Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use

Abstract

Ch-mAb7F9, a human-mouse chimeric monoclonal antibody (mAb) designed to bind (+)-methamphetamine (METH) with high affinity and specificity, was produced as a treatment medication for METH abuse. In these studies, we present the preclinical characterization that provided predictive evidence that ch-mAb7F9 may be safe and effective in humans. In vitro ligand binding studies showed that ch-mAb7F9 is specific for and only binds its target ligands (METH, (+)-amphetamine, and 3,4-methylenedioxy-N-methylamphetamine) with high affinity. It did not bind endogenous neurotransmitters or other medications and was not bound by protein C1q, thus it is unlikely to stimulate in vivo complement-dependent cytotoxicity. Isothermal titration calorimetry potency studies showed that METH binding by ch-mAb7F9 is efficient. Pharmacokinetic studies of METH given after ch-mAb7F9 doses in rats demonstrated the in vivo application of these in vitro METH-binding characteristics. While METH had little effect on ch-mAb7F9 disposition, ch-mAb7F9 substantially altered METH disposition, dramatically reducing the volume of distribution and clearance of METH. The elimination half-life of METH was increased by ch-mAb7F9, but it was still very fast compared with the elimination of ch-mAb7F9. Importantly, the rapid elimination of unbound METH combined with previous knowledge of mAb:target ligand binding dynamics suggested that ch-mAb7F9 binding capacity regenerates over time. This finding has substantial therapeutic implications regarding the METH doses against which ch-mAb7F9 will be effective, on the duration of ch-mAb7F9 effects, and on the safety of ch-mAb7F9 in METH users who use METH while taking ch-mAb7F9. These results helped to support initiation of a Phase 1a study of ch-mAb7F9.

Pharmacological effects of two anti-methamphetamine monoclonal antibodies

“…The K D for mAb4G9 binding to AMP (50 nM) has been reported, 11 however, only a K I for mAb7F9 binding to AMP (370 nM) has been published to date. 12 Because these studies aimed to consider the effects of AMP affinity on reduction of stimulant effects and alteration of METH pharmacokinetics, we determined the K D for AMP of both mAb7F9 and mAb4G9 using the same modified radioimmunoassay method as done previously. 11 Our results show that mAb4G9 has an approximately 2.5-fold greater affinity for AMP than mAb7F9.…”

“…11 MAb7F9 has a K D for METH of 8 nM and a K I for MDMA of 8 nM. 12 They are both also known to bind AMP and this characteristic was directly compared for this report.…”

“…This comparison of murine mAb4G9 and mAb7F9 was part of a series of tests that resulted in the selection of mAb7F9 for conversion to a chimeric form as described in Stevens et al 12 and subsequent clinical development. Importantly, these results were part of the data set reviewed by the US Food and Drug Administration prior to their allowing the initiation of a recently completed Phase 1a human safety study of the human-mouse chimeric form of mAb7F9 called ch-mAb7F9.…”

Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

“…These data also suggest the METH and AMP are cleared from the rats even in the presence of antibody. This clearance of the METH and AMP would presumably help to restore antibody-binding capacity (Stevens et al, 2014).…”

Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine

“…[6][7][8] A number of SUD vaccines are in preclinical development, and some have been tested in humans. [9][10][11][12][13][14][15][16] Overall, preclinical and clinical studies emphasize the importance of generating high antibody levels against the target drug to prevent its entry into the central nervous system (CNS) and thereby reduce relapse.…”