hormones ranging from tripeptides, for example
corticotrophin-releasing factor (CRF), through
cyclic nonapeptides like vasopressin analogs, to
longer polypeptide chains, for example insulins
and growth hormones. As the length of the poly-
peptide increases, the three-dimensional structure
becomes an important determinant ofin vivoactiv-
ity and properties.
However, there are also important advantages
that an increase in protein size can bring. Single
peptide mutations become less important as pro-
tein size increases. The scope for posttranslational
modification is also greater in large polypeptides
than in small ones. Good illustrations of this are the
nonapeprides with large qualitative changes in
pharmacology of the single amino acid that distin-
guishes arginine–vasopressin (the human anti-
diuretic hormone) from human oxytocin, or the
marked differences in pharmacodynamics between
calcitonin and calcitonin gene-related peptide,
which are both encoded by the same gene.
Immunologic adverse events can be viewed as
either active or passive, that is firstly what the drug
does to the patient (histamine release, B lympho-
cyte proliferation, etc.) and secondly what the
patient does to the drug (enhanced clearance, pep-
tide cleavage, hapten formation, etc.). The clinical
correlates of these cellular processes range from
tachyphylaxis (need for ever increasing doses to
maintain biological effect) to the acute emergen-
cies of anaphylaxis. For example, around 13% of
patients given aglucerase (indicated for Type 1
Gaucher disease) develop IgG antibodies to the
enzyme, and of those so immunized, approxi-
mately 25% of these have clinical symptoms of
hypersensitivity.
Hormones
Insulin is an early and classic example of a biotech-
nology product. It illustrates some of 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.
Many patients developed insulin resistance, and
this correlated with specific antibody responses
directed against the insulin of the species of origin.
Patients then had a ‘career’ of increasing insulin
dose, punctuated by hypoglycemia when changing
from oneanimalsource toanotherwithoutchanging
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 chimeric 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 have led to a sufficient supply
of exogenous, but human, insulin. Now in use by
almost all patients with diabetes in the western
world, immune responses to this molecule are
much rarer than before, and dose sizes tend to
remain more stable.
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
alfa, Epogen; Amgen, Inc.). The EMEA has
chosen three molecules from this class (insulin,
somatotropin and human growth hormone) as
worked examples (‘product-specific’) guidances
on demonstration of biological equivalence
(issued in final form March 2006). Erythropoie-
tin will probably be next. Accompanied by a
more general guidance, these documents set out
the EMEA’s requirements for follow-on (i.e.
quasi-generic) biological products. Furthermore,
these guidances clarify matters concerning scale-
up and technology transfer between production
plants, which should benefit the developers of
innovative and follow-on biologics, alike. At the
time of writing (March 2006), similar guidances
are awaited from the US Food and Drug Admin-
istration (US FDA), which have been at least two
years in the writing so far. Active litigation in the
United States Federal Court, by the developer of
one follow-on biological product whose Biolo-
gical License Application seems to have stalled
without any request for further technical infor-
mation, is doubtless complicating this advance in
regulatory practice.22.7 PEPTIDES 283