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WO1993023076A1 - Therapie utilisant des recepteurs de substitution - Google Patents

Therapie utilisant des recepteurs de substitution Download PDF

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Publication number
WO1993023076A1
WO1993023076A1 PCT/US1993/004644 US9304644W WO9323076A1 WO 1993023076 A1 WO1993023076 A1 WO 1993023076A1 US 9304644 W US9304644 W US 9304644W WO 9323076 A1 WO9323076 A1 WO 9323076A1
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Prior art keywords
ligand
conjugate
animal
cocaine
antibodies
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PCT/US1993/004644
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English (en)
Inventor
John C. Cheronis
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Johns Hopkins University
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Johns Hopkins University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C07K17/02—Peptides being immobilised on, or in, an organic carrier
    • 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
    • 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
    • A61K39/385—Haptens or antigens, bound to carriers
    • 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
    • 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
    • A61K2039/6087—Polysaccharides; Lipopolysaccharides [LPS]
    • 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
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units

Definitions

  • the present invention relates, in general, to a novel therapeutic approach that involves the use of soluble, metabolically stable and pharmaceutically acceptable constructs to induce the immune system to produce immunoglobulins that can function as alternative receptors for a specific ligand. Since the immunoglobulins produced compete with naturally occurring receptors for the ligand, the availability of the ligand to its natural receptor can be regulated. Regulation of ligand availability makes possible modulation of the response produced upon binding of the ligand to its natural receptor.
  • the immune system can be subdivided into two primary branches based upon the response under consideration and the type of cell mediating this response.
  • Classically these responses are referred to as humoral (antibody or immunoglobulin mediated) and cellular responses.
  • Lymphocytes that synthesize immunoglobulins are referred to as B-cells while lymphocytes that are responsible for modulating B- cell function and for direct cytotoxicity are referred to as T-cells.
  • the therapeutic approach of the present invention relates, at least in large part, to B-cell responses, i.e. antibody (Ab) production.
  • Antibodies have two primary functions: 1) antigen (Ag) recognition, and 2) effector function. These functions correspond to two different portions of the immunoglobulin molecule.
  • the Fab portion of the molecule is responsible for recognition (Ag binding) whereas the Fc portion is responsible for effector functions.
  • the type of Fc defines the class of immunoglobulin and the effector response produced when an Ab binds to an Ag.
  • effector functions require that the Fc region of the Ab be recognized and bound to a class-specific receptor by some other cell (macrophages, mast cells, basophils, polymorphonuclear leukocytes, etc.).
  • immune complexes consisting of multivalent antigens bound by multiple Ab molecules. Single antigen- antibody pairs do not form immune complexes and therefore do not elicit effector responses. This is an important issue with respect to the present therapeutic approach since responses such as mast cell stimulation or immune complex production may be undesirable.
  • immune complexes to form at least two
  • Ab recognition sites need to exist on a single antigen and be simultaneously available to two different immunoglobulin molecules.
  • Small molecules such as cocaine and other ligands to which the invention relates
  • Small molecules cannot be bound simultaneously by two different Abs.
  • immune complex formation or receptor crosslinking on cells cannot be achieved.
  • Allergic responses to small molecular weight ligands such as penicillin, sulfa, procainamide, etc. can be attributed to the propensity of these compounds to covalently bind to proteins, thereby producing multiple epitopes for simultaneous Ab binding on a single macromolecule. Where the pharmacology, metabolism and chemistry do not allow for such interactions, multiple binding sites on the same macromolecule are highly unlikely to occur.
