A simple nonradioactive method for the determination of the binding affinities of antibodies induced by hapten bioconjugates for drugs of abuse

Torres, Òscar; Antoline, Joshua F. G.; Li, Fuying; Jalah, Rashmi; Jacobson, Arthur E.; Rice, Kenner C.; Alving, Carl R.; Matyas, Gary R.

doi:10.1007/s00216-015-9223-z

Cited by 17 publications

(73 citation statements)

References 49 publications

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“…Antibody affinity toward morphine (13.9 nM) or oxycodone (14.5 nM) was within the range of affinities measured by other groups (0.4-24 nM) using similar immunogens (Anton and Leff, 2006;Stowe et al, 2011;Torres et al, 2016;Kimishima et al, 2017). It is not clear whether higher affinity antibodies would have performed substantially better.…”

Section: Efficacy Of Vaccines For Opioid Use Disordersmentioning

confidence: 55%

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

Raleigh

Laudenbach

Baruffaldi

et al. 2018

J Pharmacol Exp Ther

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Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The current study addressed the efficacy of a heroin vaccine [morphine hapten conjugated to keyhole limpet hemocyanin (M-KLH)] or oxycodone vaccine [oxycodone hapten conjugated to keyhole limpet hemocyanin (OXY-KLH)] for reducing drug distribution to brain after intravenous heroin or oxycodone, or subcutaneous oxycodone. Rats immunized with M-KLH or keyhole limpet hemocyanin (KLH) control received an intravenous bolus dose of 0.26 or 2.6 mg/kg heroin. Vaccination with M-KLH increased retention of heroin and its active metabolites 6-acetylmorphine (6-AM) and morphine in plasma compared with KLH controls, and reduced total opioid (heroin 1 6-AM 1 morphine) distribution to brain but only at the lower heroin dose. Immunization also protected against respiratory depression at the lower heroin dose. Rats immunized with OXY-KLH or KLH control received 0.22 or 2.2 mg/kg oxycodone intravenously, the molar equivalent of the heroin doses. Immunization with OXY-KLH significantly reduced oxycodone distribution to brain after either oxycodone dose, although the magnitude of effect of immunization at the higher oxycodone dose was small (12%). By contrast, vaccination with OXY-KLH was more effective when oxycodone was administered subcutaneously rather than intravenously, reducing oxycodone distribution to brain by 44% after an oxycodone dose of 2.3 mg/kg. Vaccination also reduced oxycodone-induced antinociception. These data suggest that the efficacy of OXY-KLH and M-KLH opioid vaccines is highly dependent upon opioid dose and route of administration.

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Section: Efficacy Of Vaccines For Opioid Use Disordersmentioning

confidence: 55%

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

Raleigh

Laudenbach

Baruffaldi

et al. 2018

J Pharmacol Exp Ther

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“…In RIA, a scintillation counter must be used for detection of the tritium-labeled tracer. As a nonradioactive alternative, deuterated drug tracer can be used and detected by liquid chromatography-mass spectrometry (LCMS) (Torres et al, 2016). Using the K d value discerned from the assay as well as the tracer concentration, the antibody concentration can be calculated using Müller's method (Muller, 1983).…”

Section: A Immunochemical Methodsmentioning

confidence: 99%

“…= 369, 315 g/mol, respectively) and contain five or more heteroatoms and a complex, three-dimensional structure. As a result, morphinan haptens can act as effective immune epitopes, and anti-hapten antibodies have shown 10 210 to 10 29 M affinity for the target drugs (Torres et al, 2016;Kimishima et al, 2017). Similarly, antiserum to a fentanyl conjugate vaccine showed affinity in the 10 29 M range for fentanyl (three heteroatoms, mol.…”

