MinireviewAntibody Structure, Instability, and Formulation
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INTRODUCTION
Protein therapies are entering a new era with the influx of a significant number of antibody pharmaceuticals. Generally, protein drugs are effective at low concentrations with less side effects relative to small molecule drugs, even though, in rare cases, protein-induced antibody formation could be serious.1 Therefore, this category of therapeutics is gaining tremendous momentum and widespread recognition both in small and large drug firms. Among protein drug therapies, antibodies play a major
ANTIBODY STRUCTURE
Antibodies (immunoglobulins) are roughly Y-shaped molecules or combination of such molecules (Fig. 1). Their structures are divided into two regions—the variable (V) region (top of the Y) defining antigen-binding properties and the constant (C) region (stem of the Y), interacting with effector cells and molecules. Immunoglobulins can be divided into five different classes −IgA, IgD, IgE, IgM, and IgG based on their C regions, respectively designated as α, δ, ε, µ, and γ (five main heavy-chain
ANTIBODY INSTABILITY
Antibodies, like other proteins, are prone to a variety of physical and chemical degradation pathways, although antibodies, on the average, seem to be more stable than other proteins. Antibody instabilities can be observed in liquid, frozen, and lyophilized states. The glycosylation state of an antibody can significantly affect its degradation rate.40 In many cases, multiple degradation pathways can occur at the same time and the degradation mechanism may change depending on the stress
ANTIBODY FORMULATION
As mentioned above, antibodies, like other proteins, may generate a variety of degradants during production, processing, and storage both in liquid and solid states. Their tendency to generate such degradants depends very much on their individual sequence, pI, hydrophobicity, and carbohydrate content.23 The antibody degradation products may have reduced activity and more importantly, increased immunogenicity.14,87 A strong immune response (antibody formation) may lead to severe neutralization
SUMMARY
Antibodies have similar tertiary structures. The presence of a significant number of disulfide bonds and intimate domain–domain interactions in antibodies make them relatively stable and more resistant to moderate thermal stress compared to other proteins. Nevertheless, antibodies do experience a variety of instabilities similar to most proteins. These physical and chemical instabilities include denaturation, aggregation, surface adsorption, deamidation, oxidation, isomerization, fragmentation,
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