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WO2005040338A2 - Immunogenes et anticorps alcaloides contraints et leurs utilisations - Google Patents

Immunogenes et anticorps alcaloides contraints et leurs utilisations Download PDF

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Publication number
WO2005040338A2
WO2005040338A2 PCT/US2004/016040 US2004016040W WO2005040338A2 WO 2005040338 A2 WO2005040338 A2 WO 2005040338A2 US 2004016040 W US2004016040 W US 2004016040W WO 2005040338 A2 WO2005040338 A2 WO 2005040338A2
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WIPO (PCT)
Prior art keywords
nicotine
immunogen
antibody
serum albumin
hapten
Prior art date
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Ceased
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PCT/US2004/016040
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WO2005040338A3 (fr
Inventor
Kim D. Janda
Peter Wirsching
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Scripps Research Institute
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Scripps Research Institute
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Publication of WO2005040338A3 publication Critical patent/WO2005040338A3/fr
Anticipated expiration legal-status Critical
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    • 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
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the field of this invention is methods of treating drug addiction. More particularly, this invention pertains to alkaloid immunogens, anti-alkaloid antibodies and the use of such immunogens and antibodies for treating alkaloid addiction.
  • the alkaloid is nicotine.
  • the present invention also relates to methods of enhancing the immunogenicity of small haptens by constraining their conformation.
  • Nicotine is the most widely used addictive drug in the world.
  • the drug is intimately linked with cigarette smoking, the leading preventable cause of death in the United States [Nelson, D. E.; Kirkendall, R. S.; Lawton, R. L.; Chrismon, J. H.; Merritt, R. K.; Arday, D. A.; Giovino, G. A. Morbid. Mortal. Wkly. Rep. 43, 1-8 (1994); US Dep. Health Hum.
  • both active immunization (immunoconjugate vaccine) and passive immunization (monoclonal antibodies, mAbs) protocols would be useful to provide therapies to counteract nicotine addiction.
  • the present invention also relates to immunogenic treatment of other alkaloid- based drugs of abuse. Unlike cocaine, which has a rigid tropine-based ring structure, nicotine and other alkaloids have less rigid structures. This flexibility makes them less effective at eliciting a strong immunogenic response. Hence, there is a need to develop methods of enhancing the immunogenicity of alkaloid haptens to improve the efficacy of imrnunogenic-based therapies for drug addiction.
  • the present invention provides a constrained nicotine immunogen.
  • the immunogen has the structure shown in FIG. 1 and designated as CNA or CNl.
  • FIG. 1 shows a synthetic scheme for making CNA and CN
  • the immunogen is linked to an immunogenic carrier such as keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA).
  • KLH keyhole limpet hemocyanin
  • BSA bovine serum albumin
  • this invention provides a method for immunizing an animal against nicotine. In accordance with that method, an animal is administered an effective immunogenic amount of the immunogen of this invention.
  • this invention provides an antibody that immunoreacts with the immunogen of this invention. Preferably, the antibody also immunoreacts with nicotine.
  • the antibody is a monoclonal antibody.
  • An anti-nicotine antibody is made by a process that comprises the step of immunizing an animal with the immunogen of this invention.
  • This invention further provides a method of immunizing an animal against nicotine that includes the step of administering to the animal an effective amount of a subject antibody.
  • the invention further provides a pharmaceutical composition containing a subject immunogen or antibody together with a physiological diluent.
  • the invention provides a method of enhancing the immunogenicity of an alkaloid hapten by constraining its conformation.
  • FIG. 1 shows nicotine haptens CNA and CNl and a scheme for making CNA and CN
  • FIGS. 2 and 3 illustrate the results of Example 2.
  • the Invention provides nicotine immunogens, anti-nicotine antibodies and the use of such immunogens and antibodies for immunizing animals against nicotine and treating nicotine addiction. This invention also provides methods of treating addictions to other alkaloids by constraining the conformation of alkaloid haptens.
  • Nicotine Immunogens [00 6] Nicotine is a small, haptenic molecule and requires coupling to an immunogenic carrier protein to elicit an immune response.
