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. 2016 Oct 15;26(20):5078-5081.
doi: 10.1016/j.bmcl.2016.08.081. Epub 2016 Aug 25.

Studies towards the improvement of an anti-cocaine monoclonal antibody for treatment of acute overdose

Bin Zhou  1 , Lisa M Eubanks  1 , Nicholas T Jacob  2 , Beverly Ellis  1 , Amanda J Roberts  3 , Kim D Janda  4
Affiliations

Studies towards the improvement of an anti-cocaine monoclonal antibody for treatment of acute overdose

Bin Zhou et al. Bioorg Med Chem Lett. .

Abstract

There is currently no clinically-approved antidote for cocaine overdose. Efforts to develop a therapy via passive immunization have resulted in a human monoclonal antibody, GNCgzk, with a high affinity for cocaine (Kd=0.18nM). Efforts to improve the production of antibody manifolds based on this antibody are disclosed. The engineering of an HRV 3C protease cleavage site into the GNCgzk IgG has allowed for increased production of a F(ab')2 with a 20% superior capacity to reduce mortality for cocaine overdose in mice.

Keywords: Cocaine; Cocaine overdose; Drugs of abuse; Monoclonal antibody; scFv-Fc.

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Figures

Figure 1
Figure 1
Cartoon depiction of the different antibody manifolds of GNCgzk with a summary of key characteristics.
Figure 2
Figure 2
Average time-dependent serum concentrations of GNCgzk scFv-Fc determined by SPR (mean ± SEM; n = 9). Half-life on the GNCgzk scFV-Fc was determined to be 3.9 days.
Figure 3
Figure 3
Overdose study for the GNCgzk scFv-Fc. a. Survival graph of treatment administered 3-mins post i.p. infusion of 110 mg/kg of cocaine (n = 10). b. LOCF of ataxia score for each treatment group 40 mins following cocaine infusion (mean + SEM). c. LOCF of severity of cocaine-induced seizures 40 mins following cocaine infusion (mean + SEM).
Figure 4
Figure 4
180 mg/kg IgG, 132 mg/kg F(ab′)2, cocaine injected i.p. at 110 mg/kg, treatment administered 3 mins after injection over 1 min by CC (n = 10). a. Survival graph for treatment group 40 minutes post-cocaine infusion. b. LOCF of ataxia score over time for each treatment group (mean + SEM). c. LOCF of seizure severity of each treatment group 40 mins post-cocaine infusion (mean + SEM). *P < 0.05 determined by Fisher's Exact Test (two-tailed).
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