For a long time, interest in biotechnology centered on the production and properties of administered hormones ranging from tripeptides, e.g. cortico-trophin releasing factor (CRF); through nonapep-tides, such as vasopressin analogues; to longer polypeptide chains, e.g. insulins and growth hormones. As the length of the molecule increases, the three-dimensional structure becomes an important determinant of in vivo activity and properties.
However, there are also important freedoms that an increase in protein size can bring. Single-peptide mutations become less important as protein size increases. The scope for post-translational modification is also greater in large polypeptides than in small ones. Good examples of this are the large qualitative changes in pharmacology of the single amino acid that distinguishes arginine-vasopressin (the human antidiuretic hormone) from human oxytocin, or the marked differences in pharmaco-dynamics between calcitonin and calcitonin gene-related peptide (CGRP), which are both encoded by the same gene.
In comparison with non-peptide, non-nucleic acid drugs, the principal specific adverse events associated with peptides may be viewed as the sum of two processes: immunological and physiological changes. The former is non-specific and familiar to most physicians, the latter is usually specific to the known function of the hormone or enzyme. Immunologic adverse events can, in turn, be viewed as either active or passive: what the drug does to the patient (histamine release, B lymphocyte proliferation, etc.) and what the patient does to the drug (enhanced clearance, peptide cleavage, etc.). The clinical correlates of these cellular processes then range from a need for ever-increasing doses to maintain biological effect, to the acute emergencies of anaphylaxis. For example, around 13% of patients given aglucerase used for Type 1 Gaucher's disease develop IgG antibodies to the enzyme; approximately 25% of these have symptoms of hypersensitivity.
Clinical trialists should be careful not to ignore the toxicological potential of the often large amounts of vehicle (ionic strengths, buffering materials, extreme pH) that may be required to maintain complex peptides in a stable form. These can include unanticipated allergens, nephrotoxins and hepatotoxins.
Historically, insulin is an early and classic example of a biotechnology product, illustrating the general problems that are associated with peptide drugs and how modern technology leads to improved therapy. Prior to the production of human insulin by cell-based fermentation processes, treatment was with pancreatic extracts of porcine or bovine origin. Insulin resistance correlated with effective, specific antibody responses in many diabetics, who had a 'career' of increasing insulin dose, punctuated by hypoglycemia when changing from one animal source to another without changing dose size. Some patients became so competent at clearing bovine or porcine insulin that they needed extracts from exotic species such as whales. The modification of recombinant chi-meric or pure cell lines to secrete human insulin, the development of large-scale fermenters to multiply such cultures, and the ability to purify cell-free insulin from other materials in the broth, has led to a sufficient supply of exogenous, but human, insulin. Now in use by almost all diabetics in the Western world, immune responses to this homo-biotic molecule are very rare, and dose sizes remain more stable than before.
We shall now consider the principal subsets of peptide therapeutic classes within the context of similarities to, and differences from, orthodox small molecules of purely chemical synthesis.
biotechnology prodlk Hormones
In addition to insulin, various other hormones made by recombinant methods have been approved or are under development. The most commonly prescribed examples at present include growth hormone (somatrem, Protropin®, Genentech, Inc.) or erythropoietin (epoeitin a, Epogen®; Amgen Inc.).
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