of treating and/or preventing sports injuries by inhibiting the formation of calcification in the injured tissue, improving the biomechanical properties of the injured tissue and/or reducing the formation of ectopic ossification of the injured tissue.
Preferably, the medicament further comprises one or more pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable adjuvant comprises at least one of sustained release agent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, and lubricant.
Preferably, the dosage form of the medicament comprises at least one of a solid formulation, a liquid formulation and a semi-solid formulation.
Preferably, the medicament comprises at least one of tablets, capsules, granules, pills, dropping pills, liquid preparations, soft extracts, suspending agents, dispersing agents, syrups, suppositories, gels, aerosols and patches.
In a second aspect of the invention, there is provided the use of a PD-1 antibody, or an antigen-binding fragment derivative thereof, in the manufacture of a medicament for inhibiting the formation of calcification in damaged tissue.
Preferably, the tissue comprises at least one of a tendon, a ligament; further a tendon.
Preferably, the tendon comprises at least one of achilles tendon, rotator cuff, supraspinatus; further the achilles tendon.
Preferably, the ligament comprises at least one of a ligament surrounding an elbow joint, a ligament surrounding a knee joint, and a cruciate ligament.
Preferably, the antibody or antigen binding fragment thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 Fd, Fv, dAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody.
Preferably, the medicament further comprises one or more pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable adjuvant comprises at least one of sustained release agent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, and lubricant.
Preferably, the dosage form of the medicament comprises at least one of a solid formulation, a liquid formulation, a semi-solid formulation.
Preferably, the medicament comprises at least one of tablets, capsules, granules, pills, dripping pills, liquid preparations, soft extracts, suspending agents, dispersing agents, syrups, suppositories, gels, aerosols and patches.
In a third aspect of the invention, there is provided the use of a PD-1 antibody or an antigen-binding fragment derivative thereof in the manufacture of a medicament for improving the biomechanical properties of damaged tissue.
Preferably, the improvement in the biomechanical properties of the damaged tissue is an increase in the elastic modulus of the damaged tissue.
Preferably, the tissue comprises at least one of a tendon, a ligament; further a tendon.
Preferably, the tendon comprises at least one of achilles tendon, rotator cuff, supraspinatus; further the achilles tendon.
Preferably, the ligament comprises at least one of a ligament surrounding the elbow joint, a ligament surrounding the knee joint, and a cruciate ligament.
Preferably, the antibody or antigen binding fragment thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 Fd, Fv, dAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody.
Preferably, the medicament further comprises one or more pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable adjuvant comprises at least one of sustained release agent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, and lubricant.
Preferably, the dosage form of the medicament comprises at least one of a solid formulation, a liquid formulation, a semi-solid formulation.
Preferably, the medicament comprises at least one of tablets, capsules, granules, pills, dripping pills, liquid preparations, soft extracts, suspending agents, dispersing agents, syrups, suppositories, gels, aerosols and patches.
In a fourth aspect of the invention, there is provided the use of a PD-1 antibody or an antigen-binding fragment derivative thereof in the manufacture of a medicament for inhibiting ectopic ossification following tissue injury.
Preferably, the tissue comprises at least one of a tendon, a ligament; further a tendon.
Preferably, the tendon comprises at least one of achilles tendon, rotator cuff, supraspinatus; further the achilles tendon.
Preferably, the ligament comprises at least one of a ligament surrounding an elbow joint, a ligament surrounding a knee joint, and a cruciate ligament.
Preferably, the antibody or antigen binding fragment thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 Fd, Fv, dAb, a complementarity determining region fragment, a single chain antibody, a humanized antibody, a chimeric antibody, or a diabody.
Preferably, the medicament further comprises one or more pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable adjuvant comprises at least one of sustained release agent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, and lubricant.
Preferably, the dosage form of the medicament comprises at least one of a solid formulation, a liquid formulation, a semi-solid formulation.
Preferably, the medicament comprises at least one of tablets, capsules, granules, pills, dripping pills, liquid preparations, soft extracts, suspending agents, dispersing agents, syrups, suppositories, gels, aerosols and patches.
The beneficial effects of the invention are:
the invention discloses the application of a PD-1 antibody or an antigen binding fragment derivative thereof in preventing and/or treating sports injury for the first time, the PD-1 antibody or the antigen binding fragment derivative thereof can obviously improve the elastic modulus of injured tissues, reduce the calcified volume of the injured tissues, reduce the formation of ectopic ossification of the injured tissues, and achieve the purpose of treating sports injury by inhibiting the formation of calcification of the injured tissues, improving the biomechanical performance of the injured tissues and/or reducing the formation of ectopic ossification of the injured tissues, so that the PD-1 antibody or the antigen binding fragment derivative thereof can be used for preparing a medicament for preventing and/or treating sports injury, and is convenient to be applied to clinical and daily health care after tendon injury.
