Full-length antibodies have captured a significant fraction of the sales volume and value of the biopharmaceuticals market. With increasing knowledge, however, it has been recognized that full-length antibodies may not always be necessary or even desirable. Antibody fragments provide the opportunity for new therapeutic possibilities. Moreover, antibody fragments have the potential for simpler, high-yielding production processes, which can translate into a lower manufacturing cost-of-goods and extended therapeutic benefit. This article discusses the structure and production strategies available for various types of antibody fragment therapeutics.
With estimated sales of $30 billion in 2007, therapeutic antibodies as a class have validated the effectiveness of using highly specific binding properties as therapies.1 Most therapeutic antibodies today are full-length IgG molecules because they are structurally stable, have long in vivo half-life and Fc-mediated biological properties. They have a number of drawbacks as therapeutics, however, which include:
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- They have high production costs arising from their expression in mammalian cells.
- They are unsuitable for intracellular targets because of their size.
- Binding can be variable depending on the protein targeted (best suited to relatively flat target surfaces).
- Their size can lead to poor tissue penetration arising from their size, which can limit their effectiveness in cases such as tumor penetration.
- The intellectual property landscape around antibody-based therapeutics discovery and development is complex. Prohibitive "royalty stacks" often affect the profitability of a resultant drug.
Antibody fragments, on the other hand, can provide highly specific binding as well as a number of therapeutic advantages including:
- flexibility in structure: a diverse range of binding structures can be assembled from antibody-binding domains giving bispecific or greater binding possibilities per molecule
- enhanced penetration of tissues (particularly of solid tumors) because of their smaller size
- elimination of immunogenicity to the Fc region (fragment structures can be designed without an Fc region)
- simpler production systems. Fragment antibody production is possible with microbial systems such as E. coli and yeasts, translating into lower cost-of-goods (CoGs) and wider application of the benefits of such therapeutic molecules.
The therapeutic effectiveness of antibody fragments has been demonstrated by the licensure of the first antibody fragments. Genentech's Lucentis, a fragment of Avastin, was approved by the FDA in 2006 and is used for the treatment of wet age-related macular degeneration.2 In 2008, UCB Pharma's certolizumab pegol (Cimzia), a PEGylated antibody fragment, was approved for the treatment of Crohn's disease in the US.3 Table 1 shows examples of antibody fragment products that have been launched or are in development. This article discusses production strategies available for antibody fragment therapeutics.
Table 1. Examples of antibody fragment products on the market or in development