  • IgM immunoglobulins
  • IgG immunoglobulin G
  • IgE immunoglobulin derived factors
  • IgD immunoglobulin D
  • IgE antibodies For example, allergic symptoms ranging from simple rhinitis to anaphylaxis can be attributed to IgE antibodies while immunoglobulins found in mucosal secretions are of the IgA class. Other classes have different attributes.
  • naive B-cells expressing membrane bound receptors albeit of low affinity
  • IgM antibodies Upon first encounter with a novel antigen, naive B-cells expressing membrane bound receptors (albeit of low affinity) which recognize this antigen, begin to differentiate into plasma cells and secrete IgM.
  • IgM antibodies Upon first encounter with a novel antigen, naive B-cells expressing membrane bound receptors (albeit of low affinity) which recognize this antigen, begin to differentiate into plasma cells and secrete IgM.
  • IgM antibodies have a binding site which is identical to the binding site of the original B-cell receptor and have binding constants on the order of 10 * to 10 ' molar.
  • Repeated challenges with such an antigen do not invoke "booster" responses or memory phenomenon but interact with the immune system as if they were simple primary challenges eliciting primary responses. This is what is seen in response to simple antigens such as bacterial polysaccharides.
  • T-cells and T-cell factors - must be involved. Once T-cells are involved, the type of antibody secreted changes initially from IgM to IgG, IgA or IgE (depending on the setting) .
  • IgG and IgA antibodies have binding constants ranging from 10 to 10 M while IgE affinities can be as high as 10 * M.
  • the kinetics of these responses are significantly different. IgG, for example, rarely is seen sooner than 10-14 days after initial challenge.
  • immunoglobulins or alternative receptors with binding constants ranging from 10 *5 to 10-9, which are key to various embodiments of the present therapeutic approach, can be readily achieved.
  • the persistence of these immunoglobulins in circulation allows for the intermittent dosing of the ligand-specific i munostimulatory constructs of the invention.
  • circulating immunoglobulins are ideally situated to interrupt or block the delivery of active ligand to the target organ, for example, the brain or cardiovascular tissues. The effect of this interruption of delivery is amplified in the case of ligands (such as cocaine) that are subject to inactivation by, for example, circulating esterases.
  • Immunoglobulins have been used successfully as alternative receptors for a number of toxicologic emergencies. As far as therapies currently approved for human use are concerned, all of these cases involve the use of exogenously administered antibody (see Smith et al, N. Engl J Med 294:797 (1976); Smith et al, N Engl J . Med, 307:1357 (1982); Spiegal et al. Am Heart J 109:1397 (1985); Wenger, et al, J Am Coll Cardiol , 5:118A (1985); Bonese et al. Nature , 252:708 (1974)). In contrast, the present invention involves the use of immunostimulatory constructs to induce the endogenous production of such antibodies. The advantages of this approach will be clear from the description of the invention that follows.
  • specific objects of the invention include providing a method of regulating the levels of tumor-associated growth factors and thereby inhibiting tumor growth and, providing a method of regulating the levels of pituitary releasing hormones and thereby controlling fertility.
  • the method of the invention has broad applicability as will be appreciated by one skilled in the art from a reading of this disclosure.
  • FIGURE 1 Administration to mice of fluorescein (Fl) conjugated to dextran of 500,000 MW (Fl-deX jQp ) ⁇ ⁇ IgM boost, ⁇ A IgM control.
  • FIGURE 2 Administration to mice of Fl- ex j r ⁇ ,; O O IgG boost, O O IgG control.
  • FIGURE 3 Injection of mice with constructs, IgM Ab titer (FIG. 3a) , IgG Ab titer
  • FIGURE 4 Structure of cocaine.
  • FIGURE 5 Cocaine analogs.
  • FIGURE 6 Opiate derivatives.
  • FIGURE 7 Opiate modifications needed for linking to immunoconjugates.
  • the present invention relates to a method of inducing the immune system to produce immunoglobulins in high enough titer and with the appropriate affinity distribution to serve as alternative receptors for a particular ligand and to thereby control the availability of that ligand to its natural receptor.
  • the invention further relates to constructs suitable for use in such a method.
