ABSTRACT
One of the most prominent technical trends of the industry has been the continued increase in the proportion of engineered
products coming to the market. The vast majority of biopharmaceuticals approved during the 1980s and early 1990s were either
first generation murine monoclonals or unmodified replacement proteins [e.g., human growth hormone (hGH), interferons, blood
factor VIII, and erythropoietins—all identical in amino acid sequence to the native human protein and administered in order
to replace or augment natural levels of that protein]. This article focuses on more recent approvals and trends in engineering
approaches for biopharmaceutical production.
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The biopharmaceutical sector continues to grow steadily, with an average of 8–10 new products entering the market each year.
By the end of 2006, almost 170 recombinant therapeutic proteins or antibody-based products had gained approval in either the
US or the EU, commanding an estimated global market value of $40 billion. One of the most prominent technical trends of the
industry has been the continued increase in the proportion of engineered products coming to the market. The vast majority
of biopharmaceuticals approved during the 1980s and early 1990s were either first generation murine monoclonals or unmodified
replacement proteins [e.g., human growth hormone (hGH), interferons, blood factor VIII, and erythropoietins—all identical
in amino acid sequence to the native human protein and administered in order to replace or augment natural levels of that
protein].
Advances in protein science and bioinformatics, along with the development of increasingly sensitive and sophisticated analytical
methodologies, continue to underscore a greater understanding of the links between protein structure and function. This method
allows knowledge-based modification of protein structure to achieve some predefined alteration of functionality.
EARLIER APPROVALS
The focus of many initial engineering experiments entailed alteration of the target protein's native amino acid sequence by
molecular techniques, such as site-directed mutagenesis. Some of the alterations included the removal or replacement of large
stretches of protein backbone (e.g., chimeric and humanized antibodies); others entailed the addition, removal, or replacement
of a single amino acid or, at most, a few amino acids. Examples of the latter approach include several engineered insulin
products such as Humalog (insulin lispro, Eli Lilly, Indianapolis, IN).
An alternative engineering approach focuses on the covalent attachment of a chemical moiety to the protein's backbone (e.g.,
the PEGylation of interferons or the acylation of insulin), or the alteration of natural post-translational modifications
that may be present, as in the case of Cerezyme (Genzyme, Cambridge, MA) a recombinant glucocerebrosidase enzyme, whose glycocoponent's
sialic acid caps are enzymatically removed to expose mannose residues, promoting macrophage-selective product uptake.
Engineering has been undertaken to achieve various therapeutic objectives, with the most common being:
- Reduction of product immunogenicity (e.g., engineered antibodies)
- Generation of a faster or slower acting product (e.g., engineered insulins)
- Increasing a protein's biological half-life (e.g., PEGylated interferons)
- Generation of a novel protein product, e.g., fusion products such as Amevive (Biogen, Cambridge, MA) or Enbrel (Immunex, Thousand
Oaks, CA).
RECENT ENGINEERED APPROVALS
Table 1. Engineered therapeutic proteins that gained approval in the EU or US (2002–2006 inclusive)
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The remainder of this article focuses on more recent approvals and trends in engineering approaches because engineered products
approved throughout the 1990s and over the earlier part of this decade have been reviewed elsewhere.1 The 14 engineered products approved since 2002, summarized in Table 1, represent 36% of the 39 new products to come on the
market for the first time in either the EU or US in that time period.
