WO2011123042A1 - Procédé de vaccination et produits destinés à être utilisés dans celui-ci - Google Patents

Procédé de vaccination et produits destinés à être utilisés dans celui-ci Download PDF

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WO2011123042A1
WO2011123042A1 PCT/SE2011/050366 SE2011050366W WO2011123042A1 WO 2011123042 A1 WO2011123042 A1 WO 2011123042A1 SE 2011050366 W SE2011050366 W SE 2011050366W WO 2011123042 A1 WO2011123042 A1 WO 2011123042A1
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hapten
carrier
target
linker
subject
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Per MÅNSSON
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Independent Pharmaceutica AB
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Independent Pharmaceutica AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K39/0013—Therapeutic immunisation against small organic molecules, e.g. cocaine, nicotine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen

Definitions

  • the invention relates to a vaccination procedure and to products for use in such procedures. More precisely, the invention relates to a method of eliciting enhanced titres of antibodies specific for a selected target hapten molecule by using at least two different hapten carrier conjugate vaccines wherein the haptens are the same selected target hapten and the carriers are different and/or the carriers are bound at different positions to the hapten directly or via a linker and/or the linker structures are different. Further, the invention relates to hapten carrier conjugate vaccine combinations and to commercial packages containing them.
  • a common method to create a potent vaccine that elicits antibodies against low molecular weight non-immunogenic molecules, so-called haptens, and other substances with low immunogenicity is to conjugate such non-immunogenic molecule or low-immunogenic substance to a suitable high molecular weight immunogenic carrier.
  • conjugate vaccines have been tested in clinical trials for potential therapies, such as treatments against drug dependences, e.g. nicotine or cocaine dependence. Many of such conjugate vaccines have proven to be safe, and have also demonstrated some efficacy in both human clinical studies as well as in animal testing.
  • the main goal when immunizing an individual with a drug vaccine is to generate antibodies that bind to the inhaled, ingested or injected drug, thereby preventing the drug in question from reaching the brain where it exerts its rewarding effects.
  • a drug vaccine e.g. a nicotine vaccine
  • the generated antibodies will alter the distribution of the drug in the body, resulting in elevated serum drug levels and decreased brain drug levels. If the antibodies bind strongly to the drug, the drug-antibody complex remains in the blood stream and thus there will be less free drug available for distribution to the brain 6 .
  • a low-molecular weight substance e.g. the nicotine molecule
  • the low molecular weight substance e.g. nicotine
  • a suitable immunogenic carrier in order to be immunogenic the low molecular weight substance, e.g. nicotine
  • the hapten e.g. nicotine molecule
  • the structure of the linker will influence the properties of the nicotine molecule and, therefore, the choice of the linker is of great importance.
  • the position of the linker on the hapten structure is also very important for the quality of the antibodies.
  • a nicotine vaccine is in general comprised of a low molecular weight nicotine molecule (the hapten) which is conjugated to a high molecular weight carrier protein via a linker.
  • the carrier is normally an immunogenic active protein that will elicit antibodies to itself as well.
  • the nicotine part of the conjugate vaccine presents its three dimensional structure as well as its physical-chemical properties to the immunological system in the vaccinated body.
  • the vaccines elicit considerable amounts of antibodies against both the linker structure as well as against the carrier, especially after repeated immunizations using the same vaccine.
  • the main goal for the vaccination is to generate as large amounts as possible of high affinity antibodies that bind strongly to the nicotine molecule. Additionally, they should be selective and not recognize nicotine's metabolites or other structures, such as the carrier and linker structure. It is important to avoid generation of antibodies against the carrier as much as possible because of the risk of a suppression effect at repeated immunization.
  • Booster immunizations i.e. repeated immunizations, using the same vaccine may results in suppression of the amount of antibody produced. All the human trials reported so far using nicotine vaccines use a repeated booster scheme with the same vaccine. The booster immunizations are given to increase the antibody titer further than obtained by the primary immunization. However, it is known that injection with an immunogenic dose of a carrier followed by immunization with hapten-carrier conjugate may selectively suppress the anti- hapten antibody response.
  • a bivalent vaccine which may be initially more effective than a certain monovalent vaccine, will, when administered as a booster dose, result in the same type of immunological drawbacks such as suppressed response, linker effects as the repeated administration of the monovalent vaccine described above.