Section: A Drug Selectionmentioning

confidence: 99%

Conjugate Vaccine Immunotherapy for Substance Use Disorder

2017

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Substance use disorder, especially in relation to opioids such as heroin and fentanyl, is a significant public health issue and has intensified in recent years. As a result, substantial interest exists in developing therapeutics to counteract the effects of abused drugs. A promising universal strategy for antagonizing the pharmacology of virtually any drug involves the development of a conjugate vaccine, wherein a hapten structurally similar to the target drug is conjugated to an immunogenic carrier protein. When formulated with adjuvants and immunized, the immunoconjugate should elicit serum IgG antibodies with the ability to sequester the target drug to prevent its entry to the brain, thereby acting as an immunoantagonist. Despite the failures of first-generation conjugate vaccines against cocaine and nicotine in clinical trials, second-generation vaccines have shown dramatically improved performance in preclinical models, thus renewing the potential clinical utility of conjugate vaccines in curbing substance use disorder. This review explores the critical design elements of drug conjugate vaccines such as hapten structure, adjuvant formulation, bioconjugate chemistry, and carrier protein selection. Methods for evaluating these vaccines are discussed, and recent progress in vaccine development for each drug is summarized.

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“…MorHap ELISA was performed with 100 uL (1 μg/mL) of coating antigen. 17 V2, A244 gp70-V1V2, and gp120 ELISAs were performed as described previously, 18 with modifications, as summarized in Table S 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…1 ). 5 , 6 , 16 , 17 For the HIV-1 arm, we examined two different antigens, consisting of either a synthetic linear (LV2) or a cyclic (CV2) 42 amino acid-free peptide, both of which were based on the V2 loop of an HIV-1 subtype AE (CRF01_AE) gp120 protein. 18 The synthetic LV2 and CV2 peptides each contained palmitic acid at the N-terminus, resulting in palm-LV2 or palm-CV2.…”

Section: Introductionmentioning

confidence: 99%

Heroin-HIV-1 (H2) vaccine: induction of dual immunologic effects with a heroin hapten-conjugate and an HIV-1 envelope V2 peptide with liposomal lipid A as an adjuvant

et al. 2017

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A synthetic heroin analog (MorHap) and a synthetic 42 amino acid V2 loop peptide from A/E strain of HIV-1 gp120 envelope protein that was previously used in a successful phase III vaccine trial were constructed as antigens together with liposomes containing monophosphoryl lipid A as an adjuvant, to explore the feasibility of producing a dual use vaccine both for treatment of heroin addiction and prevention of HIV-1 infection among injection drug users. The V2 peptide was tethered by a palmitoyl fatty acyl tail embedded in the liposomal lipid bilayer, and the heroin analog was conjugated to tetanus toxoid as a carrier protein that was mixed with the adjuvant. Upon comparison of a linear V2 peptide with a cyclic peptide, differences were found in the secondary configurations by circular dichroism, with the tethered cyclic peptide (palm-cyclic peptide) entirely in a random coil, and the tethered linear V2 peptide (palm-linear V2 peptide) entirely in a beta-sheet. Upon immunization of mice, palm-cyclic peptide induced anti-cyclic peptide endpoint titers >106 and was considered to be a better immunogen overall than palm-linear V2 peptide for inducing antibodies to gp120 and gp70-V1V2. The antibodies also inhibited the binding of V2 peptide to the HIV-1 α4β7 integrin receptor. Antibody titers to MorHap, even with the presence of injected cyclic peptide, were very high, and resulted in inhibition of the hyper-locomotion and antinociception effects of injected heroin. From these initial experiments, we conclude that with a potent adjuvant and mostly synthetic constituents, a vaccine directed to heroin and HIV-1 (H2 vaccine) could be a feasible objective.

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A simple nonradioactive method for the determination of the binding affinities of antibodies induced by hapten bioconjugates for drugs of abuse

Cited by 17 publications

References 49 publications

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

Conjugate Vaccine Immunotherapy for Substance Use Disorder

Heroin-HIV-1 (H2) vaccine: induction of dual immunologic effects with a heroin hapten-conjugate and an HIV-1 envelope V2 peptide with liposomal lipid A as an adjuvant

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