10.1021/mp200588v.s001
Jennifer
B. Treweek
Jennifer
B.
Treweek
Kim D. Janda
Kim D.
Janda
An Antidote for Acute
Cocaine Toxicity
American Chemical Society
2012
cocaine hapten GNC
optimized mAb formats
cocaine overdose
antibody
Acute Cocaine ToxicityNot
murine mAb GNC 92H
cocaine binding affinity
2012-04-02 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/An_Antidote_for_Acute_Cocaine_Toxicity/2536111
Not only has immunopharmacotherapy grown into a field
that addresses
the abuse of numerous illicit substances, but also the treatment methodologies
within immunopharmacotherapy have expanded from traditional active
vaccination to passive immunization with anti-drug monoclonal antibodies,
optimized mAb formats, and catalytic drug-degrading antibodies. Many
laboratories have focused on transitioning distinct immunopharmacotherapeutics
to clinical evaluation, but with respect to the indication of cocaine
abuse, only the active vaccine TA-CD, which is modeled after our original
cocaine hapten GNC, has been carried through
to human clinical trials. The successful
application of murine mAb GNC92H2 to the reversal of cocaine overdose
in a mouse model prompted investigations of human immunoglobulins
with the clinical potential to serve as cocaine antidotes. We now
report the therapeutic utility of a superior clone, human mAb GNCgzk
(<i>K</i><sub>d</sub> = 0.18 nM), which offers a 10-fold
improvement in cocaine binding affinity. The GNCgzk manifold was engineered
for rapid cocaine clearance, and administration of the F(ab′)<sub>2</sub> and Fab formats even after the appearance of acute behavioral
signs of cocaine toxicity granted nearly complete prevention of lethality.
Thus, contrary to the immunopharmacotherapeutic treatment of drug
self-administration, minimal antibody doses were shown to counteract
the lethality of a molar excess of circulating cocaine. Passive vaccination
with drug-specific antibodies represents a viable treatment strategy
for the human condition of cocaine overdose.