  • the chemistry of the constructs of the present invention can be readily altered with the result that the affinity and class distribution of the resulting antibodies can be controlled.
  • the method of the invention is described herein in some detail with reference to a treatment for drug abuse, specifically, cocaine and morphine (opiate) abuse.
  • the method has wide applicability, however, in that it can be employed to control the availability of endogenous ligands, in addition to compounds exogenously administered for therapeutic and non-therapeutic purposes.
  • the method can be used to control the availability of, for example, hormones and growth factors, and thereby to control, for example, fertility (by controlling availability of pituitary releasing hormones) and tumor growth (by controlling availability of tumor growth factors) .
  • the method can be used to regulate the availability of any of a number of small molecules and thereby control the effects elicited upon binding of such molecules to corresponding naturally occurring receptors.
  • peptide-protein immunoconjugates as a vaccine to raise antibody titers to the decapeptide: Gln-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly which appears to regulate gamete formation and activation in cattle and other animals.
  • Antibodies directed to this peptide will depress fertility in the immunized animals as long as circulating antibodies are present (Hoskinson et al, Australian J. Biotechnology 4(3) :166 (1990)).
  • Antibodies directed to this peptide or other peptides such as follicle stimulating hormone (FSH) and/or luteinizing hormone (LH) can be expected to have the same type of an effect in humans.
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • HCG human chorionic gonadotropin
  • hormone and/or growth factor sensitive malignancies such as estrogen sensitive breast cancers, testosterone sensitive prostate cancers, melanocyte stimulating hormone (MSH) responsive melanomas, etc. are anticipated to respond to antibodies directed against these "growth factors” or to antibodies directed against modulators of the release of such factors.
  • Immunostimulatory constructs suitable for use in the present method can be designed based on technology developed by the Dintzis 1 which is described in detail in Application No. 07/808,787 (see also Dintzis et al, Pro ⁇ . Natl . Acad . Sci . USA 73:3671 (1976); Dintzis et al, Proc. Natl . Acad. Sci . USA 79:884 (1982); Dintzis et al, J. Immunol . 131:2196 (1983); Vogelstein et al, Proc . Natl . Acad. Sci . USA 79:395 (1982)).
  • That technology defines the molecular and physical requirements for a given macromolecular construct to be stimulatory versus non-stimulatory as far as T-independent antibody production is concerned.
  • the following parameters must be met in order for a given construct to be stimulatory: i) the overall molecular weight of the macromolecular construct consisting of a biologically inert backbone (carrier or scaffold) " and the relevant antigenic epitope in question must be greater than 100,000 daltons, optimal responses are seen around 300,000-500,000 daltons; and ii) the total number of antigenic epitopes per macromolecule must be greater than 20, with the more the better.
  • Example III and IV include detailed descriptions of the design of constructs suitable for use in the present method. While Example III makes specific reference to cocaine and Example IV to opiate, one skilled in the art will appreciate that the same approach can be applied to other ligands, including endogenous hormones and growth factors. Example III further includes details of treatment regimens, etc., in the context of a method for treating cocaine abuse. The artisan will understand, however, that the same principles apply to the other treatment protocols encompassed within the scope of the invention.
  • the present invention is described in some detail with reference to a treatment of cocaine abuse.
  • Other forms of drug abuse that can be expected to be responsive to treatment using the present method, however, include opiate, benzodiazepine, phencyclidine and nicotine dependence.
  • the present method can be used to induce the production of circulating antibodies specific for this ligand that compete effectively with tissue-bound receptors for cocaine and in so doing, block its physiologic and psychologic effects by controlling its availability to the central nervous system (CNS) .
  • CNS central nervous system
