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

MAbs. Mar-Apr 2014;6(2):547-55. doi: 10.4161/mabs.27620. Epub 2013 Dec 23.

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.

Keywords: addiction; bioequivalence; chimeric antibody; human; methamphetamine; monoclonal antibody; pharmacokinetics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism*
  • Antibody Affinity
  • Complement C1q / metabolism*
  • Humans
  • Immunotherapy / methods*
  • Male
  • Methamphetamine / immunology*
  • Mice
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism*
  • Substance-Related Disorders / immunology
  • Substance-Related Disorders / therapy*
  • Tissue Distribution

Substances

  • Antibodies, Monoclonal
  • Recombinant Fusion Proteins
  • Methamphetamine
  • Complement C1q