Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use.
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.
InterveXion Therapeutics, LLC; Little Rock, AR USA.
Misty W
MW
Stevens
InterveXion Therapeutics, LLC; Little Rock, AR USA; Dept. of Pharmacology and Toxicology; University of Arkansas for Medical Sciences; Little Rock, AR USA.
Rachel L
RL
Tawney
Dept. of Pharmacology and Toxicology; University of Arkansas for Medical Sciences; Little Rock, AR USA.
C Michael
CM
West
Dept. of Biological Sciences; University of Arkansas; Fayetteville, AR USA.
Alicia D
AD
Kight
InterveXion Therapeutics, LLC; Little Rock, AR USA; Dept. of Biological Sciences; University of Arkansas; Fayetteville, AR USA.
Ralph L
RL
Henry
InterveXion Therapeutics, LLC; Little Rock, AR USA; Dept. of Pharmacology and Toxicology; University of Arkansas for Medical Sciences; Little Rock, AR USA.
S Michael
SM
Owens
InterveXion Therapeutics, LLC; Little Rock, AR USA; Dept. of Pharmacology and Toxicology; University of Arkansas for Medical Sciences; Little Rock, AR USA.
W Brooks
WB
Gentry
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000915:Antibody Affinity; D015922:Complement C1q / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008694:Methamphetamine / Q000276:immunology*; D051379:Mice; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000276:immunology / Q000628:therapy*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; D008694:Methamphetamine; D015922:Complement C1q
addiction; bioequivalence; chimeric antibody; human; methamphetamine; monoclonal antibody; pharmacokinetics