WO2003015743A1 - Immunisation par implantation locale d'antigenes irreversiblement fixes sur un bioadherent - Google Patents
Immunisation par implantation locale d'antigenes irreversiblement fixes sur un bioadherent Download PDFInfo
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- WO2003015743A1 WO2003015743A1 PCT/FR2002/002888 FR0202888W WO03015743A1 WO 2003015743 A1 WO2003015743 A1 WO 2003015743A1 FR 0202888 W FR0202888 W FR 0202888W WO 03015743 A1 WO03015743 A1 WO 03015743A1
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- antigens
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
Definitions
- the present invention relates to a new immunization method consisting in inducing or stimulating an immune reaction in humans or animals by inserting an immunogenic implant consisting of a chemical adherent for biological use, or bioadherent, on the surface of which antigens of biological origin (tissue, cells, microsomes, microorganisms, natural or synthetic biological molecules) or of chemical origin (simple molecules or in the form of complexes, chemical functional groups) are fixed irreversibly.
- the immunogenic implant thus formed is inserted either into a blood vessel, partially and temporarily, or into a tissue, partially or completely, temporarily or permanently.
- These vaccines are generally solutions which are composed of antigens (living germs, attenuated or inactivated, purified or synthetic antigenic material, active viral vectors, antibodies, DNA ”) associated with an adjuvant which often has the role of increasing the immune response.
- Biomaterials designate artificial or synthetic biocompatible materials intended to work under biological constraints and in direct contact with the living system. They are used for the production of materials implanted in humans or in contact with their biological fluids. They generally have specific applications which depend on their chemical and mechanical properties. They are schematically classified into three categories: metals and alloys, ceramics, and polymers.
- Biocompatibility is the adequacy between the implant and its insertion environment. Indeed, the material must not cause physiological disturbances and must not be damaged due to the physiological environment in which it is placed. The material and the products of its wear must not induce toxicity, either by themselves or by degradation or salting-out, or cause harmful reactions on the part of the host organism (carcinogenicity, immune or rejection reaction, thrombosis, etc.).
- microcapsules consist of a bioactive polymer or copolymer capable of passing through the gastrointestinal tract without any degradation or little degradation, so that the bioactive agent reaches Peyer's plaques or other associated lymphoid tissues to the mucosa in an effective amount to stimulate the systemic or mucosal immune system.
- Other inventors, ANDRIANON A. et al. [WO 95/02416] have developed a method of microencapsulated vaccine based on a hydrogel. This material consisting of alginate and polyphosphazene is used to encapsulate antigens and form microparticles (15 ⁇ m in diameter or less) which can be administered parenterally or through the mucous membranes.
- microparticles by adhering to the mucosa of the digestive tract, thus increase the absorption of antigens.
- Systems composed of biodegradable polymers have been used for a prolonged action of release of antigens in controlled quantity.
- SUZUKI T. et al. [WO 98/07443] have imagined an oral vaccine based on microspheres having a multilayer structure which consists of a core layer containing the antigens, and of several layers of envelope to surround this core.
- the disadvantages of the encapsulation methods relate to the control of the kinetics of release of the antigen.
- Carrier particles of pharmacological agents have been produced from 60 nm synthetic nuclei [7]. Besides, nanocrystalline or inorganic particles, covered with adsorbed antibodies are often used to locate or reveal cellular or molecular components in light or electron microscopy or in the context of immunoblots [8, 9].
- KOSSONSKY et al. [US patents nos. 5,219,577 and US 5,178,882] have coated these particles with a very fine layer of sugar (cellobiose, nitrocellulose, etc.) or oligonucleotides ( ⁇ 5 nm), before adsorbing proteins there. viral to obtain artificial viruses and thus obtain an immune response without danger of infection.
- the present invention relates to a new immunization method consisting in inducing or stimulating an immune reaction in humans or animals by inserting an immunogenic implant consisting of a chemical adherent for biological use, or bioadherent, on the surface of which antigens of biological origin (tissue, cells, microsomes, microorganisms, natural or synthetic biological molecules) or of chemical origin (simple molecules or in the form of complexes, chemical functional groups) are fixed irreversibly.
- the immunogenic implant thus formed is inserted either into a blood vessel, partially and temporarily, or into a tissue, partially or completely, temporarily or permanently.
