WO2020020090A1 - 一种特异性抗体的用途、一种植入医疗器械及其制备方法 - Google Patents

一种特异性抗体的用途、一种植入医疗器械及其制备方法 Download PDF

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WO2020020090A1
WO2020020090A1 PCT/CN2019/097000 CN2019097000W WO2020020090A1 WO 2020020090 A1 WO2020020090 A1 WO 2020020090A1 CN 2019097000 W CN2019097000 W CN 2019097000W WO 2020020090 A1 WO2020020090 A1 WO 2020020090A1
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medical device
specific antibody
hematopoietic stem
stem cell
implanted medical
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French (fr)
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王玄
周婷
李俊菲
姚瑶
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上海微创医疗器械（集团）有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/14—Materials or treatment for tissue regeneration for ear reconstruction or ear implants, e.g. implantable hearing aids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/22—Materials or treatment for tissue regeneration for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to the use of a specific antibody, an implanted medical device and a preparation method thereof.
  • AC133 is a marker of hematopoietic stem cells.
  • AC133 was officially named CD133 at the 7th International Conference on Human Leukocyte Differentiation Antigens held in Harrogate, UK.
  • the CD133 antigen is recognized by three CD133 antibodies: clones AC133, 293C3, and AC141.
  • Clone AC133 directly binds to the CD133 / 1 glycosylated epitope and can be used to analyze and sort CD133-positive cells from peripheral blood, bone marrow, umbilical cord blood and other tissues.
  • Monoclonal antibodies 293C3 and AC141 recognize the epitope CD133 / 2 and are mainly used for fluorescence staining of CD133 + cells after MACS sorting.
  • the left atrial appendage is an auricular sac protruding from the left atrium and belongs to the left atrium. It is the main component of the left atrium.
  • Left atrial appendage occlusion was developed by Boston Scientific and approved for marketing in Europe in 2006. On December 31, 2013, it was officially approved by the China Food and Drug Administration for listing and officially launched in China in March 2014.
  • the left atrial appendage the root site of thrombosis in patients with AF, can be used to reduce the risk of stroke in patients with AF.
  • the surface of the occluder is covered with an expandable polytetrafluoroethylene film, which is similar to general implanted medical devices. It also needs to be loaded with drugs that repair damaged tissues to prevent the adverse consequences of surgery.
  • medical devices that promote endothelial repair are generally achieved by loading small molecular compounds or compositions on the surface of medical devices, which are all based on the mechanism of promoting cell growth.
  • this method is generally poor in specificity. While promoting endothelial growth, it also promotes the growth of other cells including smooth muscle and fibroblasts, resulting in adverse consequences such as restenosis of blood vessels and thrombosis.
  • the side effects of the drugs in this way are large, which can bring other adverse effects.
  • the invention provides the use of a specific antibody, an implanted medical device and a preparation method thereof, so as to provide a new way to promote endothelial repair.
  • the invention provides a use of a specific antibody, the specific antibody is a specific antibody for a hematopoietic stem cell marker, and the use is in the preparation of a medicament for promoting endothelial repair.
  • Hematopoietic stem cells are adult stem cells in the blood system with long-term self-renewal capabilities and the potential to differentiate into various types of mature blood cells. Inducing hematopoietic stem cells to differentiate into the required types of cells in situ according to demand can achieve the purpose of promoting endothelial repair.
  • the specific antibody for the hematopoietic stem cell marker is an AC133 antibody.
  • CD133 / 1 and CD133 / 2 recognize the same kind of cells, but there is only a difference in expression intensity.
  • the expressions of CD133 / 1 and CD133 / 2 are different, or the normal expression intensity is disordered. Therefore, AC133 is considered to be a marker of primitive hematopoietic cell group.
  • the AC133 antibody is Clone AC133 (AC133 monoclonal antibody).
  • Clone AC133 was purchased from Miltenyi Biotech Co., Ltd., Germany.
  • the invention also provides an implanted medical device, the surface of the implanted medical device is loaded with a specific antibody of a hematopoietic stem cell marker.
  • Hematopoietic stem cell marker-specific antibodies can capture hematopoietic stem cells in the blood, further induce hematopoietic stem cells to differentiate into endothelial cells, and improve the device's treatment and tissue repair effects.
  • the specific antibody for the hematopoietic stem cell marker is an AC133 antibody.
  • the AC133 antibody is Clone AC133.