  • the current invention is based on a sequential vaccination technique in order to optimize the concentration of antibodies against the hapten (e.g. nicotine) and suppress the formation of antibodies against the linkers as well as antibodies against the carriers or both.
  • This is accomplished by sequential vaccination with at least two different vaccines that have different carriers and/or different linker structures but the same hapten. It is also important to vary the position of the linker on different sites of the hapten molecule to increase the efficacy of the vaccine therapy thus exposing different parts of the hapten molecule to the immune recognition system.
  • hapten e.g. nicotine
  • the individual vaccines are administered sequentially at different points of times, e.g. with a few weeks intervals as booster doses.
  • the booster dose of a different vaccine (Vaccine B) after the primary vaccination with "Vaccine A” will result in an enhanced activation of the plasma cells expressing high affinity antibodies against the pure hapten molecule e.g. the nicotine and suppression of the formation of antibodies against the linker structure and/or the carrier of vaccine A, which was used in the primary immunization.
  • Fig. 1 illustrates the structure of nicotine and of a typical nicotine vaccine, NIC-VAX, which consists of a conjugate between the nicotine molecule and Pseudomonas aeruginosa protein A mixed with alum as adjuvant.
  • NIC-VAX a typical nicotine vaccine
  • Fig. 2 shows two examples according to invention of schematic vaccination schedules.
  • the schemes are examples and can be different both regarding types of vaccines and times of the different vaccinations.
  • the Vaccine A, Vaccine B, Vaccine C and Vaccine D are different hapten carrier conjugate vaccines.
  • the present invention provides an improved vaccination procedure for eliciting enhanced titers of antibodies against a selected target hapten in a subject as well as a combination of at least two different hapten carrier conjugate vaccines.
  • the invention can be used to provide suitable B-cells to be used in appropriate cell systems, e.g. hybridomas, for production of monoclonal antibodies against a selected hapten that can be used in immunotherapies
  • the invention is based on at least two different hapten carrier conjugates that are administered to a subject at different points of time as a primary vaccine and a boost vaccine, both containing the same hapten, to elicit enhanced titers of antibodies against the hapten molecule, e.g. nicotine or ketamine.
  • a boost vaccine both containing the same hapten
  • the primary vaccine e.g. nicotine or ketamine
  • one to several further booster doses may be administered using the primary vaccine, the first boost vaccine or e.g. a second, third or fourth different boost vaccine.
  • first and second hapten carrier conjugates have a structural difference in relation to each other, and wherein the target hapten has a molecular weight of less than 1 kDa.
  • a method for eliciting antibodies specific for a target hapten molecule in a subject comprising the steps of
  • first and second hapten carrier conjugates have a structural difference in relation to each other, and wherein the target hapten has a molecular weight of less than 1 kDa.
  • a hapten carrier conjugate in the manufacture of a medicament for use in a method for eliciting antibodies specific for a target hapten molecule in a subject, the method comprising the steps of
  • first and second hapten carrier conjugates have a structural difference in relation to each other, and wherein the target hapten has a molecular weight of less than 1 kDa.
  • the method of the first, second or third aspects may further comprise the step of
  • Said method may further comprise the step of re-immunizing the subject with the first hapten carrier conjugate bearing the target hapten molecule subsequent to step (b).
  • Said method may also comprise timing the immunizations such that 7-90 days elapse between the immunizations. More preferably, 7-60 days elapse between the immunizations. Most preferably, 7-30 days elapse between the immunizations.
  • the hapten carrier conjugate(s) of the first, second or third aspects may comprise a linker connecting the hapten to the carrier.
  • the structural difference mentioned in the first, second and third aspects may comprise a difference in a feature selected from the group consisting of: carrier structure, linker structure, position of attachment of a linker to the carrier, position of attachment of the hapten to the carrier and position of attachment of the hapten to a linker.
  • Said structural difference may preferably comprise a feature selected from the group consisting of: linker structure and position of attachment of the linker to the hapten.
  • the carrier moieties of the conjugates mentioned in the first, second and third aspects may comprise T-cell epitope-containing proteins or particles.
  • the T-cell epitope-containing proteins or particles may be selected from proteins such as lysozymes, bovine serum albumin, ovalbumin and keyhole limpet hemocyanin; particles such as virus particles and virus-like particles (VLP); and bacterial toxoids and bacterial toxins such as tetanus toxoid, diphtheria toxoids, cholera toxin, cholera toxin subunit B (CTB) and recombinant CTB.
