Immunotoxicotherapy: Present status and future trends

Scherrmann, Jean‐Michel; Terrien, N.; Urtizberea, M.; Pierson, Pascale David; Denis, Hélène; Bourre, Jean‐Marie

doi:10.3109/15563658909038567

Cited by 35 publications

(14 citation statements)

References 23 publications

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“…As a result of omalizumab binding to IgE, lowering its free concentration, total serum IgE concentrations rise. Such an increase could occur by two mechanisms: (i) omalizumab-IgE complexes could be eliminated more slowly than free IgE due to the ability of the IgG portion of complexes to access the Brambell receptor, sparing them from lysosomal degradation [13], and (ii) the complexes, being of higher molecular mass (at least 340 kDa for the dimer but up to 1000 kDa for the hexamer [14]), filter less effectively through the vascular endothelium and are therefore retained within the smaller plasma volume of distribution [15][16][17][18].However, these mechanisms have yet to be confirmed, although a mechanism-based PK/PD model of the pharmacokinetics of omalizumab and its binding to IgE has been published for a limited number of subjects [19]. The concentration-time profiles of omalizumab, free and total IgE exhibited many of the same properties as other therapeutic antibodies.…”

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confidence: 99%

A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab

Hayashi

Tsukamoto

Sallas

et al. 2007

Brit J Clinical Pharma

159

165

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AimOmalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations. MethodsAn instantaneous equilibrium drug-ligand binding and turnover population model was built from 202 Japanese patients. A posterior predictive evaluation for the steady-state distributions of omalizumab and IgE was then carried out against 531 White patients. ResultsThe mean parameters estimated from the Japanese patients were as follows: omalizumab clearance 7.32 Ϯ 0.153 ml h -1 , IgE clearance 71.0 Ϯ 4.68 ml h -1 and the difference between that for omalizumab and the complex 5.86 Ϯ 0.920 ml h -1 , the volume of distribution for omalizumab and IgE 5900 Ϯ 107 ml, and that for the complex 3630 Ϯ 223 ml, the rate of IgE production 30.3 Ϯ 2.04 mg h -1 . Half-lives of IgG (23 days) and IgE (2.4 days) were close to previous reports. The dissociation constant for binding, 1.07 nM, was similar to in vitro values. Clearance and volume of distribution for omalizumab varied with bodyweight, whereas the clearance and rate of production of IgE were predicted accurately by baseline IgE. Overall, these covariates explained much of the interindividual variability. ConclusionsThe predictiveness of the Japanese model was confirmed by Monte-Carlo simulations for a White population, also providing evidence that the pharmacokinetics of omalizumab and IgE were similar in these two populations. Furthermore, the model enabled the estimation of not only omalizumab disposition parameters, but also the binding with and the rate of production, distribution and elimination of its target, IgE. IntroductionOmalizumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds human immunoglobulin E (IgE). The antibody is an immunoglobulin (Ig) G 1 k with a human framework and complementarity determining regions (CDRs) from a humanized anti-IgE murine antibody [1]. The causal role of IgE in allergic disease is well established [1-3]. The British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2006 Administration of omalizumab significantly decreases serum free IgE concentrations, resulting in improved control of atopic asthma and, most probably, other atopic conditions. As a result of omalizumab binding to IgE, lowering its free concentration, total serum IgE concentrations rise. Such an increase could occur by two mechanisms: (i) omalizumab-IgE complexes could be eliminated more slowly than free IgE due to the ability of the IgG portion of complexes to access the Brambell receptor, sparing them from lysosomal degradation [13], and (ii) the complexes, being of higher molecular mass (at least 340 kDa for the dimer but up to 1000 kDa for the hexamer [14]), filter less effectively through the vascular endothelium and are therefore retained within the smaller plasma volume of distribution [15][16][17][18].However, these ...