  • a specific antibody of the hematopoietic stem cell marker is carried on at least one side of the implanted medical device.
  • the implanted medical device is a vascular prosthesis, a prosthetic valve membrane, a prosthetic valve stent, a left atrial appendage occluder membrane, a left atrial appendage occluder stent, a heart occluder membrane, a heart occluder stent, or an artificial Patch.
  • the specific antibody concentration range of the hematopoietic stem cell marker on the surface of the implanted medical device is: 10-1000 g / mm 2 .
  • concentration is too low, the antibody is quickly dissolved in the blood; when the concentration reaches a certain level, the antibody binding site is saturated, and the above effect is no longer increased.
  • the present invention also provides a method for preparing the above-mentioned implanted medical device, comprising: loading a specific antibody of the hematopoietic stem cell marker on at least a part of the surface of the implanted medical device; and / or loading the hematopoietic stem cell marker. Specific antibodies are loaded in the holes or grooves of the implanted medical device.
  • the specific antibody of the hematopoietic stem cell marker is loaded on the surface of the implanted medical device by at least one of a direct coating method, a chemical graft method, and an electrostatic adsorption method.
  • the direct coating method is to directly apply the specific antibody solution of the hematopoietic stem cell marker to the surface of the implanted medical device, and the coating method is spray coating, dip coating, or spin coating.
  • the chemical grafting method may be to chemically modify the antibody molecules so that they can be chemically connected to the surface of the device or the surface of the device coating, or it may use an antibody linker or a cross-linking agent to bind the antibody molecules to the surface of the device. .
  • the electrostatic adsorption method is to coat the surface of the device with an oppositely charged coating, so that the antibody molecules are coated on the surface of the device by electrostatic adsorption.
  • the technical scheme provided by the present invention creatively uses specific antibodies of hematopoietic stem cell markers to achieve the effect of promoting endothelial repair of medical devices.
  • the technical scheme provided by the present invention captures the human hematopoietic stem cells and induces them to produce cells, thereby achieving targeted endothelial repair. Therefore, the side effects of the drug in this way are small, and no other adverse effects are brought about, and the comprehensive effect is more ideal.
  • FIG. 1 is a fluorescence diagram of a sample loaded with a specific antibody of a hematopoietic stem cell marker in an antibody loading experiment of Example 5 after staining with a secondary antibody fluorescent dye, in which (1) to (4) correspond to Examples 1 to 4 in order sample;
  • FIG. 2 is a fluorescence diagram of a sample loaded with a specific antibody against a hematopoietic stem cell marker in a cell capture experiment of Example 5 to capture cells in the blood, and fluorescently stain the cells with specific antibodies, in which (1) to (4) are sequentially Corresponding to the samples in Examples 1 to 4;
  • FIG. 3 is an SEM characterization image of the stent loaded with AC133 antibody and the drug stent in the rabbit iliac artery 14 days after implantation in the animal experiment of Example 5.
  • the left side is the stent sample of Example 1, and the middle is the stent sample of Example 2.
  • On the right is a stent sample from the control group;
  • FIG. 4 is an SEM characterization image of an AC133 antibody-loaded membrane suture in an animal experiment of Example 5 after 14 days of implantation of the left atrial appendage occluder stent.
  • the left side is the sample of Example 3, and the middle is the sample of Example 4.
  • the "medical device” referred to in the present invention may be a device implanted in a body.
  • the device can be used temporarily for short periods or permanently implanted for long periods.
  • suitable devices are commonly used for arrhythmia, heart failure, valvular disease, vascular disease, diabetes, neurological diseases and disorders, orthopedics, neurosurgery, oncology, ophthalmology, and ENT Surgery provides medical and / or diagnostic equipment.
  • the medical devices involved in the present invention include, but are not limited to, the following devices: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, wires, catheters, sensors, surgical instruments, angioplasty balls, and wound drainage tubes , Shunt, tube, infusion sleeve, urethral intubation, pellet, implant, blood oxygen generator, pump, vascular graft, vascular access box port), heart valves, annuloplasty rings, sutures, surgical clips, surgical staples, pacemakers, implantable defibrillators, neurostimulators, orthopedic surgical instruments, cerebrospinal fluid shunt tubes, implantable Medication pumps, cages, artificial discs, alternative devices to the nucleus pulposus, ear canals, intraocular lenses, and any tubes used in interventional procedures.
  • the medical devices according to the present invention are in particular: stents, balloons, occluders, valves or artificial blood vessels.