  • Said carrier moieties are preferably selected from the group consisting of tetanus toxoids, viruslike particles, recombinant cholera toxin B and Pseudomonas aeruginosa exoprotein.
  • the target hapten of the first, second or third aspects may be selected from the group consisting of nicotine, cocaine, ketamine, benzodiazepines, amphetamines,
  • the target hapten is nicotine.
  • the hapten carrier conjugates of the first, second or third aspects may be selected from the group consisting of NiccineTM , TA-NicTM, NicVaxTM and ⁇ TM.
  • the method of the first, second or third aspects may further comprise the step of identifying a subject in need of antibodies to the target hapten molecule.
  • the subject of the first, second or third aspects is preferably human.
  • a package comprising:
  • a primary vaccine comprising a first hapten carrier conjugate bearing the target hapten molecule and separately b) A booster vaccine comprising a second hapten carrier conjugate bearing the target hapten molecule,
  • first and second hapten carrier conjugates are structurally different, and wherein the hapten has a molecular weight of less than 1 kDa.
  • the package of the fourth aspect may further comprise a third hapten carrier conjugate bearing the target hapten molecule, wherein the first, second and third hapten carrier conjugates have a structural difference in relation to each other.
  • At least one of the hapten carrier conjugates of the fourth aspect may comprise a linker connecting the hapten to the carrier.
  • the structural difference of the fourth aspect may comprise a difference in a feature selected from the group consisting of: carrier structure, linker structure, position of attachment of a linker to the carrier, position of attachment of the hapten to the carrier and position of attachment of the hapten to a linker.
  • Said structural difference may preferably comprise a feature selected from the group consisting of: linker structure and position of attachment of the linker to the hapten.
  • the carrier moieties of the conjugates of the fourth aspect may comprise T-cell epitope- containing proteins or particles.
  • Said T-cell epitope-containing proteins or particles may be selected from proteins such as lysozymes, bovine serum albumin, ovalbumin and keyhole limpet hemocyanin; particles such as virus particles and virus-like particles (VLP); and bacterial toxoids or toxins such as tetanus toxoid, diphtheria toxoids, cholera toxin, cholera toxin subunit B (CTB) and recombinant CTB.
  • Said carrier moieties are preferably selected from the group consisting of tetanus toxoids, virus-like particles, recombinant cholera toxin B and Pseudomonas aeruginosa exoprotein.
  • the target hapten of the fourth aspect may be selected from the group consisting of nicotine, cocaine, ketamine, benzodiazepines, amphetamines, tetrahydrocannabinols, opiates, cholesterol and low molecular weight hormones such as steroid hormones such as estradiol, testosterone and anabolic steroids.
  • the target hapten is nicotine.
  • the hapten carrier conjugates of the fourth aspect may be selected from the group consisting of NiccineTM, TA-NicTM, NicVaxTM and NicQpTM.
  • the package of the fourth aspect may further comprise a set of instructions for performing the method of the second aspect.
  • the package of the fourth aspect may be for use in a method of the second aspect.
  • hapten antibodies induced by hapten-carrier conjugates will to varying degrees be selected to react against not only the hapten but also against linker specific-determinants created by the hapten when linked to the carrier.
  • nicotine can be regarded as a comparatively small hapten in this regard, thus the relative proportion of antibodies that have their specificity for nicotine+linker will be high when using a fixed hapten-carrier complex.
  • Boosting with the same same nicotine-carrier complex will normally result in antibodies with an increase in avidity/affinity in parallel for the nicotine-linker complex epitopes.
  • an optimal selection and production of high affinity antibodies for the free hapten e.g. nicotine
  • the various hapten carrier complexes should only have one common denominator, the presence of the nicotine hapten, whereas especially the linker but also the carrier should be different.
  • a second immunization using hapten-linker Y-carrier B will have a select capacity to preferentially induce those relatively few memory B cells induced by hapten-linker X-carrier A with very high affinity for the hapten (that is not also reactive with linker determinants).
  • a similar outcome would also take place if the first and second carrier proteins used are the same but the linkers used for coupling the hapten were distinctly different and not generating crossreacting antibodies against the linker parts.