- the principle on which the process is based consists in inducing an immune response, by introducing an immunogenic material which is not phagocytosed quickly by the cells of the host organism, contrary to the case of conventional vaccines or microbeads or vaccinating nanoparticles. To prevent antigens from disappearing too quickly in the body by phagocytosis or catabolism, these are fixed irreversibly on a non-circulating material, and immobilized within a vessel or tissue.
- the antigens attached to the material attract a large number of immune cells, in particular neutrophilic granulocytes and phagocytes (monocytes and macrophages) active in the blood and tissues. These cells will phagocyte partly or entirely these antigens and trigger the specific immune system in which macrophages, humoral antibodies and different types of lymphocytes collaborate closely, ultimately leading to the production of antibodies. This process makes it possible to trap microorganisms, molecules, dangerous antigenic cells etc., to expose them to circulating immune cells without risk of infection for the organism.
- the dangerousness of virulent organisms comes from the fact that, when they are in free circulation, they adhere to the surface of certain target cells of the organism host through specific receptors, before fully entering the cytoplasm to spill and duplicate their genetic material.
- the present invention makes it possible to partially and definitively enclose part of the viral capsule in the adherent material, in order to present to the immune cells of the organism only the antigens present on the emerging part, accessible to antibodies, to phagocytic cells or complement factors. This landlocking on the adherent support therefore prevents the internalization of the virus at the level of non-phagocytic immune cells and thereby prevents infection of the host organism.
- this process allows the insertion into the body of the material to obtain a lower catabolic rate for the degradation of antigens than current processes.
- a low catabolic rate helps maintain the immune response and prevents the need for subsequent boosters.
- connection established between the biological or chemical material and its support is irreversible, stable, and durable otherwise there is a risk to introduce into the body of dangerous organisms or molecules, especially in case of prolonged implantation, for the physico-chemical agents contained in the blood, by progressively degrading the binding of the antigen to its support, risk releasing infectious or toxic agents, and this well before a specific immune response is triggered.
- the use of chemical adhesives for multiple biological or bioadherent uses have the best adhesion and biocompatibility characteristics for safe application.
- the adhesives are designed from polymers, polymer resin or silicone. The characteristic of the bioadherent is that it establishes chemical bonds with the antigens to be bound, during its polymerization.
- bioadherents have developed in particular in numerous clinical applications, including aid for tissue repair [15, 16, 17, 18], and for suturing blood vessels [19, 20].
- the suturing properties and therefore the adhesion to the tissues of certain cyanoacrylates sometimes prove to be superior to certain adhesives based on purely biological molecules [21].
- Pharmaceutical applications involving micro or nanoparticles of non-bioadherent cyanoacrylates in the field of transport of active molecules, by adsorption, have been developed [22, 23]. If these micro or nanoparticles of cyanoacrylates increase the diffusion of physiological molecules [22], they have also recently served both as adjuvant and transporter of antigens [24, 25, 26,] or transporter of antibodies used as vector directed on a specific target [27].
- the mechanical properties of the material must be compatible with the environmental conditions imposed on it in its place of insertion (biophysical constraints, physico-chemical processes, etc.).
- the bioadhesive can be previously spread on a material of variable nature: carbon, organic compounds comprising: synthetic polymers or copolymers made from different families of polymers (polyolefins, vinyl, styrenics, acrylics, polyamides, saturated polyesters, polycarbonates, polyacetals , fluoropolymers, silicones, polyurethanes), silicones, natural biopolymers (example: cellulose, silk ...), modified natural biopolymers (example: polysaccharide with a carboxylic function ...), artificial biopolymers (e.g.
- homopolypeptide if any suitable biocopolymer (example: copolymer of lactic and glycolic acid), non-organic materials including appropriate metals (gold, silver, nickel, platinum %) and alloys, ceramics, fabrics treated specifically for give them the essential biomechanical properties (example: natural catgut, hair ).
- the method according to the invention has another advantage in the context of its development.
- the techniques for producing microparticles are cumbersome and depend on many parameters in their development, in particular the surfactants used during their preparation.
- the method according to the invention uses a simple technique which consists in depositing antigens directly on a bioadherent, without the need for a sophisticated and expensive installation.
- the biological or chemical material is deposited in the presence of physiological liquid or after having undergone dehydration or lyophilization before being deposited on the surface of the bioadherent. Indeed, it is possible to dehydrate biological material while retaining its immunogenic character to make vaccines. THEURER K.