  • AC133 monoclonal antibody Clone AC133 100 g of AC133 monoclonal antibody Clone AC133 (purchased from Miltenyi Biotech Co., Ltd., Germany) was dissolved in 10 mL of the antibody dilution to prepare an antibody solution with a concentration of 10 g / mL.
  • polyelectrolyte chitosan (CS) 1mg / mL dissolved in 0.1% NaCl solution
  • Amine (PEI) 5 mg / mL was dissolved in a 0.1% NaCl solution.
  • PEI polyacetimide
  • HA sodium hyaluronate
  • CS chitosan
  • the above-mentioned HA / CS electrostatic assembly process was repeated 7 times to obtain a sodium hyaluronate / chitosan self-assembled multilayer film, which is denoted as PEI (HA / CS) 7 .
  • PEI sodium hyaluronate / chitosan self-assembled multilayer film
  • the stent treated as above was immersed in the antibody solution for 30 min, and N 2 was taken out and blow-dried.
  • the preparation of the AC133 antibody-loaded scaffold was completed.
  • the concentration of the AC133 antibody on the surface of the stent was 19 g / mm 2 .
  • AC133 monoclonal antibody Clone AC133 (purchased from Miltenyi Biotech Co., Ltd., Germany) was dissolved in 1 mL of antibody dilution to prepare an antibody solution with a concentration of 100 g / mL.
  • the stent after the treatment is immersed in the antibody solution, left for 30 minutes, taken out, air-dried, and stored at 4 ° C.
  • the preparation of the AC133 antibody-loaded scaffold was completed. After weighing calculation, the final concentration of the AC133 antibody on the surface of the stent was 71 g / mm 2 .
  • AC133 monoclonal antibody Clone AC133 (purchased from Miltenyi Biotech Co., Ltd., Germany) was dissolved in 1 mL of antibody dilution to prepare an antibody solution with a concentration of 1 mg / mL.
  • the antibody solution was sprayed onto the surface of the left atrial appendage occluder membrane with an ultrasonic sprayer, air-dried, and stored at 4 ° C. Preparation of AC133 antibody-loaded left atrial appendage occluder membrane was completed. After weighing calculation, the concentration of AC133 antibody on the surface of the membrane was finally measured to be 690 g / mm 2 .
  • This example is an in vivo and in vitro function evaluation of the antibody-loaded samples in Examples 1, 2, 3, and 4.
  • AC133 antibody-loaded samples were stained with TRITC-labeled anti-mouse IgG secondary antibodies to identify whether the antibodies were successfully loaded. As shown in Figure 1, the sample can be dyed to a fluorescent color after loading. This indicates that the antibody can be successfully loaded on the sample surface.
  • 6-well plates covered with fibronectin were used, and the scaffolds bearing the AC133 antibodies in Examples 1, 2, 3, and 4 were placed in different 6-well plate wells. Take the mixed cell suspension and add 2mL of cell suspension to each well. The six-well plate was placed in a 37 ° C incubator with a CO 2 concentration of 5% with shaking culture. After 2 hours, the 6-well plate was removed, the cells were fixed, and the cells were stained with an antibody dye (AC133-PE) grafted with a phycoerythrin fluorescent group, and the cell performance was identified.
  • AC133-PE antibody dye
  • AC133-PE dye can be used to fluorescently capture cells. As shown in Figure 2, the cells captured on the surface of the sample can be stained with phycoerythrin fluorescent dye to fluorescent color, indicating that the antibody-loaded sample can successfully capture hematopoietic stem cells.
  • AC133 antibody-supported scaffolds or membranes were prepared according to the methods in Examples 1, 2, 3, and 4.
  • the tools and reagents used in the preparation process need to be sterilized beforehand, and the entire preparation process is completed in a sterile environment.
  • the obtained stent is crimped, blow-molded, packaged in a sterile environment, and stored at 4 ° C until use.
  • the obtained membrane was sewn on the surface of the stent of the left atrial appendage occluder, sterilized, packaged, and stored at 4 ° C until use.
  • the experimental group was two different cell capture scaffolds of Examples 1 and 2, and the control group was a rapamycin drug scaffold, with 3 animals in each group.
  • Each rabbit implanted a stent in the left and right iliac arteries as a parallel sample.
  • target vessels Prior to stent implantation, target vessels were evaluated by angiography. After the stent is implanted, all target vessels will be evaluated again by angiography.