  • a nicotine hapten requires attention to stereochemistry, ionic/acid-base properties, and the site of attachment and characteristics of a linker moiety.
  • Nicotine which occurs as the (S)-configuration in nature (e.g. tobacco), contains two rings with an asymmetric center. There are two sites of basicity: the pyridyl and pyrrolidyl nitrogens. Nicotine is expected to carry a positive charge at physiological pH.
  • an optimal immunogen i.e., hapten
  • nicotinic compounds useful in the design of immunogens are shown in FIG. 1. Those compounds are CNA and CNl. [0019] CNA and CNl were designed and synthesized based on reported conformationally constrained nornicotine analogues 1 and 2 (FIG. 1). The N-Me nicotine-like derivative of 1 had analgesic effects, but the receptor remains unidentified. Recertry, other constrained analogues were developed, and shown to bind with low nanomolar affinity to the nicotinic acetylcholine receptor. The present invention focuses on 1 and 2, since they are readily prepared and provide a reasonable mirnic of the two trans confojmers of nicotine that is supported by crystal-structure data.
  • An immunogen is typically operatively linked to an immunogenic carrier before immunization of an animal.
  • Useful carriers are well known in the art and are generally proteins themselves.
  • Exemplary of such carriers are keyhole limpet hemocyanin (KLH), edestin, thyroglobulin, albumins such as bovine serum albumin or human serum albumin (BSA or HSA, respectively), red blood cells such as sheep erythrocytes (SRBC), tetanus toxoid, cholera toxoid as well as polyamino acids such as poly(D-lysine:D- glutamic acid), and the like.
  • KLH keyhole limpet hemocyanin
  • edestin edestin
  • thyroglobulin albumins
  • BSA or HSA human serum albumin
  • red blood cells such as sheep erythrocytes (SRBC)
  • tetanus toxoid tetanus toxoid
  • cholera toxoid as well as polyamino acids
  • poly(D-lysine:D- glutamic acid) poly(D-lysine:D- glutamic
  • the conjugate is to be used in laboratory animals, a carrier that does not generate an untoward reaction in the particular animal should be selected.
  • the carrier-hapten conjugate is dissolved or dispersed in an aqueous composition of a physiologically tolerable diluent such as normal saline, PBS, or sterile water to form an inoculum.
  • An adjuvant such as complete or incomplete Freund's adjuvant or alum can also be included in the inoculum.
  • the inoculum is introduced as by injection into the animal used to raise the antibodies in an amount sufficient to induce antibodies, as is well known.
  • HI. Anti-nicotine Antibodies [0021] The present invention provides antibodies that immunoreact with an immunogen of this invention.
  • An antibody can be a polyclonal or monoclonal antibody or an immunoreactive fragment thereof. Means for making polyclonal and monoclonal antibodies are well known in the art. Still further an antibody of this invention can be a recombinant antibody. Means for making recombinant antibodies are well known in the art. By way of example, immunoglobulin mRNA can be cloned from specific hybridomas and expessed using phage display. A recombinant antibody can be manipulated or mutated so as to improve its binding ability to an antigen such as nicotine. Means for such manipulation/mutation are also well known in the art. An antibody of this invention also cross reacts with nicotine.
  • the antibody cross reacts with S-(-), but not R-(+) nicotine.
  • Murine mAbs can be "humanized” via several techniques well known in the art [James, K. Human monoclonal antibodies. In: Handbook of Experimental Pharmacology : The Pharmacology of Monoclonal Antibodies, Rosenberg, M.; Moore, G. P., eds. New York: Springer- Verlag, vol. 113, pp. 3-19, 1994; Padlan, E. A., Mol. Immunol. 28, 489-498 (1991); Daugherty, B. L; DeMartino, J. A.; Law, M.-F.; Kawka, D. W.; Singer, 1. 1.; Mark, G.
  • “Humanization” of anti-cocaine antibodies can be accomplished in which the binding properties are similar to the starting murine mAb.
  • a methodology for selecting antibodies of desired specificity from combinatorial libraries makes human mAbs (scFvs or Fabs) directly available.
  • protein engineering can be utilized to prepare human IgG constructs. Access to humanized or fully human mAbs makes clinical application feasible.
