The Antibody Molecule
The importance of antibody molecules was first recognized in the 1890s, when it was shown that immunity to tetanus and diphtheria was caused by antibodies against the bacterial exotoxins (1 ). Around the same time, it was shown that antisera against chole
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1 The Antibody Molecule Andrew J. T. George 1. Introduction The importance of antibody molecules was first recognized in the 1890s, when it was shown that immunity to tetanus and diphtheria was caused by antibodies against the bacterial exotoxins (1). Around the same time, it was shown that antisera against cholera vibrios could transfer immunity to naïve animals, and also kill the bacteria in vitro (1). However, although antitoxin antibodies rapidly found clinical application, there was little understanding regarding the nature of the antibody molecule. Indeed, the earliest theories suggested that the antitoxins were derived by modification of the toxin— intriguingly similar “antigen incorporation” theories were propounded as late as 1930 (1). In more recent times, thanks to the efforts of both cellular and molecular immunologists, we have a more complete understanding of the structure, genetics, and function of an antibody molecule. As is discussed in the rest of this volume, this knowledge has allowed the design of improved molecules for clinical application. 2. Structure of the Antibody Molecule The basic structure of an antibody (immunoglobin G [IgG]) molecule is shown in Fig. 1, and is reviewed in detail in ref. 2. It consists of four chains: two identical heavy (H) and two identical light (L) chains. The heavy chains vary between different classes and subclasses of antibody (e.g., ¡ heavy chains are found in IgE, μ in IgM, a1 in IgG1, and so forth). These different classes and subclasses have specialized roles in immunity. There are two types of light chains, g and h. These do not have different functions, but represent alternatives that help increase the diversity of immune recognition by antibodFrom: Methods in Molecular Medicine, Vol. 40: Diagnostic and Therapeutic Antibodies Edited by: A. J. T. George and C. E. Urch © Humana Press Inc., Totowa, NJ
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Fig. 1. The antibody molecule. The structure of IgG is shown, with the domains represented by separate blocks. The hinge region contains multiple disulfide bonds; one is shown for convenience.
ies. The four chains are held together by both noncovalent interactions and disulfide bonds, as shown in Fig. 1. The H and L chains are made up of a number of domains of approx 110 amino acids arranged as two layers of antiparallel `-sheets held together by a conserved disulfide bond. These Ig domains, which fold independently, provide a modular structure to the antibody molecule, which has been exploited in antibody engineering studies (see Chapter 3). These domains are the archetype of those found in members of the immunoglobulin superfamily. In addition to the Ig domains, there is a hinge region, which has an extended structure that provides flexibility for the molecule. A comparison of the sequence similarity between the domains of the antibody molecule shows that the majority of the domains have the same sequence between antibody molecules of the same subclass, and so are termed constant (C) domains (CH1, CH2, and so forth on the H chain, and CL o
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