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Elimination mechanisms of therapeutic monoclonal antibodies

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Targeted therapies using monoclonal antibodies have achieved important therapeutic applications in the treatment of various human diseases. Understanding the factors that impact the pharmacokinetics of monoclonal antibodies is of high importance for effective therapy. Many factors related to the target antigen, antibody and patients can affect antibody elimination. Evaluation of these factors will facilitate the understanding of the processes involved in antibody elimination.

Section snippets

Antibody structure and function

Antibodies serve two important functions: they bind and modulate antigens and they bind complement and immune effector cells, such as natural killer cells and monocytes. Each IgG molecule contains two identical heavy chains and two identical light chains (Figure 1). Antibody structure has evolved to accommodate the diverse antigen binding specificities through the ‘variable region'. The antigen binding site is formed by the intertwining of the light chain variable domain (VL) and the heavy

Salvage pathway

IgG is the most abundant serum immunoglobulin (average concentrations ∼11–14 mg/ml [6]) and serum IgG homeostasis is of particular importance in mediating humoral immunity. The protective role of neonatal Fc receptor (FcRn), a major histocompatibility complex class-1-related receptor, in regulation of IgG homeostasis was postulated by Brambell [7]. Recent studies have further clarified the details of Brambell hypothesis and indicated that FcRn functions as a salvage receptor which regulates IgG

Future prospects

The number of approved mAbs is expected to increase during the next five years. Advances in innovative technologies and a diversity of novel and validated therapeutic targets will provide many future opportunities for the clinical development of novel mAb-based therapeutics. With further validation of novel targets, new and interesting challenges will be encountered, related to antibody, antigen and host factors. Understanding the factors that impact pharmacokinetics and pharmacodynamics of

Acknowledgements

The authors would like to thank Pat Torello, James Liu and Juan Li for their assistance in preparation of the manuscript and the figures included in this article. In addition, Rosalinda Arends, Bing Wang, the ABX-IL8 and ABX-MA1 teams are acknowledged for their contributions to the work that resulted in generation of study-related data presented in this article.

References (55)

  • W.K. Bleeker

    Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect

    Blood

    (2001)
  • D.A. Mahler

    Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study

    Chest

    (2004)
  • J.F. Cohen-Solal

    Fc gamma receptors

    Immunol. Lett.

    (2004)
  • G. Cartron

    Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene

    Blood

    (2002)
  • G. Cartron

    From the bench to the bedside: ways to improve rituximab efficacy

    Blood

    (2004)
  • T.K. Hart

    Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys

    J. Allergy Clin. Immunol.

    (2001)
  • L.K. Roskos

    Human Antiglobulin Responses

  • M. Clark

    Antibody humanization: a case of the ‘Emperor's new clothes’?

    Immunol. Today

    (2000)
  • P.J. Anderson

    Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles

    Semin. Arthritis Rheum.

    (2005)
  • C.G. Su et al.

    Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease

    Gastroenterology

    (2003)
  • J. Reichert et al.

    Monoclonal antibodies market

    Nat. Rev. Drug Discov.

    (2004)
  • L.K. Roskos

    The clinical pharmacology of therapeutic monoclonal antibodies

    Drug Dev. Res.

    (2004)
  • V. Ghetie et al.

    Transcytosis and catabolism of antibody

    Immunol. Res.

    (2002)
  • R.P. Junghans

    Finally! The Brambell receptor (FcRB). Mediator of transmission of immunity and protection from catabolism for IgG

    Immunol. Res.

    (1997)
  • V. Ghetie

    Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice

    Eur. J. Immunol.

    (1996)
  • W.F. Dall'Acqua

    Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences

    J. Immunol.

    (2002)
  • M. Raghavan

    Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants

    Biochemistry

    (1995)
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