  • the experimental group was a sample made of the membranes in Examples 3 and 4, the control group was a left atrial appendage occluder made of untreated membranes, and the experimental group and the control group had 3 animals each.
  • the left atrial appendage of the experimental group was loaded with antibodies, and the left atrial appendage of the control group was not treated. After the animals were anesthetized, atrial septal puncture was performed under X-ray fluoroscopy.
  • the puncture sheath was pushed into the left atrium, the puncture needle was withdrawn, the superhard guide wire was inserted along the dilator, the left atrial appendage occluder sheath was exchanged, and a 6F pigtail catheter was sent along the sheath to the left atrial appendage for imaging.
  • an occluder of appropriate specifications was selected for implantation in the left atrial appendage, and the occlusive effect was observed by angiography and the occlusion stability was tested by traction. If the occlusion effect is good and the occluder is stable, release the occluder. Withdraw the sheath tube and complete the operation to complete the left atrial appendage occluder implantation operation.
  • the blood vessels in the stent segment were taken out, cut along the axial direction of the blood vessel, rinsed with normal saline containing heparin for 1 minute, and then transferred to 2.5% glutaraldehyde to fix. Then, the endothelium coverage was observed with a scanning electron microscope.
  • the stent samples were characterized by SEM 14 days after they were implanted into the iliac artery of the rabbit.
  • Figure 3 shows the SEM characteristics of the stent samples of Example 1, 2 and the control group in order from left to right. It can be seen from FIG.
  • the animals were euthanized.
  • the left atrial appendage occluder was dissected out and the left atrial appendage occluder membrane was removed from the stent.
  • the endothelialization of the membrane surface was observed by SEM.
  • the left side is the sample of Example 3
  • the middle is the sample of Example 4