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confidence: 99%

A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab

Hayashi

Tsukamoto

Sallas

et al. 2007

Brit J Clinical Pharma

159

165

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“…Immunotoxicotherapy is a potential alternative for TCA detoxi®cation. The patient is given drug-speci®c antibodies which sequester the drug in the vascular compartment and thus remove drug molecules from the peripheral organs to the vascular compartment, leading to the reversal of drug toxicity (Scherrmann et al, 1989). Speci®c antibodies have been used in man to treat digitalis poisoning (Smith et al, 1976) and more recently, colchicine intoxication (Baud et al, 1995).…”

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confidence: 99%

Influence of various combinations of specific antibody dose and affinity on tissue imipramine redistribution

Ragusi

Boschi

Risède

et al. 1998

British J Pharmacology

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This study was designed to evaluate the distribution kinetics of imipramine (Imip) in the brain and the main peripheral organs (heart, kidney, liver and lung) of rats, and to establish the relationship between the redistribution of Imip from these tissues and the immunoreactive capacity (dose and affinity) of anti‐TCA IgG. [3H]‐Imip (1 nmol kg−1 body weight) was injected intravenously 6 min before the i.v. injection of antibodies. At this time, the concentrations of Imip and its main metabolites in plasma were determined. The radioactivity measured corresponded to 91.7% Imip, indicating that the pharmacokinetics reflected essentially Imip. Plasma and tissue Imip contents were measured over the interval 1 to 90 min in control and in treated rats. The antibodies used were a murine monoclonal IgG1 (Ka=3.8 107 M−1) at an IgG1/Imip molar ratio of 1000 (IgG1 1000), and a sheep polyclonal IgG (TAb, Ka=1.3 1010 M−1) at IgG/Imip molar ratios of 1, 10 and 100 (TAb1, TAb10 and TAb100). The anti‐TCA IgG increased the plasma [3H]‐Imip concentrations: the AUC1→60 min for [3H]‐Imip were 4 (IgG1 1000), 9 (TAb1), 33.9 (TAb10) and 41.4 (TAb100) times higher in the treated groups than in the controls. The opposite effect occurred in the brain, heart and lungs, with large, rapid decreases in Imip. The increase in plasma Imip and the decrease in tissue Imip depended on the immunoreactive capacity (NKa) of the antibody, where N=molar concentration of IgG binding sites and Ka=IgG affinity constant. Maximal plasma and tissue redistribution occurred when NKa=33.8×104. Imip redistribution can be controlled using various doses or affinities of specific antibodies, and the resulting rapid, extensive Imip redistribution from the main target organs could be very promising for TCA detoxification. British Journal of Pharmacology (1998) 125, 35–40; doi:10.1038/sj.bjp.0702033

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“…These problems include the feasibility of giving an adequate dose of mAb to neutralize drug effects, the likelihood of drug abusers surmounting the protective effects of the antibody by simply taking more drug, and the possibility of allergic or autoimmune problems resulting from vaccine or mAb therapy. A common perception is that a mole of antibody binding sites would be needed to neutralize the effects of each mole of drug (Scherrmann et al, 1989). Since serious drug abusers may use gram(s) per day of drug (Burns and Lerner, 1976;Cho, 1990), it appears that the lack of economic and/or medical feasibility would preclude the use of mAbs for the treatment of the high dose self-administration of most drug users.…”

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Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody

Laurenzana¹,

Gunnell²,

Gentry³

et al. 2003

J Pharmacol Exp Ther

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The range of medical effects and complications resulting from excessive use of drugs of abuse like phencyclidine (PCP) has hindered the development of effective medications. Drug-specific monoclonal antibodies (mAbs) provide an appealing medication approach since they can be selective for the drug, without concern for the sites of action of the drug. The use of mAb medications has been considered impractical because it is commonly believed that very large doses of mAb would be required to treat the adverse medical effects resulting from excessive drug use. In this study, a single dose of an anti-PCP mAb was found to significantly reduce the negative health impact of excessive, prolonged PCP treatment in rats (18 mg/ kg/day for 2 weeks). The protective effects were mAb dosedependent, and mAb doses as low as 1/100th the molar equivalent amount of the PCP body burden were effective at preventing PCP-induced deaths, reducing PCP-induced behaviors, reducing PCP brain concentrations, and improving the general health status of the animals. They also show that treatment with monoclonal antibody medications can have medically important outcomes without the need to neutralize the entire dose of the offending drug. These results could help establish the feasibility of using carefully designed monoclonal antibody medications to treat drug abuse and addiction, a chronic and re-occurring illness of the central nervous system.

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Immunotoxicotherapy: Present status and future trends

Cited by 35 publications

References 23 publications

A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab

A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab

Influence of various combinations of specific antibody dose and affinity on tissue imipramine redistribution

Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody

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