Development of an Effective Monoclonal Antibody against Heroin and Its Metabolites Reveals Therapies Have Mistargeted 6-Monoacetylmorphine and Morphine over Heroin

Abstract

The opioid epidemic is a global public health crisis that has failed to abate with current pharmaceutical treatments. Moreover, these FDA-approved drugs possess numerous problems such as adverse side effects, short half-lives, abuse potential, and recidivism after discontinued use. An alternative treatment model for opioid use disorders is immunopharmacotherapy, where antibodies are produced to inhibit illicit substances by sequestering the drug in the periphery. Immunopharmacotherapeutics against heroin have engaged both active and passive vaccines targeting heroin’s metabolites, 6-monoacetylmorphine (6-AM) and morphine, since decades of research have stated that heroin’s psychoactive and lethal effects are mainly attributed to these compounds. However, concerted efforts to develop effective immunopharmacotherapies against heroin abuse have faced little clinical advancement, suggesting a need for reassessing drug target selection. To address this issue, four unique monoclonal antibodies were procured with distinct affinity to either heroin, 6-AM, or morphine. Examination of these antibodies through in vitro and in vivo tests revealed monoclonal antibody 11D12 as the optimal therapeutic and provided crucial insights into the key chemical species to target for blunting heroin’s psychoactive and lethal effects. These findings offer clarification into the problematic attempts of therapeutics targeting heroin’s metabolites and provide a path forward for future heroin immunopharmacotherapy development.

Heroin metabolism in human blood and its impact for the design of an immunotherapeutic approach against heroin effects

“…34 Thus, several lines of evidence point to the importance of binding 6-AM instead of heroin. A recent study concluded that mAbs binding heroin and not 6-AM are critical for the reduction of heroin analgesia 37 ; however, uncertainties regarding the pharmacokinetics of heroin when given intraperitoneally could challenge this conclusion.…”

Revolutionary Approaches to Managing Neuropathies: A Review of Innovative Therapies

“…The colonies that produced active antibodies were then identified and isolated. The complete elimination of murine components resulted in the development of mAbs that were largely less immunogenic and, in many cases, had enhanced pharmacokinetic profiles that slowed their clearance from plasma [62].…”

Determination of trace morphine and its metabolites in mouse urine using a TpBD functionalized bivalve magnetic nano-adsorbent

“…This is crucial not only to mitigate the risk of abuse-induced overdose 9 but also to facilitate dosage monitoring. 10 To date, various analytical methodologies have been employed to quantify morphine and its metabolites 11 in diverse biological matrices, including enzyme immunoassay, 12 gas chromatography 13 (GC), liquid chromatography 14 (LC), gas chromatographymass spectrometry 15 (GC-MS), and liquid chromatography-mass spectrometry 16 (LC-MS). Mass spectrometry is widely recognized as the predominant analytical method among these techniques due to its unparalleled detection sensitivity.…”