ReviewElimination mechanisms of therapeutic monoclonal antibodies
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)
Antibody pharmacokinetics and pharmacodynamics
J. Pharm. Sci.
(2004)Pharmacokinetic aspects of biotechnology products
J. Pharm. Sci.
(2004)- et al.
Molecular basis of Fc receptor function
Adv. Immunol.
(1994) Serum Concentrations of IgG Subclasses
The transmission of immunity from mother to young and the catabolism of immunoglobulins
Lancet
(1966)- et al.
FcRn: the MHC class I-related receptor that is more than an IgG transporter
Immunol. Today
(1997) Engineered human IgG antibodies with longer serum half-lives in primates
J. Biol. Chem.
(2004)High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R
J. Biol. Chem.
(2001)Does endogenous glycosylation prevent the use of mouse monoclonal antibodies as cancer therapeutics?
Immunol. Today
(1993)- et al.
Pharmacokinetic effects of 4C9, an anti-FcRn antibody, in rats: implications for the use of FcRn inhibitors for the treatment of humoral autoimmune and alloimmune conditions
J. Pharm. Sci.
(2005)
Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect
Blood
Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study
Chest
Fc gamma receptors
Immunol. Lett.
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene
Blood
From the bench to the bedside: ways to improve rituximab efficacy
Blood
Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys
J. Allergy Clin. Immunol.
Human Antiglobulin Responses
Antibody humanization: a case of the ‘Emperor's new clothes’?
Immunol. Today
Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles
Semin. Arthritis Rheum.
Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease
Gastroenterology
Monoclonal antibodies market
Nat. Rev. Drug Discov.
The clinical pharmacology of therapeutic monoclonal antibodies
Drug Dev. Res.
Transcytosis and catabolism of antibody
Immunol. Res.
Finally! The Brambell receptor (FcRB). Mediator of transmission of immunity and protection from catabolism for IgG
Immunol. Res.
Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice
Eur. J. Immunol.
Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences
J. Immunol.
Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants
Biochemistry
Cited by (422)
Promises and challenges of single-domain antibodies to control influenza
2024, Antiviral ResearchPhysiologically based pharmacokinetic (PBPK) model that describes enhanced FcRn-dependent distribution of monoclonal antibodies (mAbs) by pI-engineering in mice
2023, Drug Metabolism and PharmacokineticsAllosteric synthetic antibody (Allo-SyAb) for improved cancer immunotherapy
2023, Chemical Engineering JournalPharmacokinetics of antibodies during pregnancy: General pharmacokinetics and pregnancy related physiological changes (Part 1)
2023, International ImmunopharmacologyRoute of monoclonal antibodies administration
2023, Formulation of Monoclonal Antibody Therapies: From Lab to Market