  • an aspect of the current invention is directed to a method of eliciting, in a subject, enhanced titers of antibodies specific for a selected target hapten molecule, which hapten molecule is included in at least two different hapten carrier conjugates.
  • the method comprises the steps of initially immunizing the subject with one hapten carrier conjugate, wherein the hapten is the selected hapten molecule, and subsequently booster immunizing the subject with at least one other hapten carrier conjugate, wherein the hapten is the selected hapten molecule.
  • the first two immunizations are optionally and probably most commonly, followed by at least one further booster immunization of the subject with a hapten carrier conjugate selected from the group consisting of the initial one hapten carrier conjugate and other hapten carrier conjugates wherein the hapten is the selected hapten molecule.
  • the subject that will be immunized according to the method of the invention, can be selected from various kinds of animals, preferably mammals, such as humans and laboratory animals, e.g. rats and mice, or domestic animals, e.g. rabbits and dogs.
  • animals preferably mammals, such as humans and laboratory animals, e.g. rats and mice, or domestic animals, e.g. rabbits and dogs.
  • the enhanced titers of selective antibodies against the free hapten that will result from the method of the invention is not only enhanced compared to the use of only one hapten carrier conjugate but also to the use of two different hapten carrier conjugates in a bivalent vaccine.
  • Such a bivalent vaccine has been reported in the prior art 8 to give additive titers compared to a monovalent vaccine.
  • the subsequent booster immunization(s) will be made after a period of time that is commonly used for booster immunizations, i.e. after a few weeks, such as after 4, 5 and/or 10 weeks.
  • the immunizations are performed in commonly known ways and are suitably made with appropriate doses of the conjugates by oral, intradermal, subcutaneous, nasal, sublingual, intramuscular, intraperitoneal and/or transdermal administration.
  • the different hapten carrier conjugates that include the same selected target hapten molecule, are preferably selected from hapten carrier conjugates that have and at least one differing feature selected from the group consisting of different carriers, carriers that are bound at different positions to the hapten directly or via a linker, and different linker structures.
  • Examples of a selected hapten molecule is a low molecular weight molecule selected from the group consisting of nicotine, cocaine, ketamine, benzodiazepines, amphetamines, terahydrocannabinols, opiates, low molecular weight hormones and cholesterol.
  • Examples of the carriers in the different hapten carrier conjugates are carriers selected from the group consisting of different T-cell epitope-containing large molecules, preferably proteins, virus particles, virus-like particles (VLP), bacterial toxoids, such as tetanus toxoid, diphtheria toxoids, cholera toxoids, and derivatives of toxins and toxoids.
  • the one hapten carrier conjugate and the one other hapten carrier conjugate are nicotine carrier conjugates, wherein the carriers are selected from the group consisting of tetanus toxoids, virus-like particles, recombinant cholera toxin B and Pseudomonas aeruginosa exoprotein.
  • Another aspect of the invention is directed to a hapten carrier conjugate vaccine combination comprising at least two different hapten carrier conjugate vaccines,
  • At least one hapten carrier conjugate boost vaccine at least one hapten carrier conjugate boost vaccine
  • hapten of the one hapten carrier conjugate primary vaccine as well as the hapten of the at least one hapten carrier conjugate boost vaccine are the same selected hapten molecules
  • the hapten carrier conjugates have at least one differing feature selected from the group consisting of different carriers, carriers that are bound at different positions to the hapten directly or via a linker, and different linker structures.
  • the recommended immunization doses of the different hapten carrier conjugate vaccines and final pharmaceutically acceptable composition of the vaccines will be decided by the vaccine producers based on the contemplated the kind of subject and route of administration.
  • Common vaccine components are, in addition to the immunizing component, adjuvants, diluents, surfactants, lubricants, preservatives and stabilizers.
  • Examples of a selected hapten molecule is a low molecular weight molecule selected from the group consisting of nicotine, cocaine, ketamine, benzodiazepines, amphetamines, terahydrocannabinols, opiates, low molecular weight hormones and cholesterol;
  • examples of the carriers in the different hapten carrier conjugates are carriers selected from the group consisting of different T-cell epitope-containing large molecules, preferably proteins, virus particles, virus-like particles (VLP), bacterial toxoids, such as tetanus toxoid, diphtheria toxoids, cholera toxins, and derivatives of toxins and toxoids; and in an embodiment of the invention the one hapten carrier conjugate and the one other hapten carrier conjugate are nicotine carrier conjugates, wherein the carriers are selected from the group consisting of tetanus toxoids, virus-like particles, recombinant cholera toxin B and Pseudomonas aeruginos
  • a yet further aspect of the invention is directed to a commercial package that comprises the vaccine combination according to the invention.