  • the constrained haptens utilize a linker for coupling to a carrier protein, such as keyhole limpet hemocyanin (KLH).
  • KLH keyhole limpet hemocyanin
  • the same linker is used to prepare native nicotine-hapten conjugates (NIC-KLH) for use as controls.
  • the NIC-KLH immunoconjugate provides low titers having a mean value of about 3,200.
  • Competition ELISA and equilibrium dialysis measurements yield the serum affinity for (5)-nicotine as a Kj-avg, -1.7 ⁇ M ⁇ 0.20 ⁇ M.
  • Other groups reported titers for nicotine-based haptens of 10,000 or less and affinities in the micromolar range.
  • CNA-KLH and CNI-KLH antisera had low cross-reactivity in binding CNI-bovine serum albumin (BSA) (1:15) and CNA-BSA (1:6) conjugates used for titering, respectively, suggesting an important role for the pyridyl nitrogen in the antibody-hapten interactions and that recognition of the distinct trans species of nicotine is possible.
  • BSA CNI-bovine serum albumin
  • CNA-BSA CNA-BSA
  • this example of augmenting immunogenicity using conformational constrain of other alkaloid haptens provides a general route towards vaccination strategies for other pharmacologically important small molecules.
  • the present invention relates to a constraining structural modification of the hapten itself to improve immunogenicity. This approach may involve closing a ring around the chiral center of the hapten to "lock" it into one conformation or the other. However, any approach that would result in a more conformationally constrained hapten structure is also applicable. TV.
  • Pharmaceutical Composition [0027] The present invention further provides a pharmaceutical composition.
  • the pharmaceutical composition includes a compound of this invention (immunogen, antibody) together with a physiologically tolerable carrier.
  • compositions, carriers, diluents and reagents are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
  • physiological effects such as nausea, dizziness, gastric upset and the like.
  • compositions are prepared as injectables either as liquid solutions or suspensions, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified.
  • the active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
  • the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient.
  • the therapeutic composition of the present invention can include pharmaceutically acceptable salts of the components therein.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-aminoethanol, histidine, procaine and the like. Particularly preferred are the salts of TFA and HC1. [0032] Physiologically tolerable carriers are well known in the art.
  • Exemplary liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, polyethylene glycol and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, and water- oil emulsions.
  • A. Active Immunization One goal in an immunological approach aimed at the abatement of nicotine addiction is the de novo design of a vaccine.
  • vaccination imparts to the host's immune system the ability to defend against the acute psychostimulant and toxic effects of nicotine and its powerful reinforcing properties.
  • an active immunization against nicotine offers a means of blocking the actions of the drug by preventing it from entering the central nervous system and should have fewer side effects than treatments based on manipulation of central neurotransmitter function.
  • immunopharmacotherapy offers a nontoxic, substance-specific strategy that should not affect normal neurochemical physiology, presenting a solid scientific approach for the treatment of nicotine dependence.
  • the cell chamber is innoculated with 1-1.5 x 10 8 hybridoma cells (generally 200 ml of between 5-7 x 10 5 cells/ml) in 15 ml of complete media (RPMI with 2 mM L-glutamine, 10 mM Hepes, 1 mM Na pyruvate, 100 ⁇ g ml gentamycin sulfate, 500 units penicillin, 500 units streptomycin supplemented with 20% fetal calf serum).
  • the basal chamber has one liter of complete media without serum. After one week, the cell density and viability is checked. The cells are harvested and fed the cell compartment, keeping the viability over 50% and the density 5 x 10 6 cells/ml, and change the basal media.
  • the harvested cells (generally 15-20 ml) are centrifuged at 1500 rpm for 10 min.
  • the supernatant is filtered through a 0.22 ⁇ m filter and purified through a protein G column.
  • the concentration of antibody in the cell supernatant is usually ⁇ l-2 mg/ml.
  • the administration of antibodies to suppress the effects of nicotine can be accomplished using known methods of cocaine immunopharmacotherapy [Carrera, M. R. A.; Ashley, J. A.; Wirsching, P.; Koob, G. F.; Janda, K. D., Proc. Natl. Acad.