  • the right side is the untreated film.
  • the SEM images of the two samples on the left and the middle show that the membrane surface is completely covered by endothelial cells
  • the SEM images on the right show a large amount of fibrin and blood cell deposition on the untreated membrane surface. This shows that the left atrial appendage occluder using an antibody-loaded membrane can rapidly achieve endothelialization.
  • the technical solution provided by the present invention creatively uses the specific antibody of the hematopoietic stem cell marker to realize the effect of promoting endothelial repair of medical devices.
  • the technical scheme provided by the present invention captures the human hematopoietic stem cells and induces them to produce cells, thereby achieving targeted endothelial repair. Therefore, the side effects of the drug in this way are small, and no other adverse effects are brought about, and the comprehensive effect is more ideal.

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Abstract

一种特异性抗体的用途、一种植入医疗器械及其制备方法。该用途为造血干细胞标记物的特异性抗体在制备促进内皮修复的药物中的应用。该植入医疗器械表面负载有造血干细胞标记物的特异性抗体。该制备方法包括将造血干细胞标记物的特异性抗体负载在植入医疗器械的至少一部分表面和/或将造血干细胞标记物的特异性抗体负载在植入医疗器械的孔内或槽内的工序。

Description

一种特异性抗体的用途、一种植入医疗器械及其制备方法 技术领域
本发明属于生物医药技术领域，具体涉及一种特异性抗体的用途、一种植入医疗器械及其制备方法。
背景技术
1997年Yin等人证实AC133是造血干细胞的标志物。2000年，在英国Harrogate举行的第7届人类白细胞分化抗原国际工作会议上，AC133被正式命名为CD133。CD133抗原可被3种CD133抗体识别：克隆AC133、293C3和AC141。克隆AC133直接与CD133/1糖基化抗原表位结合，可用于从外周血、骨髓、脐带血及其它组织中分析和分选CD133阳性细胞。单克隆抗体293C3和AC141识别抗原表位CD133/2，主要用于MACS分选后CD133+细胞的荧光染色。
左心耳是从左心房伸出的耳状小囊，属于左心房的一部分，它是左心房的主要组成部位。左心耳封堵术由波士顿科学公司研发，于2006年在欧洲获批上市，2013年12月31日，正式获得中国国家食品药品监督管理总局上市批准，并于2014年3月在中国正式上市。通过这种介入手术闭合房颤病人血栓发生的根源部位——左心耳，由此可降低房颤病人中风的风险。封堵器的表面覆盖的是可扩张的聚四氟乙烯膜，同一般植入医疗器械类似，其也需要负载一些对损伤组织进行修复的药物，以防止手术带来的不良后果。
目前促进内皮修复的医疗器械一般都是通过在医疗器械表面负载小分子化合物或组合物来实现的，都是基于促进细胞生长的机理。但，这种方式一般特异性差，其在促进内皮生长的同时也促进包括平滑肌、纤维细胞等其他细胞的生长，从而造成血管再狭窄、血栓等不良后果。此外，这种方式的药物副作用大，会带来其他不良影响。
发明内容
本发明提供一种特异性抗体的用途、一种植入医疗器械及其制备方法， 以提供一种全新的促进内皮修复的方式。
本发明提供了一种特异性抗体的用途，所述特异性抗体是造血干细胞标记物的特异性抗体，所述用途为在制备促进内皮修复的药物中的应用。造血干细胞是血液系统中的成体干细胞，具有长期的自我更新能力和分化成各类成熟血细胞的潜能。根据需求诱导造血干细胞原位分化为所需要类型的细胞，可实现促进内皮修复的目的。
