A Chimeric Human/Murine Anticocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Mice

ABSTRACT The predominantly human sequence, high-affinity anticocaine monoclonal antibody (mAb) 2E2 was cleared slowly from mouse blood by a first-order process with an elimination t 1/2 of 8.1 days. Infused 2E2 also produced a dramatic dose-dependent increase in plasma cocaine concentrations and a concomitant decrease in the brain cocaine concentrations produced by an i.v. injection of cocaine HCl (0.56 mg/kg). At the highest dose of 2E2 tested (3:1, mAb/drug), cocaine was not detectable in the brain. Pharmacokinetic studies showed that the normal disappearance of cocaine from plasma was described by a two-compartment pharmacokinetic model with distribution t 1/2␣ and terminal elimination t 1/2␤ values of 1.9 and 26.1 min, respectively. In the presence of an equimolar dose of mAb 2E2, there was a 26-fold increase in the area under the plasma cocaine concentration-time curve (AUC) relative to the AUC in the absence of 2E2. Consequently, 2E2 decreased the volume of distribution of cocaine from 6.0 to 0.20 l/kg, which approximated that of 2E2 (0.28 l/kg). However, cocaine was still rapidly cleared from plasma, and its elimination was now described by a single-compartment model with an elimination t 1/2 of 17 min. Importantly, 2E2 also produced a 4.5-fold (78%) decrease in the cocaine AUC in the brain. Therefore, the effect of 2E2 on plasma and brain cocaine concentrations was predominantly caused by a change in the distribution of cocaine with negligible effects on its rate of clearance. These data support the concept of immunotherapy for drug abuse. Despite decades of basic and clinical research there is still no approved pharmacotherapy for the prevention of relapse in cocaine abusers Passive immunization using a monoclonal antibody (mAb) with a defined affinity, specificity, and dose may be even more efficacious. Indeed, passive immunization with murine anticocaine mAb attenuates the behavioral effects of cocain

Methods in clinical chemistry/ Pesce

xxii, 1366 hal: ill; 29 cm

Methods in clinical chemistry/ Pesce

xxii, 1366 hal: ill; 29 cm

Nephrotoxicity of Bence Jones proteins in the rat: Importance of protein isoelectric point

Although Bence Jones proteins have been recognized for well over 100 years, it was not until 1962 that Edelman and Gaily [1] demonstrated these proteins to be in fact the light polypeptide chains of all immunoglobulin classes. Strictly speaking, the term “Bence Jones protein” is reserved for those proteins identified by their solubility properties on heating [2]. These properties, however, have been shown to be somewhat nonspecific [3], and the term is now commonly used to denote appreciable amounts of, usually monoclonal, light chain appearing in the urine or serum of patients with multiple myeloma, primary amyloidosis [4], and monoclonal gammopathies [5]. Such light chains of mol wt of approximately 22,000 daltons commonly exist in dinner form in aqueous solution [1]. Bence Jones proteinuria is reported in various studies as being present in 40 to 80% of patients with myeloma [6, 7] and as being almost invariably present in 23% of patients with light-chain myeloma, in over 90% of patients with rarely occurring IgD-myeloma, in 35% of patients with IgG-myeloma, and 20% of those with IgA-myeloma [7]

Enhancement of Antigen-Specific Suppression by Muramyl Dipeptide

The effect of the synthetic adjuvant MDP (N-acetyl-muramyl-L-alanyl-D-isoglu-tamine) on the generation of antigen-specific suppression was investigated. Suppression of the anti-bovine serum albumin response, which was achieved by intravenous administration of a peptic fragment of the antigen, was greatly enhanced by simultaneous administration of MDP. Induction of suppression by a combination of bovine serum albumin fragments and MDP was found to be antigen specific and appeared to occur via the generation of antigen-specific suppressor T cells