Preclinical Efficacy and Characterization of Candidate Vaccines for Treatment of Opioid Use Disorders Using Clinically Viable Carrier Proteins

Federico Baruffaldi, April Huseby Kelcher, Megan Laudenbach, Valeria Gradinati, Ajinkya Limkar, Michaela Roslawski, Angela Birnbaum, Andrew Lees, Carla Hassler, Scott Runyon, Marco Pravetoni

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Vaccines may offer a new treatment strategy for opioid use disorders and opioid-related overdoses. To speed translation, this study evaluates opioid conjugate vaccines containing components suitable for pharmaceutical manufacturing and compares analytical assays for conjugate characterization. Three oxycodone-based haptens (OXY) containing either PEGylated or tetraglycine [(Gly)4] linkers were conjugated to a keyhole limpet hemocyanin (KLH) carrier protein via carbodiimide (EDAC) or maleimide chemistry. The EDAC-conjugated OXY(Gly)4-KLH was most effective in reducing oxycodone distribution to the brain in mice. Vaccine efficacy was T cell-dependent. The lead OXY hapten was conjugated to the KLH, tetanus toxoid, diphtheria cross-reactive material (CRM), as well as the E. coli-expressed CRM (EcoCRM) and nontoxic tetanus toxin heavy chain fragment C (rTTHc) carrier proteins. All vaccines induced early hapten-specific B cell expansion and showed equivalent efficacy against oxycodone in mice. However, some hapten-protein conjugates were easier to characterize for molecular weight and size. Finally, heroin vaccines formulated with either EcoCRM or KLH were equally effective in reducing heroin-induced antinociception and distribution to the brain of heroin and its metabolites in mice. This study identifies vaccine candidates and vaccine components for further development.

Original languageEnglish (US)
Pages (from-to)4947-4962
Number of pages16
JournalMolecular pharmaceutics
Volume15
Issue number11
DOIs
StatePublished - Nov 5 2018

Bibliographical note

Funding Information:
We thank Drs. Maria Luisa Gelmi and Francesca Clerici for establishing an institutional and educational agreement between the Facolt? di Scienze del Farmaco, Universit? degli Studi di Milano, and the University of Minnesota Medical School.

Funding Information:
†Hennepin Healthcare Research Institute (HHRI, formerly Minneapolis Medical Research Foundation or MMRF), 701 Park Avenue, Minneapolis, Minnesota 55415, United States ‡Dipartimento di Chimica e Tecnologie Farmaceutiche, Socrates Program, Universitá degli Studi di Milano, Milan 20122, Italy §University of Minnesota, Minneapolis, Minnesota 55455, United States ∥Fina Biosolutions, LLC, Rockville, Maryland 20850, United States ⊥RTI International, Research Triangle Park, North Carolina 27709-2194, United States #Departments of Medicine and Pharmacology, Center for Immunology, University of Minnesota, Minneapolis, Minnesota 55455, United States

Publisher Copyright:
© 2018 American Chemical Society.

Keywords

  • carrier protein
  • conjugate vaccine
  • hapten
  • heroin
  • linkers
  • oxycodone

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