可选地，所述造血干细胞标记物的特异性抗体为AC133抗体。多数情况下CD133/1和CD133/2识别同种细胞，只是有表达强度的差别。但是，在骨髓增生异常综合征和某些急性髓性白血病中发现CD133/1和CD133/2表达不同，或者正常表达强度紊乱，故认为AC133为原始造血细胞群标志。
可选地，所述AC133抗体为Clone AC133(AC133单克隆抗体)。Clone AC133购于德国美天旎生物科技有限公司。
本发明还提供了一种植入医疗器械，所述植入医疗器械表面负载有造血干细胞标记物的特异性抗体。造血干细胞标记物的特异性抗体可在血液中捕获造血干细胞，进一步诱导造血干细胞向内皮细胞分化，可完善器械的治疗和组织修复效果。
可选地，所述造血干细胞标记物的特异性抗体为AC133抗体。
可选地，所述AC133抗体为Clone AC133。
可选地，所述造血干细胞标记物的特异性抗体负载在所述植入医疗器械的至少一个面。
可选地，所述植入医疗器械为人工血管、人工瓣膜的膜、人工瓣膜支架、左心耳封堵器膜、左心耳封堵器支架、心脏封堵器膜、心脏封堵器支架或人工补片。
可选地，所述植入医疗器械表面上所述造血干细胞标记物的特异性抗体的浓度范围是：10～1000g/mm 2。浓度过低，抗体在血液中很快被溶解；浓度达到一定程度抗体结合位点饱和，上述效果不再增加。
本发明还提供了上述植入医疗器械的制备方法，包括将所述造血干细胞标记物的特异性抗体负载在所述植入医疗器械的至少一部分表面上和/或将所 述造血干细胞标记物的特异性抗体负载在所述植入医疗器械的孔内或槽内。
可选地，所述造血干细胞标记物的特异性抗体通过直接涂覆法、化学接枝法和静电吸附法中的至少一种负载到所述植入医疗器械的表面。
其中，直接涂敷法是将所述造血干细胞标记物的特异性抗体溶液直接涂覆到植入医疗器械表面，涂覆的方法为喷涂、浸涂或旋涂。
其中，化学接枝法可以是对抗体分子进行化学改性，使其能够和器械表面或器械涂层表面发生化学连接，也可以是通过使用抗体连接剂或交联剂将抗体分子和器械表面结合。
其中，静电吸附法是在器械表面涂覆带相反电荷的涂层，使得抗体分子通过静电吸附力涂覆到器械表面。
本发明提供的技术方案创造性地采用造血干细胞标记物的特异性抗体来实现医疗器械的促进内皮修复的功效。与现有内皮修复方式相比，本发明提供的技术方案捕获人体自身的造血干细胞并诱导其产生细胞，从而实现有针对性的内皮修复。因此，这种方式的药物副作用小，不会带来其他不良影响，综合疗效更加理想。
附图说明
图1是实施例5的抗体负载实验中负载有造血干细胞标记物的特异性抗体的样本用二抗荧光染料染色后的荧光图，其中(1)～(4)依次对应实施例1～4中的样品；
图2是实施例5的细胞捕获实验中负载有造血干细胞标记物的特异性抗体的样本捕获血液中的细胞，对细胞进行特异性抗体荧光染色的荧光图，其中(1)～(4)依次对应实施例1～4中的样品；
图3是实施例5的动物实验中负载有AC133抗体的支架和药物支架植入兔髂动脉14天后的SEM表征图，左侧为实施例1的支架样品，中间为实施例2的支架样品，右侧为对照组的支架样品；
图4是实施例5的动物实验中负载有AC133抗体的膜缝织在左心耳封堵器支架植入体内14天后的SEM表征图，左侧为实施例3的样品，中间为实 施例4的样品，右侧为未处理的膜。
具体实施方式
为了便于理解，下面结合实施例阐述所述造血干细胞标记物的特异性抗体的用途，应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
本发明中所用的原材料及器械，如无特别指出，均为可市购商品。
本发明中所涉及的“医疗器械”可以是植入体内的器械。该器械可以短期暂时使用，或者长期永久性植入。在某些实施方式中，合适的器械是通常用于为心律失调、心力衰竭、瓣膜性疾病、血管病、糖尿病、神经疾病和失调症、整型外科、神经外科、肿瘤学、眼科学和ENT手术提供医疗和/或诊断的器械。本发明所涉及的医疗器械包括但不限于以下设备：支架、支架移植物、吻合连接器、合成贴片、引线、电极、针、导线、导管、传感器、手术仪器、血管成形球、创口引流管、分流管(shunt)、管子、输液套简(infusion sleeve)、尿道插管、小球、植入物、血液充氧发生器、泵、脉管移植物、埋入式介入药盒(vascular access port)、心瓣膜、瓣环成形术环、缝合线、手术夹、手术钉、起博器、可植入去纤颤器、神经刺激器、整型外科器械、脑脊髓液分流管、可植入药泵、椎笼、人造椎间盘、髓核的替代器械、耳管、眼内晶状体和在介入手术中使用的任何管。优选地，本发明所涉及的医疗器械尤其是：支架、球囊、封堵器、瓣膜或人工血管。
实施例1
100g AC133单克隆抗体Clone AC133(购于德国美天旎生物科技有限公司)溶解于10mL抗体稀释液中，配制成浓度为10g/mL的抗体溶液。聚电解质透明质酸钠(HA)1mg/mL溶于0.1％的NaCl溶液中，聚电解质壳聚糖(CS)1mg/mL溶于0.1％的NaCl溶液中，基础涂层用聚电解质聚酰亚胺(PEI)5mg/mL溶于0.1％的NaCl溶液中。
