Methamphetamine (METH) is a principal drug threat in the US and worldwide and there are no FDA approved medications to treat the medical problems caused by METH. One exciting potential medication for the treatment of METH abuse is antibody therapy. Preclinical studies have shown that high affinity monoclonal antibodies (mAb) against METH can quickly reduce the amount of METH in the brain, and reduce METH-induced behavioral effects. There are currently two forms of anti-METH mAbs in preclinical testing: a long-acting intact IgG form and the extremely short-acting single chain variable fragment (scFv). The smaller scFv can be produced more economically than intact mAbs and the protein dose required to deliver the same number of METH-binding fragments is only one-third the intact mAb dose; however, the in vivo half-life of scFv is currently too short to offer longer-term protection from the effects of METH effects. Since the pharmacokinetic properties of a medication have dramatic influences on the effectiveness and potency, an anti-METH antibody antagonist could be improved by creatively applying molecular engineering and nanotechnology to the rational design of these medications. Advances in nanotechnology have introduced exciting new possibilities for customizing protein and antibody therapies. One of these innovations is the new class of molecule called dendrimers, which are synthesized by polymerizing molecules into repeating branched chains. The hypothesis for this project is that the efficacy and duration of action of an anti-METH antibody fragment can be customized and optimally controlled by conjugating it to a dendrimer delivery system. The aims of this project are: 1- Use molecular engineering techniques to produce high affinity anti-METH antibody fragments. 2- Generate and characterize anti-METH scFv dendrimer delivery systems (dendribodies) for in vivo pharmacological testing. 3- Examine the safety and pharmacological properties of the novel anti-METH scFv and dendribody medications in preclinical studies in rats. These proposed studies will integrate the fields of molecular biology, nanotechnology, pharmacokinetics, and therapeutics and apply them to medications development for drug abuse. If successful, these studies will develop new antibody medications for treating a range of clinical problems related to METH abuse, and could possibly create a new paradigm for customizing antibody pharmacokinetic antagonists. PUBLIC HEALTH RELEVANCE: These studies have immediate relevance to public health because they will create new medications to treat medical problems associated with methamphetamine abuse, a principal drug threat in the US and the world. Through the combination of molecular biology and nanotechnology, we will create antibody antagonists with customized properties for direct application to methamphetamine-related medical needs like drug overdose and addiction.

R01DA026423

2009-04-01

2014-03-31