Monoclonal antibodies (MAbs) represent the fastest growing pharmaceutical market segment. Even with conservative assumptions
about growing attrition rates, substitution pressure, and margin squeezes, MAb sales will probably reach a stable plateau
of $20 billion by 2010. While the commercialization of MAbs is gathering momentum, the sector is facing a worldwide shortfall
of available biomanufacturing capacity that is becoming a critical strategic limitation, especially for companies without
established market access.
Improvements are due in all areas of the pharmaceutical supply chain but especially in downstream processing to manage current
manufacturing challenges and are therefore vital for the long-term success of the sector.
Antibodies represent a class of flexible molecular adaptors that play a vital role in the adaptive immune systems of vertebrates.1 They are bifunctional molecules with a basic symmetrical structure consisting of pairs of identical heavy and light chains
linked through disulfide bridges (Figure 1).2
Figure 1. Form Follows Function: Domain Structure of an IgG Antibody
The individual chains are globular domains that are highly conserved between different immunoglobulins (constant region) or
contain sequence variability (variable region). Antigen binding sites are formed by the interaction of hypervariable loop
regions exposed near the N-terminus of the polypeptide chains — the complementary determining regions (CDRs), which are surrounded by relatively invariant
framework residues. Their diversity (idiotypic variation) represents the central aspect of the humoral immune response. Functions
that are essential for the cellular immune response, such as complement activation and lymphocyte binding, reside in the constant
Immunoglobulins (Igs) are glycoproteins that contain 3 to 12 percent carbohydrates.4 In an IgG molecule, the sugar part is N-linked to a highly conserved site at Asn 297 in the CH2 domain of both heavy chains (Figure 2). Although N-linked glycosylation does not interfere with antigen recognition, a number of implications are linked to this functionality,
such as: stability, pharmacokinetics, antigenicity, Fc-related effector functions, and serum stability of antibodies.5 Removing terminal sialic acid results in drastically reduced half-life and increased liver uptake through the asialoglycoprotein
Figure 2. Glycosylation Pattern of a Human IgG Antibody
The traditional method of MAb production generates molecules of murine origin with an immunogenic potential and a short serum
half-life in humans.7,8 Although a number of murine antibodies are still commercially available, the focus today is on chimeric, humanized, and (eventually)
human antibodies, generated with the use of transgenic mice or large combinatorial libraries in bacteriophages or yeast.9
In a mere 30 years of development, a total of 23 MAbs and MAb-related proteins have been approved for medical treatments.
MAbs represent the fastest growing segment within biopharmaceuticals and are outperforming recombinant proteins with a compound
annual growth rate of 20 percent.10 Hundreds of second and third generation antibody-based products are in preclinical and clinical development.