将血管支架用H 2SO 4:H 2O 2(30％,v/v)＝3:1溶液浸泡30分钟，用纯化水漂 洗3次，氮气吹干。首先浸于聚乙酰亚胺(PEI)溶液中得到PEI层；将PEI处理过的支架浸于透明质酸钠(HA)溶液中得到HA外层；接着将支架浸于壳聚糖(CS)溶液中得到CS外层。重复上述HA/CS静电组装过程7次，得到透明质酸钠/壳聚糖自组装多层膜，记为PEI(HA/CS) 7。将经上述处理的支架浸泡在抗体溶液中30min，取出N 2吹干。完成AC133抗体负载支架的制备。支架表面的AC133抗体的浓度为19g/mm 2。
实施例2
100g AC133单克隆抗体Clone AC133(购于德国美天旎生物科技有限公司)溶解于1mL抗体稀释液中，配制成浓度为100g/mL的抗体溶液。将血管支架用H 2SO 4:H 2O 2＝3:1溶液浸泡30分钟，用纯化水漂洗3次，氮气吹干。经上述处理后的支架浸于抗体溶液中，静置30分钟后取出，自然晾干，于4℃条件下保存。完成AC133抗体负载支架的制备。经称重计算，最终测得支架表面的AC133抗体的浓度为71g/mm 2。
实施例3
1mg AC133单克隆抗体Clone AC133(购于德国美天旎生物科技有限公司)溶解于1mL抗体稀释液中，配制成浓度为1mg/mL的抗体溶液。用超声喷涂仪将抗体溶液喷涂到左心耳封堵器膜表面，自然晾干，于4℃条件下保存。完成AC133抗体负载的左心耳封堵器膜的制备。经称重计算，最终测得该膜表面的AC133抗体的浓度为690g/mm 2。
实施例4
1mg AC133单克隆抗体Clone AC133(购于德国美天旎生物科技有限公司)溶解于1mL抗体稀释液中，配制成浓度为1mg/mL的抗体溶液。聚电解质透明质酸钠(HA)1mg/mL溶于0.1％的NaCl溶液中，聚电解质壳聚糖(CS)1mg/mL溶于0.1％的NaCl溶液中，基础涂层用聚电解质聚酰亚胺(PEI)5mg/mL溶于0.1％的NaCl溶液中。抗体连接剂NHS(100mM)/EDC(400mM)溶解于 0.1％的NaCl溶液中。
将左心耳封堵器膜洗净。首先浸于PEI溶液中，得到PEI层；将PEI处理过的支架浸于透明质酸钠溶液中，得到HA外层；接着将支架浸于壳聚糖溶液中得到CS外层。重复上述HA/CS静电组装过程7次，得到透明质酸钠/壳聚糖自组装多层膜，记为PEI(HA/CS) 7。将经上述处理的膜浸泡在抗体连接剂NHS(100mM)/EDC(400mM)溶液中并在4℃下反应2小时后，取出放入抗体溶液中并在37℃下反应2小时，取出N 2吹干。完成AC133抗体负载膜的制备。经称重计算，最终测得膜表面的AC133抗体的浓度为956g/mm 2。
实施例5
本实施例是实施例1、2、3、4中的负载抗体的样品的体内外功能评价。
5.1抗体负载结果评价
将AC133抗体负载样品用TRITC标记抗小鼠IgG二抗进行荧光染色，以鉴定抗体是否负载成功。如图1所示，样品经负载后可以被染成荧光色。说明抗体能够成功的被负载在样品表面。
5.2细胞捕获实验
采集兔静脉血液5mL，用PBS进行稀释混匀，兔静脉血液与PBS的体积比为1:1；将稀释血液缓慢滴加到Ficoll淋巴细胞分离液表面，稀释血液与分离液的体积比为1:1；2500rpm速度离心30分钟；吸取中间富含血小板血浆的淋巴细胞层至干净离心管中，加入5mL PBS，吸管吹打混匀，2000rpm速度离心10分钟；去除上层澄清液，再加入5mL PBS，吸管吹打混匀，2000rpm速度离心10分钟，去除上清液获得底部细胞，盖好离心管盖，转移到无菌操作台内。打开离心管盖，向管底加入6mL EGM-2培养基，吹打混匀，得到细胞悬浮液。选用铺好纤粘连蛋白的6孔板，将实施例1、2、3、4中的负载AC133抗体的支架分别置于不同的6孔板孔内。取混匀的细胞悬浮液，每孔加入2mL细胞悬浮液。将六孔板置于37℃，CO 2浓度为5％的培养箱内摇 晃培养。2小时后，取出6孔板，固定细胞，用接枝有藻红蛋白荧光基团的抗体染料(AC133-PE)对细胞进行染色后，鉴定细胞表现。
由于AC133捕获的细胞一定表达AC133。因此，用AC133对应的抗体荧光染料AC133-PE染料可以对捕获细胞进行荧光标记。如图2所示，样品表面捕获的细胞可以被藻红蛋白荧光染料染成荧光色，说明负载了抗体的样品可以成功捕获到造血干细胞。
5.3动物实验
(一)支架制备
按照实施例1、2、3、4中的方法制备AC133抗体负载支架或膜。制备过程中使用的工具和试剂均需事前灭菌，制备工艺全程在无菌环境内完成。获得的支架在无菌环境内压握、吹塑、包装、在4℃温度下保存，待用。获得的膜缝织在左心耳封堵器支架表面，灭菌、包装、在4℃温度下保存，待用。
(二)支架植入