- [EP 0083 673 A1] uses, for preventive and therapeutic purposes, solutions, emulsions or dispersions based on dry powders (totally water-soluble and emulsifiable) from isolated organs or mixtures of organs.
- Many methods make it possible to strengthen the bonds between antigens and the support, within the framework of the method according to the invention, by increasing the number of chemical bonds. It is possible to spray antigens on the bioadherent or to impose pressure inside a pressurized enclosure, to enclose the antigens a little more on their support during the polymerization of the latter.
- the cyanoacrylates may be in the form of a film made porous.
- the porosity is obtained by using this bioadhesive in aerosol or by its degassing by means of a gas such as freon (fluorocarbon) during its polymerization.
- freon fluorocarbon
- Porosity adds the added benefit of easier biodegradability, drainage and phagocytosis [29]. Therefore the cyanoacrylate polymer can be introduced in different porous forms according to the process of the invention.
- ⁇ • - Insertion into a blood vessel The most suitable form is the filament. This must be long enough for one part to remain inside the blood vessel while the other, outside the vessel, immobilizes the filament.
- the filament must be thin, regular, preferably flexible so as not to disturb the blood circulation, but also strong enough not to break during its stay in the blood vessel and during its removal.
- This antigen-coated filament is partially introduced into a blood vessel using a cannula or syringe (containing physiological saline, or a buffered solution, whether or not combined with an anticoagulant) and then withdrawn after use.
- the time required for immunization by this method is relatively shorter than that required by standard immunization procedures such as injections.
- the most imperative constraint for an implant in contact with the blood is hemocompatibility, that is to say that it must not damage the proteins, the enzymes and the figured elements of the blood, and in particular not to create hemolysis and platelet reaction.
- the most important factor in hemocompatibility is coagulation, the mechanisms of which are still poorly understood and which depend on hemodynamic parameters ( blood shear forces on the surface of the material) imposing suitable geometries on the implant.
- Heparin remains the most powerful antithrombotic molecule. It improves the biocompatibility of many implants [30] and it can be combined with other molecules for complementary functions [31, 32].
- the modification by heparinisation of the surface of polymers or copolymers intended for medical use has shown that in all cases it improves hemocompatibility [33, 34].
- a general heparinization method applicable to all polymers has been developed and another more specific to polyurethanes although polyurethanes are a family of elastomers which have the best hemocompatibility properties compared to any other. type of polymer, [35].
- the shape of the immunogenic bioadherent can vary depending on the mechanical properties of the tissue (lozenges, flexible or rigid filaments, needles, sticks, films %) from the moment when the characteristics of the material create no trauma or tissue damage.
- the method according to the invention can be introduced into a blood vessel or into other tissues of the body by means other than the needle of a syringe or by a cannula.
- the material can be designed sufficiently rigid and provided with a pointed end acting as a penetration needle.
- the implant is then introduced either manually or by projection using a device provided for this purpose [39].
- the method according to the invention can also be used in different variants which can be inserted into a fabric, for example:
- - a type of vaccinostyle comprising a slot for containing a film according to the process, - a needle or a type of vaccinostyle fitted with a shrink film according to the process which can be released into a tissue after removal.
- the dimensions of the implant according to the method of the invention depend on the type of substrate chosen and on the size of the host which therefore remains to be determined empirically with conventional means.
- the method according to the invention has many advantages:
- the material can be coated with specific antibodies to detect in the blood the presence of particular biological organisms, of biochemical or chemical molecules.
- Authors have managed, in vitro, to separate a cell type in small quantities in a mixed solution containing other cell types in very high concentration, using polystyrene beads coated with antibodies [40].
- This immunization method according to the invention offers great potential in terms of vaccination, and well-founded hopes allow us to hope for rapid results in the fight against serious diseases other than infectious ones such as benign or malignant tumors or the development of metastases. Immunization by this method is carried out in a shorter time than conventional methods which require boosters to obtain the same level of antibodies. Furthermore, the repetition of vaccines to achieve perfect immunity for children or adults is not accessible materially or financially all over the world. Also, this invention makes it possible to avoid the drawback of repeated immunizations and their costs by optimizing the immune response by a limited exposure of the immunogens.