Drawings
FIG. 1 is a graph of the effect of PD-1 antibody on biomechanical parameters following injury to Achilles tendon disruption in mice; wherein A is a graph showing the influence of the PD-1 antibody on the elastic modulus of the mouse achilles tendon after rupture and injury, B is a graph showing the influence of the PD-1 antibody on the cross-sectional area of the mouse achilles tendon after rupture and injury, and C is a graph showing the influence of the PD-1 antibody on the maximum tensile force of the mouse achilles tendon after rupture and injury; d is a graph of the effect of PD-1 antibody on maximal stress following rupture injury of the Achilles tendon in mice, where a indicates P <0.05 and ns indicates no statistical difference.
FIG. 2 is a graph showing the effect of PD-1 antibody on tendon calcification after injury to the Achilles tendon in mice; wherein, A is a CT scanning 3D reconstruction picture of the influence of the PD-1 antibody on the calcification formation of the tendon after the rupture and the injury of the achilles tendon of the mouse, B is a statistical result picture of the influence of the PD-1 antibody on the calcification formation of the tendon after the rupture and the injury of the achilles tendon of the mouse, and p is less than 0.05 in the picture.
FIG. 3 is a graph showing the HE staining results of a tissue section of a mouse with 1mm scale after injury due to achilles tendon rupture.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The materials, reagents and the like used in the present examples are commercially available materials and reagents unless otherwise specified.
Example 1 Effect of PD-1 antibodies on biomechanical Properties of mice post Achilles tendon rupture injury repair
30C 57 mice (provided by the center of laboratory animals of southern medical university, bred in SPF animal room of southern hospital of southern medical university, with squirrel cage and vessels strictly disinfected, freely fed and drunk with purified water; and mice observed before experiment to have other clinical symptoms) with the age of 9 weeks are randomly divided into two groups, and an achilles tendon cutting model is adopted to simulate tendon rupture injury, and the construction method of the achilles tendon cutting model is as follows: after the mice are successfully anesthetized by injecting tribromoethanol before the operation, the mice are supine on an operating table, and the skin at the right heel is depilated and disinfected conventionally; making a longitudinal incision of about 1 cm in the skin at the right heel under sterile conditions to expose the sarcolemma and Achilles tendon; the medial Achilles tendon transects the metatarsus tendon and Achilles tendon, and the skin is sutured.
Administration was started the second day after molding (control group: 50. mu.L PBS/mouse; experimental group: 50. mu.g PBS/mouse)PD-1 antibody, diluting the antibody stock solution to 1mg/mL before injection; the injection amount of the PD-1 antibody is obtained by relevant documents and early experiments, and does not cause adverse reaction on mice; PD-1 antibody was purchased from Bio X Cell, cat #: BP0146), administered by intraperitoneal injection 1 time every 3 days for 4 weeks. Then taking the Achilles tendon of the mouse to carry out a biomechanical tensile test, wherein the specific method comprises the following steps: mice were sacrificed by euthanasia, right lower limbs of mice were taken, rinsed with PBS, and then treated with 3D laser scanner (HandySCAN 3D) TM ) The Cross-sectional area (Cross area) of the achilles tendon is detected, a universal material testing machine (INSTRON) is used for carrying out tensile test on the achilles tendon, and the elastic Modulus (Modulus), the maximum Stress (Max Stress) and the maximum tensile Force (Max Force) are calculated.
The biomechanical performance is the most important index for evaluating the tendon injury repair effect, in the embodiment, the PD-1 antibody is injected into the abdominal cavity of the mouse with the broken and damaged achilles tendon to detect the relevant biological performance of the achilles tendon of the mouse, and the result is shown in figure 1, compared with a control group, the elastic modulus of the achilles tendon of an experimental group is remarkably improved (P is less than 0.05), which indicates that the PD-1 antibody can improve the elastic modulus of the achilles tendon of the mouse. Meanwhile, the cross sectional area, the maximum stress and the maximum tension of the achilles tendon of the experimental group of mice are not statistically different from those of the achilles tendon of the control group of mice, which shows that the PD-1 antibody has no influence on the cross sectional area, the maximum stress and the maximum tension of the achilles tendon of the mice. In conclusion, the PD-1 antibody can effectively improve the biomechanical property of the mouse achilles tendon after being fractured and damaged, namely the PD-1 antibody has a better repairing effect on the mouse tendon damage.
