The pharmacokinetics and pharmacodynamics of monoclonal antibodies – mechanistic modeling applied to drug development

Projections Research Inc, 535 Springview Lane, Phoenixville, PA 19460, USA.
Current opinion in drug discovery & development (Impact Factor: 5.12). 02/2007; 10(1):84-96.
Source: PubMed


The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.

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    • "XP_003640095.1], which potentiates IgG half-life in vivo[23,24]. "
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    ABSTRACT: Monoclonal antibodies are a major class of biological therapies in human medicine but have not yet been successfully applied to veterinary species. We have developed a novel approach, PETisation, to rapidly convert antibodies for use in veterinary species. As an example, anti-nerve growth factor (anti-NGF) monoclonal antibodies (mAbs) which are effective in reducing acute and chronic pain in rodents and man are potentially useful for treating pain in dogs but a fully caninised mAb is required in order to avoid an immune response. The aim of this study was to determine the optimal properties of a caninised anti-NGF mAb for safe, repeated administration to dogs, to determine its pharmacokinetic properties and to evaluate its efficacy in a model of inflammatory pain in vivo. Starting with a rat anti-NGF mAb, we used a novel algorithm based on expressed canine immunoglobulin sequences to design and characterise recombinant caninised anti-NGF mAbs. Construction with only 2 of the 4 canine IgG heavy chain isotypes (A and D) resulted in stable antibodies which bound and inhibited NGF with high-affinity and potency but did not bind complement C1q or the high-affinity Fc receptor gamma R1 (CD64). One of the mAbs (NV-01) was selected for scale-up manufacture, purification and pre-clinical evaluation. When administered to dogs, NV-01 was well tolerated, had a long serum half-life of 9 days, was not overtly immunogenic following repeated dosing in the dog and reduced signs of lameness in a kaolin model of inflammatory pain. The combination of stability, high affinity and potency, no effector activity and long half-life, combined with safety and activity in the model of inflammatory pain in vivo suggests that further development of the caninised anti-NGF mAb NV-01 as a therapeutic agent for the treatment of chronic pain in dogs is warranted.
    BMC Veterinary Research 11/2013; 9(1):226. DOI:10.1186/1746-6148-9-226 · 1.78 Impact Factor
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    • "In this regards, it has been reported that there are antibodies which instead of preventing ligand binding may cause receptor binding to be non-productive. These interactions can result in either an inhibition of new receptor formation, stimulation of the loss of existing receptors , or a blockage followed by internalization or downregulation of the receptors [36]. On the other hand, nondepleting mAbs have been used to establish persistent T-cell tolerance [37]. "
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    Results in Immunology 12/2012; 2:204-211. DOI:10.1016/j.rinim.2012.11.001
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    • "Both animal models and human clinical studies have been reported for studying pharmacokinetics in support of drug product comparability studies [34e36]. Further, mechanistic modeling of pharmacokinetic and pharmacodynamic profiles has been suggested as a tool for monoclonal antibody product development [37]. One such study listed in Table 2 described the use of a human clinical trial for evaluating the impact of introducing a liquid formulation of the mAb Xolair Ò on pharmacokinetic and pharmacodynamic parameters versus the lyophilized presentation [35]. "
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    Biologicals 11/2012; 41(3). DOI:10.1016/j.biologicals.2012.10.001 · 1.21 Impact Factor
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