  • One skilled in the art will appreciate that ideally an alternative receptor therapeutic approach to cocaine, nicotine or opiate abuse should have the characteristics described below, which characteristics are fulfilled by the present method and constructs as indicated:
  • the Ab population should be of moderate to low affinity. If high affinity Abs are produced, their ability to be saturated and, as a result, neutralized as competitive receptors would obviate their utility.
  • these alternative receptors have rapid (1-5 millisecond) on and relatively slow (100-500 second) off rates (nominal affinity constants on the order of 10 * to 10 * M) . This allows for rapid binding and slow (but measurable) release, thereby allowing for receptor regeneration.
  • the alternative receptor need not bind all of the available drug for long periods of time; all it need accomplish is to retard the availability of cocaine (nicotine or opiate) to the CNS by blunting peak free levels.
  • IgM and low affinity IgG Abs produced in accordance with the present invention, have binding constants on the order of 10 * to 10 * M with fast on and slow (but measurable) off characteristics and IgG3 passes placental barriers without difficulty thereby potentially affording significant fetal protection.
  • Circulating Ab titers should be of the same order of magnitude (on a molar ligand binding basis) as the peak free drug level seen in serum under normal use. This does not mean that the concentration of Ab should be the same as the concentration of drug at steady state, but that, preferably, the total amount of ligand binding equivalents of immunoglobulin in the circulation should be approximately equal to the dose of drug administered on a molar basis.
  • IgM produced in accordance with the present invention, has a ligand binding capacity of 10 binding sites per protein molecule and levels produced (taking this binding capacity into account) can be expected to be adequate for purposes of the present invention.
  • Ab titers should be relatively long lived requiring only intermittent enhancement or induction. Repeated stimulation should not change the pharmacologic characteristics of the competitive receptor, nor should repeated induction or stimulation carry with it any significant risk of toxicity.
  • IgM levels produced by the present method, have adequate serum half lives but, more importantly, repeated stimulation or induction using the constructs described herein does not produce affinity maturation or class switching (both potential detriments in the present method) . Changes in affinity or class could have serious deleterious consequences including changes in receptor affinity such that the Abs can be inactivated by ligand binding and the production of undesired im unologic side effects. 5) Administration of drug in the presence of Ab should not have any untoward effects.
  • IgM because of its relatively low affinity does not normally produce Ag-Ab complexes (unless epitope expression on the antigen is highly multivalent) or untoward immune-mediated side effects.
  • the immune response can be controlled so that IgM is the primary immunoglobulin produced. Accordingly, side effects in the presence of drug can be expected to be minimal.
  • the behavioral effects of cocaine and likewise nicotine and the opiates
  • the behavioral consequences of drug use can be altered. All of these aspects of substance abuse pharmacology are expected to be amenable to modification by the induction of alternative immunoglobulin receptors using the present invention.
  • conjugates consisting of a biologically inert backbone (high molecular weight dextran >100,000 daltons has been used as a plasma expander) and a cocaine analog (see Example III) can be used for epitope-specific T-independent Ab induction.
  • conjugates can be expected to produce IgM and IgG3 Ab responses analogous to those seen for other simple haptens.
  • the data that follow relate to such constructs.
  • peptides based on T-cell epitopes from vaccines for example, against tetanus, diptheria or pertussus, or commonly experienced viral pathogens (measles, mumps, rubella, chicken pox, influenza A or B, etc) can be employed. While the foregoing comments include specific reference to fluorescein, one skilled in the art will appreciate that cocaine, morphine or nicotine analogs, for example, will behave as B-cell epitopes analogous to fluorescein.
  • Ab stimulation is critically dependent on the biologic stability of the construct used to stimulate the immune response.