  • the commercial package can be designated a kit.
  • the commercial package or kit will contain instructions for use and optionally aids useful for the contemplated administration of the vaccines, such as syringes and tags.
  • one of the two different hapten carrier conjugate vaccines is formulated as a sustained release preparation, then both of the two vaccines can be contained in the same administration unit for simultaneous administration so that the primary vaccine will be released first in the body and the boost vaccine is released subsequently after an appropriate time.
  • mice were immunized with only one type of a conjugated ketamine with a linker, the mice showed a good titer of antibodies against the ketamine- conjugate but no or very low titer of antibodies against free ketamine molecules.
  • mice female, about 8 weeks old, were used.
  • Spleen cells were immortalized by cell fusion using myeloma cell line SP2/0-Ag14.
  • conjugates A and B Two different ketamine conjugates were used in the immunization protocols.
  • mice Five mice were intraperitoneally immunized over a period of 39 days.
  • immunization a water-in-oil emulsion of equal volumes of antigen and Freund ' s complete or incomplete adjuvant was prepared.
  • Preparation of the antiserum a water-in-oil emulsion of equal volumes of antigen and Freund ' s complete or incomplete adjuvant was prepared.
  • Antiserum was prepared during the immunization in order to check the immune response in an ELISA assay.
  • mice were killed and spleens were aseptically removed, pooled and homogenized.
  • the spleen cells and the myeloma cells were fused in the presence of PEG 3350, re-suspended in complete growth medium, plated out onto eight 96-well tissue culture flat-bottom plates fed twice with HAT medium, before testing the culture supernatants by ELISA.
  • An ELISA was used for screening of IgG antibodies in cell culture supernatants.
  • Polystyrene microtiter plates were coated with the respective ketamine conjugates.
  • plates were incubated with anti-mouse IgG conjugated to alkaline phosphatase 1 :5000) followed by several washes and addition of 150 ⁇ /well substrate buffer (2 mM 4-nitrophenyl phosphate in 5% diethanolamine + 0.5 mM MgCI2, pH 9.8).
  • the optical density (OD) was estimated in a microplate reader at 405 nm.
  • the procedure of the competitive ELISA was the same as the procedure of the screening ELISA.
  • the ELISA plates were coated and blocked as described above.
  • the cell culture supernatants were mixed with blocking buffer containing various concentrations of free ketamine.
  • As control the same concentration of cell culture supernatant in blocking buffer was used.
  • the mixtures were pre-incubated for 1 h at room temperature and subsequently transferred to the coated and blocked ELISA plates with ketamine-conjugate. ELISA procedures were then continued as described above.
  • mice The polyclonal antiserum from mice (dilution 1 :1000) was pre-incubated with 10 pg/ml of free ketamineand subsequently transferred to ELISA plates with immobilized ketamine-conjugate. All mice that have been immunized with only "conjugate A” or only “conjugate B” showed high titre against the conjugate, but almost no competition with the free Ketamine. However, when the mice in one of the vaccinated groups (Conjugate A immunized) were boosted with the second conjugate (“Conjugate B”) a high degree of competition with the free Ketamine was shown and we were able to detect 7 positive clones that showed good competition against the free ketamine after the fusion and screening procedure.

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Abstract

L'invention porte sur un procédé consistant à déclencher chez un sujet des titres améliorés d'anticorps spécifiques pour une molécule haptène choisie, telle que la nicotine, ladite molécule haptène étant comprise dans au moins deux conjugués haptène support différents. Le procédé comprend les étapes d'immunisation initiale du sujet avec un conjugué haptène support, puis d'immunisation par injection de rappel du sujet avec au moins un autre conjugué haptène support. L'invention porte également sur des produits destinés à être utilisés dans ledit procédé. L'invention porte également sur une combinaison de vaccins de conjugué haptène support comprenant au moins deux vaccins de conjugué haptène support différents, un vaccin primaire et au moins un vaccin de rappel, ainsi que sur un conditionnement industriel les contenant.