- the method according to the invention is particularly intended for immunization and relates particularly to the biomedical field of the bio-technology or bio-engineering industries intended for human or animal health.
- FIG. la shows a section of an immunogenic implant according to the invention the invention (1) consisting of a bioadherent (2) on the surface of which antigens (3) are fixed irreversibly.
- FIG. lb shows a section of an immunogenic implant according to the invention (1) consisting of a bioadherent (2)) on the surface of which antigens the cells of a tissue (4) are fixed irreversibly.
- the bioadhesive is spread over a material (5).
- FIG. 2 shows a means of insertion into the body of the immunogenic implant (1) according to the method.
- the implant is introduced via a pointed end (6) acting as a penetration needle.
- FIG. 3 shows a variant of the process in the form of a patch (7) with immunogenic tips according to the process (8) inserted into the skin (9).
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0110842A FR2828648A1 (fr) | 2001-08-16 | 2001-08-16 | Constitution d'un vaccin extractible a partir d'un insert immunogene. |
FR01/10842 | 2001-08-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003015743A1 true WO2003015743A1 (fr) | 2003-02-27 |
Family
ID=8866554
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2002/002888 WO2003015743A1 (fr) | 2001-08-16 | 2002-08-14 | Immunisation par implantation locale d'antigenes irreversiblement fixes sur un bioadherent |
Country Status (2)
Country | Link |
---|---|
FR (1) | FR2828648A1 (fr) |
WO (1) | WO2003015743A1 (fr) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1985003635A1 (fr) * | 1984-02-16 | 1985-08-29 | Unigene Laboratories, Inc. | Immunisation par implant immunogene |
FR2695563A1 (fr) * | 1992-09-11 | 1994-03-18 | Pasteur Institut | Microparticules portant des antigènes et leur utilisation pour l'induction de réponses humorales ou cellulaires. |
WO1994025065A1 (fr) * | 1993-04-28 | 1994-11-10 | Cytech Biomedical, Inc. | Agent immunisant et support pour chromatographie par affinite |
WO1998034968A1 (fr) * | 1997-02-11 | 1998-08-13 | The Council Of The Queensland Institute Of Medical Research | Polymeres dans lesquels sont incorpores des peptides |
WO2000021568A1 (fr) * | 1998-10-12 | 2000-04-20 | Csl Limited | Colle de fibrine utilisee comme adjuvant biologique |
WO2001089622A1 (fr) * | 2000-05-22 | 2001-11-29 | Becton, Dickinson And Company | Applicateur dote d'une surface abrasive recouverte d'une substance devant etre appliquee sur la peau |
-
2001
- 2001-08-16 FR FR0110842A patent/FR2828648A1/fr not_active Withdrawn
-
2002
- 2002-08-14 WO PCT/FR2002/002888 patent/WO2003015743A1/fr not_active Application Discontinuation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1985003635A1 (fr) * | 1984-02-16 | 1985-08-29 | Unigene Laboratories, Inc. | Immunisation par implant immunogene |
FR2695563A1 (fr) * | 1992-09-11 | 1994-03-18 | Pasteur Institut | Microparticules portant des antigènes et leur utilisation pour l'induction de réponses humorales ou cellulaires. |
WO1994025065A1 (fr) * | 1993-04-28 | 1994-11-10 | Cytech Biomedical, Inc. | Agent immunisant et support pour chromatographie par affinite |
WO1998034968A1 (fr) * | 1997-02-11 | 1998-08-13 | The Council Of The Queensland Institute Of Medical Research | Polymeres dans lesquels sont incorpores des peptides |
WO2000021568A1 (fr) * | 1998-10-12 | 2000-04-20 | Csl Limited | Colle de fibrine utilisee comme adjuvant biologique |
WO2001089622A1 (fr) * | 2000-05-22 | 2001-11-29 | Becton, Dickinson And Company | Applicateur dote d'une surface abrasive recouverte d'une substance devant etre appliquee sur la peau |
Non-Patent Citations (1)
Title |
---|
KREUTER J ET AL: "LONG-TERM STUDIES OF MICROENCAPSULATED AND ADSORBED INFLUENZA VACCINE NANOPARTICLES", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON, US, vol. 70, no. 4, April 1981 (1981-04-01), pages 367 - 371, XP001015815, ISSN: 0022-3549 * |
Also Published As
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FR2828648A1 (fr) | 2003-02-21 |
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