An Oxycodone Conjugate Vaccine Elicits Drug-Specific Antibodies that Reduce Oxycodone Distribution to Brain and Hot-Plate Analgesia

Abstract

Opioid conjugate vaccines have shown promise in attenuating the behavioral effects of heroin or morphine in animals. The goal of this study was to extend this approach to oxycodone (OXY), a commonly abused prescription opioid. Haptens were generated by adding tetraglycine (Gly) 4 or hemisuccinate (HS) linkers at the 6-position of OXY. Immunization of rats with OXY(Gly) 4 conjugated to the carrier proteins bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH) produced high-titer antibodies to OXY and its metabolite oxymorphone with substantially lower affinities for other structurally related opioid agonists and antagonists. There was no measurable binding of antibody by the (Gly) 4 linker alone or off-target opioids methadone and buprenorphine. OXY(HS) conjugates were less immunogenic despite achieving protein haptenation ratios comparable to OXY(Gly) 4 -BSA. In rats given a single intravenous dose of OXY, immunization with OXY(Gly) 4 -KLH increased OXY protein binding and retention in serum while decreasing its unbound (free) concentration in plasma and distribution to brain. Vaccine efficacy correlated with serum antibody titers, and it was greatest in rats given the lowest OXY dose (0.05 mg/kg) but was significant even after a larger OXY dose (0.5 mg/kg), equivalent to the high end of the therapeutic range in humans. These effects of OXY(Gly) 4 -KLH on drug disposition were comparable to those of nicotine or cocaine vaccines that are in clinical trials as addiction treatments. Immunization with OXY(Gly) 4 -KLH also reduced OXY analgesia in a thermal nociception test. These data support further study of vaccination with the OXY(Gly) 4 -KLH immunogen as a potential treatment option for OXY abuse or addiction.

Dynamic vaccine blocks relapse to compulsive intake of heroin

“…This approach is becoming increasingly pertinent, with the increase in prescription opiate abuse raising concerns about vaccinated heroin addicts transitioning to alternative opiates. The design of vaccines against oxycodone and hydrocodone were also recently reported (39,40), along with examples of effective mixtures of multiple opiate vaccines (21,41), pointing to progress that will widen the spectrum of potential opiate blockade via vaccination.…”

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

“…M-KLH generates antibodies specific for heroin, 6-acetylmorphine (6-AM), morphine, and morphine-6-glucuronide, but do not appreciably cross react with methadone, buprenorphine, naloxone, naltrexone, oxycodone, or leu-enkephalin . OXY-KLH generates antibodies specific for oxycodone and oxymorphone, but do not appreciably cross react with naloxone, naltrexone, methadone, buprenorphine, or leu-enkephalin (Pravetoni et al, 2012b).…”

“…The total number of moles per kilogram of opioid-specific IgG in rats vaccinated with M-KLH or OXY-KLH was estimated as the product of the measured antibody concentration in serum and the reported IgG volume of distribution (131 ml/kg) in rats (Bazin-Redureau et al, 1997;Pravetoni et al, 2012b).…”

“…Antibody affinity (K d ) was measured as half-maximum binding at equilibrium and converted to molar concentrations using Prism version 7.0 (GraphPad Software, Inc., La Jolla, CA). Opioid-specific antibody concentrations were calculated from the B max value using a molecular weight of 150 kDa for IgG (Bazin-Redureau et al, 1997;Pravetoni et al, 2012b) and two binding sites per IgG.…”

“…Therapeutic vaccines for heroin and prescription opioid abuse have shown efficacy in a wide range of preclinical models, demonstrating that immunization can reduce opioid distribution to the brain and attenuate opioid-related behaviors including self-administration, locomotor activation, and analgesia in mice, rats, and non-human primates (Bonese et al, 1974;Anton and Leff, 2006;Li et al, 2011Li et al, , 2014Stowe et al, 2011;Pravetoni et al, 2012bPravetoni et al, ,c, 2013Pravetoni et al, , 2014aKosten et al, 2013;Raleigh et al, 2013Raleigh et al, , 2014Schlosburg et al, 2013;Laudenbach et al, 2015;Bremer et al, 2017). However, vaccine efficacy is often tested in animals using immunization protocols involving routes of administration (e.g., intraperitoneal) and adjuvants (e.g., Freund's complete adjuvant) that are not used in humans, or at opioid doses that are suitable for the animal models chosen but are at the lower end of the range that may be abused by humans.…”