PCT/SE2011/050366 2010-04-01 2011-03-30 Procédé de vaccination et produits destinés à être utilisés dans celui-ci Ceased WO2011123042A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022116782A1 (fr) * 2020-12-04 2022-06-09 江南大学 Lignée cellulaire d'hybridome d'anticorps monoclonal d'éthyl-maltol et application associée

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0427347A1 (fr) * 1989-11-10 1991-05-15 ENIRICERCHE S.p.A. Peptides synthétiques utiles comme porteurs universels pour la préparation des conjugués immunogéniques el leur emploi dans le développment des vaccins synthétiques
WO1997049425A1 (fr) * 1996-06-25 1997-12-31 Stichting Instituut Voor Dierhouderij En Diergezondheid Vaccins comprenant des antigenes fixes sur leurs supports par des liaisons labiles
WO1998014216A2 (fr) * 1996-09-30 1998-04-09 Immulogic Pharmaceutical Corporation Conjugues haptene-porteur destines a etre utilises dans une therapie pour toxicomanes et procedes de preparation de ceux-ci
US20050136047A1 (en) * 1998-12-01 2005-06-23 Nabi Biopharmaceuticals Hapten-carrier conjugates for treating and preventing nicotine addiction
WO2006067632A2 (fr) * 2004-12-24 2006-06-29 Novartis Vaccines And Diagnostics Srl Vaccins à base de conjugués de saccharide
EP1849780A1 (fr) * 2006-04-21 2007-10-31 De Staat der Nederlanden, vert. door de minister van VWS Vaccin contre la toxicomanie de nicotine
WO2011014679A1 (fr) * 2009-07-31 2011-02-03 Nabi Biopharmaceuticals Procédé et trousse pour traiter la dépendance à la nicotine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0427347A1 (fr) * 1989-11-10 1991-05-15 ENIRICERCHE S.p.A. Peptides synthétiques utiles comme porteurs universels pour la préparation des conjugués immunogéniques el leur emploi dans le développment des vaccins synthétiques
US5876727A (en) * 1995-03-31 1999-03-02 Immulogic Pharmaceutical Corporation Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
WO1997049425A1 (fr) * 1996-06-25 1997-12-31 Stichting Instituut Voor Dierhouderij En Diergezondheid Vaccins comprenant des antigenes fixes sur leurs supports par des liaisons labiles
WO1998014216A2 (fr) * 1996-09-30 1998-04-09 Immulogic Pharmaceutical Corporation Conjugues haptene-porteur destines a etre utilises dans une therapie pour toxicomanes et procedes de preparation de ceux-ci
US20050136047A1 (en) * 1998-12-01 2005-06-23 Nabi Biopharmaceuticals Hapten-carrier conjugates for treating and preventing nicotine addiction
WO2006067632A2 (fr) * 2004-12-24 2006-06-29 Novartis Vaccines And Diagnostics Srl Vaccins à base de conjugués de saccharide
EP1849780A1 (fr) * 2006-04-21 2007-10-31 De Staat der Nederlanden, vert. door de minister van VWS Vaccin contre la toxicomanie de nicotine
WO2011014679A1 (fr) * 2009-07-31 2011-02-03 Nabi Biopharmaceuticals Procédé et trousse pour traiter la dépendance à la nicotine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BUSKAS T. ET AL.: "The immunogenicity of the tumor- associated antigen Lewis<y> may be suppressed by a bifunctional cross-linker required for coupling to a carrier protein", CHEM. EUR. J., vol. 10, no. 14, 2004, pages 3517 - 3524, XP055085926, DOI: doi:10.1002/chem.200400074 *
JEGERLEHNER A. ET AL.: "Carrier induced epitopic suppression of antibody responses induced by virus-like particles is a dynamic phenomenon caused by carrier-specific antibodies", VACCINE, vol. 28, no. 33, 2010, pages 5503 - 5512, XP027171080 *
KEYLER D.E.: "Enhanced immunogenicity of a bivalent nicotine vaccine", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 8, 2008, pages 1589 - 1594, XP025408613, DOI: doi:10.1016/j.intimp.2008.07.001 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022116782A1 (fr) * 2020-12-04 2022-06-09 江南大学 Lignée cellulaire d'hybridome d'anticorps monoclonal d'éthyl-maltol et application associée

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