Example 2 Effect of PD-1 antibody on tendon calcification following injury to Achilles tendon rupture in mice
Randomly dividing 20C 57 mice 9 weeks old into two groups, and simulating tendon rupture injury by using an achilles tendon cutting model, wherein the construction method of the achilles tendon cutting model comprises the following specific steps: after the mice are successfully anesthetized by injecting tribromoethanol before the operation, the mice are supine on an operating table, and the skin at the right heel is depilated and disinfected conventionally; a longitudinal incision of about 1 cm was made in the skin at the right heel under sterile conditions, exposing the sarcolemma and Achilles tendon; the medial Achilles tendon transects the metatarsus tendon and Achilles tendon, and the skin is sutured.
Administration was started the next day after the model creation (control group: 50. mu.L PBS per mouse; experimental group: 50. mu.g PD-1 antibody per mouse, diluted 1mg/mL of antibody stock solution before injection; the amount of PD-1 antibody injected was found by relevant literature and preliminary experiments, and no adverse reaction was caused to mice; PD-1 antibody was purchased from Bio X Cell Co., Ltd., cat # BP0146), and 1 intraperitoneal injection administration was performed every 3 days for 4 weeks. And then, taking the mouse achilles tendon for micro-CT detection and analysis, and meanwhile, carrying out conventional HE staining on the mouse achilles tendon tissue. The micro-CT detection of the achilles tendon of the mouse comprises the following specific detection steps: mice were sacrificed by euthanasia, and the right lower limbs of the mice were rinsed with PBS, fixed with paraformaldehyde for 24 hours, and then stored in PBS tubes. The right lower limb is placed and fixed in a detection cabin of a small animal living body X-ray Micro-CT (Skyscan 1276) in parallel, and after scanning is finished, the calcification size is analyzed by using CTAn software.
The calcification formation is a common and serious complication after sports injury, and the micro-CT detection is performed on the achilles tendon of the mouse in the embodiment, and the result is shown in fig. 2, compared with the control group, the calcification volume in the achilles tendon of the experimental group is obviously reduced (P is less than 0.05), that is, the PD-1 antibody can obviously reduce the calcification volume after tendon injury, which indicates that the PD-1 antibody can inhibit the tendon calcification formation after tendon rupture injury. By HE staining of the tissues of the achilles tendon of the mouse, the result shows that compared with the control group, the mice with tendon rupture injury are injected with the PD-1 antibody, and the tissues of the achilles tendon of the mouse have no obvious ectopic ossification forming area (figure 3, wherein the inside of the dotted circle is divided into the ectopic ossification forming area), which shows that the PD-1 antibody can obviously reduce the ectopic ossification formation after tendon injury.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
- Use of a PD-1 antibody or antigen-binding fragment derivative thereof in the manufacture of a medicament for the prevention and/or treatment of sports injuries.
- 2. The use of claim 1, wherein the athletic injury comprises at least one of an acute injury and a chronic injury.
- 3. The use of claim 2, wherein the athletic injury comprises at least one of a tendon injury, a ligament injury.
- 4. The use according to any one of claims 1 to 3, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 Fd, Fv, dAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody.
- Use of a PD-1 antibody or antigen-binding fragment derivative thereof in the manufacture of a medicament for inhibiting calcification of damaged tissue.
- Use of a PD-1 antibody or antigen-binding fragment derivative thereof in the manufacture of a medicament for improving the biomechanical properties of damaged tissue.
- Use of a PD-1 antibody or antigen-binding fragment derivative thereof in the manufacture of a medicament for inhibiting ectopic ossification formation following tissue injury.
- 8. The use according to any one of claims 5 to 7, wherein the tissue comprises at least one of a tendon, a ligament.
- 9. The use of claim 8, wherein the tendon comprises at least one of achilles tendon, rotator cuff, supraspinatus.
- 10. Use according to claim 9,wherein said antibody or antigen binding fragment thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 Fd, Fv, dAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody.
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| CN117442703A (en) * | 2023-11-29 | 2024-01-26 | 南方医科大学南方医院 | Application of Elamipretide in preparation of drugs for preventing and/or treating tendon injury |
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| CN111363041A (en) * | 2016-03-23 | 2020-07-03 | 迈博斯生物医药(苏州)有限公司 | Novel anti-PD-L1 antibodies |
| CN113694204A (en) * | 2021-08-26 | 2021-11-26 | 南方医科大学南方医院 | Composition for treating osteomyelitis and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111363041A (en) * | 2016-03-23 | 2020-07-03 | 迈博斯生物医药(苏州)有限公司 | Novel anti-PD-L1 antibodies |
| CN113694204A (en) * | 2021-08-26 | 2021-11-26 | 南方医科大学南方医院 | Composition for treating osteomyelitis and application thereof |
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| Title |
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| MARY E. KEIR等: "PD-1 and Its Ligands in Tolerance and Immunity", 《ANNU. REV. IMMUNOL》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117442703A (en) * | 2023-11-29 | 2024-01-26 | 南方医科大学南方医院 | Application of Elamipretide in preparation of drugs for preventing and/or treating tendon injury |
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