  • One of the advantages of adjuvants is that they decrease the metabolic degradation of the immunogen and thereby prolong its biological activity.
  • many of the problems with adjuvants such as local inflammatory reactions, tissue injury and discomfort are at least in part due to their "depot” like behavior.
  • the macromolecular constructs used in the method of the present invention are designed to be freely soluble and easily distributed by intravenous, subcutaneous or intramuscular injection so as to eliminate local side-reactions or inflammatory stimuli. This is particularly important for agents that are to be used on a regular or repeated basis.
  • Ag/Ab complexes or "serum sickness” type reactions are unlikely to occur since low to moderate affinity antibodies will be produced.
  • Cocaine is rapidly degraded by circulating esterases which would alter the chemical nature of the epitope in question.
  • metabolically stable cocaine analogs can be used that bear sufficient homology to cocaine to induce production of Abs that recognize the intact cocaine molecule.
  • use of molecular analogs is advantageous since chemical moieties such as ketones, amides or phosphates, bear sufficient homology to esters to induce Abs that recognize esters for catalytic and other purposes and are relatively metabolically inert.
  • the intact cocaine molecule can be subdivided into four regions, as shown in FIG. 4.
  • the immunoglobulins (alternative receptors) generated by the present method must be capable of recognizing and binding the active compound at least as well as (if not better than) the inactive metabolites.
  • regions 2 and 3 are highly sensitive to metabolic degradation by circulating serum esterases.
  • conjugates utilizing compounds (haptens) that retain esters in these positions will be rapidly degraded, thereby preferentially generating Abs to cocaine metabolites as opposed to the active compound.
  • phosphonates are transition state analogs for compounds that undergo esterase cleavage, compounds 8-13
  • phosphonates are transition state analogs for compounds that undergo esterase cleavage, compounds 8-13
  • they are advantageous in that they generate Ab's that are not only specific for active compounds but also potentially have "catalytic” qualities.
  • they retain this type of "catalytic binding” they satisfy the criteria of active compound specificity in addition to fast off rates (in this case with ester hydrolysis and the release of an inactive molecule) .
  • actual catalysis is less important than the specificity for active compound that would be potentially available from these types of Abs. It is important to realize, however, that in these cases the stereochemistry at the appropriate carbon will be critical for the activity of the resulting immunoglobulins.
  • Target haptens are conjugated to carrier molecules of various known immunogenic sizes
  • haptens synthesized should also be tested for pharmacologic activity as cocaine agonists or antagonists themselves. 6
  • Conjugates can be injected into mice using immunization protocols described in Application No. 07/808,797 in order to characterize their immunogenicity.
  • Ab titer and affinity can be assessed to both the ligand used to raise the Ab response as well as to cocaine itself (competition and direct ligand binding) .
  • the distribution of immunoglobulin class (IgM, IgGl, IgG2, etc) over time can be assessed.
  • sera can be tested for actual esterase activity in addition to Ag binding capabilities.
  • affinity and class for a selected group of conjugates that develop the higher titers and a range of affinities can be evaluated.
  • One of the preferred types of chemistries that has been employed in the generation of immunogenic conjugates is the formation of maleimide containing backbone carriers which then can be reacted with thiol containing haptens. This type of reaction results in the generation of metabolically stable thioether linkages between the hapten and the carrier.
  • the synthesis of modified morphine based haptens for the formation of these types of conjugates is illustrated in FIGURE 7a or b.
  • the reactive thiol is protected by an easily removable sulfhydral protecting group (nitropyridinesulfenyl (Npys) , in compound E, FIGURE 7a and benzyl (Bn) in compound B, FIGURE 7b) . Once made, these compounds can be deprotected and reacted with the maleimide containing carriers described previously and used to induce the production of alternative receptors in a manner similar to that described above.