  • the passive administration of anti-nicotine antibodies is expected to be beneficial to reduce serum levels and attenuate "toxic" (cardiovascular, metabolic, endocrine) effects, or as (bi)weekly pharmacotherapy during smoking cessation programs.
  • the latter is accomplished by self-injection of mAb to maintain a high circulating level of antibody.
  • aerosolized immunoglobulin [Crowe, J. E., Jr.; Murphy, B. R.; Chanock, R. M.; Williamson, R. A.; Barbas, C. F., IJJ; Burton, D. R., Proc. Natl. Acad.
  • NIC9D9 in a volume of approximately 1.5 ml/kg.
  • Control rats were treated with an equivalent volume of physiological saline (i.v.).
  • All locomotor activity test sessions were preceded by a 90 min habituation session following s.c. saline injection (1 ml/kg).
  • the dose-response to NIC9D9 was produced by testing each dose two weeks apart, in order to avoid carry-over effects. All locomotor data reported refer to the ambulatory measure or crossovers.
  • inhalation of anti-nicotine antibodies via compact, portable inhalers may constitute the single most effective means to treat the problem of nicotine addiction. More particularly, binding nicotine in the systemic circulation using a vaccine or with passive antibodies should be an effective therapy.
  • a direct blockade in the pulmonary system, together with systemic protection, or even as a stand-alone treatment would greatly suppress the concentrations of nicotine that rapidly reach the brain during the action of smoking.
  • a passive immunization approach is likely effective by keeping nicotine below a threshold concentration required for reinforcement.
  • passive immunization protocols are as well.
  • the binding and blockade of nicotine is of paramount importance for therapy.
  • the additional treatment with a "cocktail" of mAbs specific for nomicotine and cotinine may also serve to reduce reinforcement and relapse potential, especially for some individuals.
  • the haptens described provide the essential elements in a program of immunopharmacotherapy that offers a new avenue in the challenging battle against nicotine addiction.
  • the plates were washed with PBS and then milk solution (1% w/v in PBS, 0.1 mL) was added and allowed to stand at room temperature for 2 h.
  • the plates were washed with PBS and the mouse serum (serially diluted with PBS) was added (50 ⁇ L) and allowed to stand overnight at 4 °C.
  • the plates were washed with PBS and a goat anti-mouse horseradish peroxidase conjugate (0.01 ⁇ g, 50 ⁇ L) was added and incubated at 37 °C for 2 h.
  • the plates were washed and substrate solution (50 ⁇ L) 3,3',5,5'-tetramethylbenzidine [(0.1 mg in 10 mL of 0.1 M sodium acetate, pH 6.0 and hydrogen peroxide (0.01% w/v)] was added. The plates were developed in the dark for 30 min. Sulfuric acid (1.0 M, 50 ⁇ L) was added to quench the reaction and the OD was measured at 450 nm. The reported titer is the serum dilution that corresponds to 50% of the maximum OD.
  • NIC-BSA as the plate antigen with serum dilutions ranging from 1:800 (CNA) to 1:6400 (NIC) and varying concentrations of competing agent (nicotine, cotinine, acetylcholine or N- methylpyrrolidine) were added. Competing agents were compared with respect to the concentration of agent that reduced serum affinity to the plate bound antigen by 50%. The results are shown in FIG. 2 for the experiment that compares serum specificities for nicotine with those for cotinine. [0057] Equilibrium dialysis.
  • mice immunized with the following immunoconjugates CNA-KLH, CNI-KLH or NIC-KLH and a conjugate based on nomicotine coupled via glutaric anhydride, TD1-KLH.
  • Serum samples were diluted 1 :50 (NIC-KLH) or 1 : 100 (the other samples) in PBS and added to 10 wells in a 96-well micro titer plate (60 ⁇ L/well).
  • Wells (10 per sample) in a second microtiter plate were filled (40 ⁇ L) with serially diluted [ 3 H]-nicotine in PBS, starting with 10 ⁇ M and 20 ⁇ L PBS was added to each well.
  • the two plates were very tightly connected with filled wells facing each other and separated with a dialysis membrane (cutoff 6000-8000 Da).