准备体重为2.2-2.6kg的新西兰大白兔9只，动物体重与年龄相匹配。实验组为实施例1和2的两种不同的细胞捕获支架，对照组为雷帕霉素药物支架，每组3只动物。每只兔子在左右髂动脉各植入1枚支架作为平行样。器械按照目标支架:动脉尺寸＝1.10:1.0～1.20:1.0的比例进行植入。支架植入前通过血管造影术对目标血管进行评价。支架植入后所有目标血管也将再次通过血管造影术进行评价。
(三)封堵器植入
准备体重为30kg左右的比格犬9只。实验组为采用实施例3、4中的膜制成的样本，对照组为未处理的膜制成的左心耳封堵器，实验组和对照组每组3只动物。实验组的左心耳膜负载有抗体，对照组的左心耳膜未经过处理。动物麻醉后，在X射线透视环境下进行房间隔穿刺。穿刺成功后，推送穿刺鞘进入左心房，撤出穿刺针，沿扩张器插入超硬导丝，交换左心耳封堵器鞘管，沿鞘管送入6F猪尾导管至左心耳后，进行造影。通过观察左心耳形状并 测量左心耳开口宽度及深度，选择合适规格的封堵器植入左心耳，并通过造影观察封堵效果以及牵拉测试封堵稳固性。若封堵效果良好且封堵器稳固，则解脱封堵器。撤出鞘管，进行手术收尾工作，完成左心耳封堵器植入手术。
(四)实验结果
支架植入14天后，取出植入支架段血管，沿血管轴向剖开，用含肝素的生理盐水冲洗1分钟，然后将血管转移到2.5％戊二醛中固定，24小时后取出脱水、干燥后，用扫描电镜观察内皮覆盖情况。支架样品植入兔髂动脉14天后通过SEM进行表征，图3从左到右依次为实施例1、2和对照组的支架样品的SEM表征图。从图3可以发现，实施例1和2的支架样品植入14天后，血管内皮有完整的内皮组织覆盖，内皮细胞形态良好。对照组药物支架血管内壁图显示，血管内壁有大量的纤维蛋白覆盖，内皮生长不良。结果表明，所制备的干细胞捕获支架可以达到更好的促内皮修复效果。
封堵器植入14天后，对动物实施安乐死，解剖取出左心耳封堵器，将左心耳封堵器膜从支架上取下。固定、脱水后用SEM观察膜表面的内皮化情况。如图4所示，左侧为实施例3的样品，中间为实施例4的样品，右侧为未处理的膜。左侧和中间的两个样品的SEM图显示，膜表面被内皮细胞完整覆盖，右侧的SEM图显示未处理的膜表面有大量纤维蛋白和血液细胞沉积。说明，使用负载抗体的膜的左心耳封堵器可迅速实现内皮化。
本发明提供的技术方案创造性地采用用造血干细胞标记物的特异性抗体来实现医疗器械的促进内皮修复的功效。与现有内皮修复方式相比，本发明提供的技术方案捕获人体自身的造血干细胞并诱导其产生细胞，从而实现有针对性的内皮修复。因此，这种方式的药物副作用小，不会带来其他不良影响，综合疗效更加理想。
应说明的是，以上实施例仅用以说明本发明的技术方案，而非对本发明的保护范围进行限制。尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员依然可以对前述实施例所记载的技术方案进行修改，或者对其中的部分或者全部技术特征进行等同替换，而这些修改或替换，并不使相应技术方案的本质脱离本发明各实施例的技术方案的保护范围。

Claims (10)

  1. 一种特异性抗体的用途，其特征在于，所述特异性抗体是造血干细胞标记物的特异性抗体，所述用途为在制备促进内皮修复的药物中的应用。
  2. 根据权利要求1所述的用途，其特征在于，所述造血干细胞标记物的特异性抗体为Clone AC133。
  3. 一种植入医疗器械，其特征在于，所述植入医疗器械表面负载有Clone AC133。
  4. 根据权利要求3所述的植入医疗器械，其特征在于，所述造血干细胞标记物的特异性抗体负载在所述植入医疗器械的至少一个面。
  5. 根据权利要求4所述的植入医疗器械，其特征在于，所述植入医疗器械为人工血管、人工瓣膜的膜、人工瓣膜支架、左心耳封堵器膜、左心耳封堵器支架、心脏封堵器膜、心脏封堵器支架或人工补片。
  6. 根据权利要求5所述的植入医疗器械，其特征在于，所述植入医疗器械为左心耳封堵器膜或心脏封堵器膜。
  7. 根据权利要求3-6中任一项所述的植入医疗器械，其特征在于，所述植入医疗器械表面上所述造血干细胞标记物的特异性抗体的浓度范围是：10～1000g/mm 2。
  8. 一种根据权利要求3-6中任一项所述的植入医疗器械的制备方法，其特征在于，包括
    将所述造血干细胞标记物的特异性抗体负载在所述植入医疗器械的至少一部分表面上；和/或
    将所述造血干细胞标记物的特异性抗体负载在所述植入医疗器械的孔内或槽内。
  9. 根据权利要求8所述的制备方法，其特征在于，所述造血干细胞标记物的特异性抗体通过直接涂覆法、化学接枝法和静电吸附法法中的至少一种负载到所述植入医疗器械的表面。
  10. 根据权利要求9所述的制备方法，其特征在于，所述造血干细胞标 记物的特异性抗体通过化学接枝法与静电自组装法的结合负载到所述植入医疗器械的表面。
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