Human clinical trials of cocaine conjugate vaccines have provided new hope for a way to treat cocaine addiction. This is singularly important because there is presently no FDA approved therapy for cocaine addiction. The central hypothesis underlying this vaccine is that it is possible to generate sufficient quantities of highy specific, high affinity antibody to capture most of the cocaine that drug addicts insert into their circulation before the drug reaches the brain. We postulate that a successful vaccine will inhibit the pharmacological effects of cocaine in the addict, blocking the "high" and subsequent craving result. Clinical experience to date demonstrates that only a subset of vaccinated subjects get enough of an antibody response to these vaccines that they curtail their use of cocaine. Currently efforts are being made using different hapten and novel carriers to improve the vaccine efficacy. However, there is a fundamental gap in our understanding of how these antibodies interact with cocaine, in terms of kinetic rate constants (association and dissociation rate), and the influence of the presence of serum components. Recently we demonstrated an approximate 15 fold decrease in affinity for anti-cocaine monoclonal antibody binding in the presence of 20-50% human serum compared to that measured in phosphate buffer. We hypothesize that similar reductions in affinity will likely be observed when polyclonal antibodies elicited by cocaine conjugate vaccines are tested. Moreover we postulate that clinical efficacy will be closely linked to the specificity and binding properties measured in presence of serum. The objective of this grant application is to develop analytical methods that measure antibody-cocaine interactions in the presence of serum, and find out how these measurements relate to the clinical outcomes of the phase IIA TA-CD cocaine vaccine clinical trials. Briefly, the followin specific aims will be pursued: (1) Using microscale thermophoresis measure concentration and affinity of anti-cocaine as well as anti-CTB antibodies directly from vaccinated humans and mice sera. (2) Using biosensor platforms, (a) measure the average kinetics of purified anti-cocaine antibodies from patient sera;(b) determine the concentration of anti-cocaine and anti-cholera toxin (carrier) antibodies in samples from the cocaine conjugate vaccine clinical trial, (c) compare affinity distribution of vaccinated human/mouse serum based on cocaine inhibition experiments with those of monoclonal of known affinity. The proposed research is significant because it will reveal the key in vivo binding parameters for antibodies on which the benefits of cocaine conjugate vaccines depend.
With a lack of any FDA approved therapy, the severity of cocaine addiction continues to plague all parts of the world. Development of cocaine conjugate vaccines will likely provide an effective way to help people free themselves of this addiction so long as the vaccine provides sufficient quantities of high affinity antibody that can capture the drug before it passes from the circulation to the brain. This research will provide a way to determine which specific vaccines generate antibody responses that can do this job.
|Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen et al. (2014) The future potential for cocaine vaccines. Expert Opin Biol Ther 14:1271-83|
|Ramakrishnan, Muthu; Kinsey, Berma M; Singh, Rana A et al. (2014) Hapten optimization for cocaine vaccine with improved cocaine recognition. Chem Biol Drug Des 84:354-63|