  • the plates were attached vertically to a shaker and were shaken at high frequency for 6-10 h at 4 °C after which they were carefully separated.
  • the membrane was discarded and 50 ⁇ L from each well was transferred to a scintillation vial containing 5 mL of scintillation fluid. The samples were counted for 5 min. The experiment was repeated twice for each serum sample.

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Abstract

L'invention concerne des immunogènes utilisés pour produire des anticorps anti-nicotine. L'invention concerne également des anticorps anti-nicotine qui réagissent de manière immunitaire avec les immunogènes et la nicotine et les utilisations de ces immunogènes et anticorps pour traiter l'addiction à la nicotine. L'invention concerne enfin des procédés permettant d'améliorer la capacité immunogène d'un haptène par introduction d'une modification afin de contraindre sa conformation.
PCT/US2004/016040 2003-05-21 2004-05-20 Immunogenes et anticorps alcaloides contraints et leurs utilisations Ceased WO2005040338A2 (fr)

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US47267103P 2003-05-21 2003-05-21
US60/472,671 2003-05-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009120954A3 (fr) * 2008-03-27 2010-01-07 The Scripps Research Institute Immunoconjugués de nicotine
WO2011151807A1 (fr) 2010-06-04 2011-12-08 Pfizer Vaccines Llc Conjugués pour la prévention ou le traitement de la dépendance à la nicotine
US8344111B2 (en) 2007-11-29 2013-01-01 Cytos Biotechnology Ag Human monoclonal nicotine specific antibodies
WO2015173685A1 (fr) 2014-05-16 2015-11-19 Pfizer Inc. Conjugués utilisables en vue de la prévention ou du traitement de la dépendance à la nicotine et leurs procédés de production
US9629832B2 (en) 2002-12-20 2017-04-25 Niconovum Usa, Inc. Physically and chemically stable nicotine-containing particulate material
US10219999B2 (en) 2006-03-16 2019-03-05 Niconovum Usa, Inc. Snuff composition

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9801923D0 (sv) * 1998-05-29 1998-05-29 Independent Pharmaceutical Ab Nicotine vaccine
US6232082B1 (en) * 1998-12-01 2001-05-15 Nabi Hapten-carrier conjugates for treating and preventing nicotine addiction
US20050089524A1 (en) * 2002-03-01 2005-04-28 Sanderson Sam D. Compositions and compounds for use as molecular adjuvant for a nicotine vaccine

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9629832B2 (en) 2002-12-20 2017-04-25 Niconovum Usa, Inc. Physically and chemically stable nicotine-containing particulate material
US12219983B1 (en) 2006-03-15 2025-02-11 Modoral Brands Inc. Compositions for buccal administration
US10219999B2 (en) 2006-03-16 2019-03-05 Niconovum Usa, Inc. Snuff composition
US11129792B2 (en) 2006-03-16 2021-09-28 Modoral Brands Inc. Snuff composition
US11547660B2 (en) 2006-03-16 2023-01-10 Niconovum Usa, Inc. Snuff composition
US12465566B2 (en) 2006-03-16 2025-11-11 Modoral Brands Inc. Snuff composition
US8344111B2 (en) 2007-11-29 2013-01-01 Cytos Biotechnology Ag Human monoclonal nicotine specific antibodies
WO2009120954A3 (fr) * 2008-03-27 2010-01-07 The Scripps Research Institute Immunoconjugués de nicotine
WO2011151807A1 (fr) 2010-06-04 2011-12-08 Pfizer Vaccines Llc Conjugués pour la prévention ou le traitement de la dépendance à la nicotine
WO2015173685A1 (fr) 2014-05-16 2015-11-19 Pfizer Inc. Conjugués utilisables en vue de la prévention ou du traitement de la dépendance à la nicotine et leurs procédés de production
US9303013B2 (en) 2014-05-16 2016-04-05 Pfizer Inc. Conjugates and associated methods of producing them for the prevention or treatment of nicotine addiction
US9475793B2 (en) 2014-05-16 2016-10-25 Pfizer Inc. Conjugates and associated methods of producing them for the prevention or treatment of nicotine addiction

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