Functional and biological determinants affecting the duration of action and efficacy of anti-(+)-methamphetamine monoclonal antibodies in rats

Abstract

IntroductionMonoclonal antibody (mAb) medications offer promising treatment for autoimmune disease, cancer, and a host of other diseases including substance abuse [1][2][3]. These medications have several advantages over traditional small molecule medicines. For example, mAbs have high affinity and precise selectivity for their disease targets, act as pharmacokinetic antagonists to block or blunt the action of their target antigen, and have an extremely long biological halflife (e.g., ~21 days for human IgG 1 ) [4]. The long half-life is a particularly valuable pharmacological property since it allows for very long intervals between dosing. This long mAb half-life is usually assumed to result in an equally prolonged binding function, but direct evidence for prolonged function is often difficult to obtain. The use of antibodies for treatment of drug abuse and addiction provides a novel therapeutic opportunity that would greatly benefit from a prolonged pharmacological action and less need for daily patient compliance. Toward this goal, our group has produced a significant number of mouse mAbs for use in preclinical studies of the acute and chronic treatments of adverse health effects associated with (+)-methamphetamine (METH) abuse [5][6][7]. The METHspecific mAb were produced using several METH-like haptens, coupled to a carrier protein. These METH antigens are useful for active immunizations, in addition to generating mAb for passive immunization. Our METH-specific mAbs reverse or reduce the pharmacological actions of METH by pharmacokinetic antagonism, which includes high affinity mAb binding, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptVaccine. Author manuscript; available in PMC 2010 November 23. METH's primary sites of action are in the brain [8], and the drug has extensive extravascular distribution with an apparent volume of distribution (Vd) = 9 L/kg in rats [9]. In contrast, mAb medications are confined mostly to the plasma and extracellular fluid space, which has a Vd = 0.141 L/kg for mouse mAbs in rats [10]. This suggests the maximum theoretical reduction in the METH Vd in the presence of an anti-METH mAb would be about 64-fold. MAb high affinity binding is considered a critical mechanism for therapeutic action, and it is generally assumed that in vivo efficacy (and binding function) can be predicted by the in vitro mAb affinity (or K D value) for the target ligand. However, comparison of pharmacological data from acute and chronic in vivo studies with METH and various moderate-to-high affinity anti-METH mAbs has now lead ...

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

“…[1][2][3][4][5] Anti-METH mAbs reside in the blood and extracellular fluid compartments where they bind METH with such high affinity that they rapidly redistribute METH from its sites of action in the brain and other organs into the blood stream. [6][7][8] MAbs offer specific advantages as a drug abuse therapy. Compared with other immunotherapies such as vaccines, mAbs necessarily do not require the function of the user's immune system to work, making them appropriate for immunosuppressed patients, including those with HIV/AIDS or autoimmune conditions.…”

Pharmacological effects of two anti-methamphetamine monoclonal antibodies

“…An additional important characteristic is the duration of in vivo activity. We have shown that despite having a similar biological half-life to other mAbs (i.e., »6-7 d in the rat 6 ), one of our highest affinity anti-METH mAbs only effectively reduces METH effects for a short time period. 2 The reasons for this in vivo inactivation have not been completely determined, 9 but the ability to reduce the effects of repeated METH doses over an extended time period is important for long-term success of new mAbs.…”

“…2 Anti-METH mAbs function via pharmacokinetic antagonism of METH effects. By dramatically altering the disposition of METH via high-affinity binding and redistribution, 1,6 they reduce its stimulant effects. 1,2 The binding interactions between METH and mAb are, however, complex.…”

“…6,9,10 Furthermore, both mAbs have high affinity for METH and differing affinities for the related compounds (C)-amphetamine (AMP) and (C)-3,4-methylenedioxymethamphetamine (MDMA). MAb4G9 has a K D for METH of 16 nM and a K I for MDMA of 68 nM.…”

Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

“…We previously suggested that the blood-brain barrier restricts anti-METH mAb (but not METH) to the vasculature, which allows temporary greater drug-mAb occupancy and more removal of METH from the brain with each passage through the brain vasculature (Laurenzana et al, 2009).…”