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Abstract

L'invention concerne d'une manière générale une nouvelle approche thérapeutique qui implique l'utilisation de structures solubles pharmaceutiquement acceptables et métaboliquement stables afin de provoquer la production par le système immunitaire d'immunoglobulines pouvant fonctionner comme des récepteurs de substitution pour un ligand spécifique. Etant donné que les immunoglobulines produites sont en compétition avec les récepteurs produits naturellement pour le ligand, la disponibilité du ligand par rapport à son récepteur naturel peut être régulée. La régulation de la disponibilité du ligand permet de moduler la réponse produite lors de la liaison du ligand à son récepteur naturel.
PCT/US1993/004644 1992-05-20 1993-05-20 Therapie utilisant des recepteurs de substitution Ceased WO1993023076A1 (fr)

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US88587392A 1992-05-20 1992-05-20
US07/885,873 1992-05-20

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Cited By (16)

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Publication number Priority date Publication date Assignee Title
WO1995005849A1 (fr) * 1993-08-26 1995-03-02 Mouritsen & Elsner A/S Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes
WO1996030049A3 (fr) * 1995-03-31 1997-03-06 Immulogic Pharma Corp Conjugues vecteurs de haptene utilises dans une therapie contre l'usage de drogues
US5662911A (en) * 1995-02-02 1997-09-02 Boehringer Mannheim Gmbh Benzodiazepine protein conjugates
US5760184A (en) * 1995-03-31 1998-06-02 Immulogic, Inc. Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
WO1998014216A3 (fr) * 1996-09-30 1998-12-10 Immulogic Pharma Corp Conjugues haptene-porteur destines a etre utilises dans une therapie pour toxicomanes et procedes de preparation de ceux-ci
WO2000032239A1 (fr) * 1998-12-01 2000-06-08 Nabi Tonjugues haptene-porteur pour traiter et prevenir l"accoutumance a la nicotine
US6284533B1 (en) 1996-05-01 2001-09-04 Avant Immunotherapeutics, Inc. Plasmid-based vaccine for treating atherosclerosis
US6410022B1 (en) 1995-05-01 2002-06-25 Avant Immunotherapeutics, Inc. Modulation of cholesteryl ester transfer protein (CETP) activity
WO2002066056A3 (fr) * 2001-02-19 2003-01-03 Pharmexa As Agents de vaccin synthetiques
WO2002058635A3 (fr) * 2001-01-26 2003-03-20 Scripps Research Inst Immunogenes a la nicotine, anticorps et leurs applications
US6846808B1 (en) 1996-05-01 2005-01-25 Avant Immunotherapeutics, Inc. Plasmid-based vaccine for treating atherosclerosis
US7074407B1 (en) 1995-06-06 2006-07-11 Avant Immunotherapeutics, Inc. Method for increasing HDL cholesterol level
US7097837B2 (en) 2001-02-19 2006-08-29 Pharmexa A/S Synthetic vaccine agents
US7135181B2 (en) 2000-02-21 2006-11-14 Pharmexa A/S Method for down-regulation of amyloid
US7285273B1 (en) 1999-04-23 2007-10-23 Pharmexa A/S Method for down-regulating IL5 activity
US8871212B2 (en) 2001-08-20 2014-10-28 H. Lundbeck A/S Amyloid-beta polypeptide vaccine

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EP0378881A1 (fr) * 1989-01-17 1990-07-25 ENIRICERCHE S.p.A. Peptides synthétiques et leur utilisation comme support universel pour la préparation de conjugués immunogènes convenant au développement de vaccins synthétiques

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EP0378881A1 (fr) * 1989-01-17 1990-07-25 ENIRICERCHE S.p.A. Peptides synthétiques et leur utilisation comme support universel pour la préparation de conjugués immunogènes convenant au développement de vaccins synthétiques

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Title
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THE FASEB JOURNAL, Volume 4, Number 3, issued 26 February 1990, BAGASRA et al., "A Potential Vaccine for Cocaine", page A493. *
THE JOURNAL OF IMMUNOLOGY, Volume 143, Number 4, issued 15 August 1989, DINTZIS et al., "The Immunogenicity of Soluble Haptenated Polymers is Determined by Molecular Mass and Hapten Valence", pages 1239-1244. *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005849A1 (fr) * 1993-08-26 1995-03-02 Mouritsen & Elsner A/S Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes
US5662911A (en) * 1995-02-02 1997-09-02 Boehringer Mannheim Gmbh Benzodiazepine protein conjugates
US5840307A (en) * 1995-03-31 1998-11-24 Immulogic Pharmacuetical Corp. Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation
EP1782835A3 (fr) * 1995-03-31 2008-06-11 Xenova Research Limited Conjugués comprenant un haptène et un vecteur utilisés dans la thérapie des abus de drogues
EP1782837A3 (fr) * 1995-03-31 2008-01-09 Xenova Research Limited Conjugués comprenant un haptène et un vecteur utilisés dans la thérapie des abus de drogues (nicotine)
EP1329226A3 (fr) * 1995-03-31 2004-01-21 Xenova Research Limited Conjugués vecteurs de haptène utilisés dans une thérapie contre l'usage de drogues
WO1996030049A3 (fr) * 1995-03-31 1997-03-06 Immulogic Pharma Corp Conjugues vecteurs de haptene utilises dans une therapie contre l'usage de drogues
US5760184A (en) * 1995-03-31 1998-06-02 Immulogic, Inc. Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
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