Enzymes
Several peptide drugs are enzymes. Dornase alpha
(Pulmozyme; Genentech, Inc.) is an example,
which is used to improve the management of
chest infections and pulmonary function in patients
with cystic fibrosis. It works because the rate of
DNA release from dead and dying leukocytes is
sufficient to significantly increase sputum viscos-
ity. The enzyme (inhaled through a nebulizer)
digests this released DNA, thus liquifying the spu-
tum, and enhancing expectoration. The clinical
trials of this product were generally of orthodox
design, using dose–response analysis and placebo-
controlled designs. The fact that the product is
made by fermentation of genetically engineered
Chinese hamster ovary cells containing DNA
encoding for the native human protein, deoxyribo-
nuclease I (DNAase), was essentially irrelevant to
the design of the clinical development program.
Other enzymes in clinical use, manufactured
using similar processes, include tissue plasmino-
gen activator, other thrombolytic agents and aglu-
cerase (Ceredase, Genzyme Corp.) for Type 1
Gaucher disease. These illustrate the diverse
clinical applications that enzymes may find.
Antibodies
Because antibodies bind to antigens, their function
is often to augment intrinsic clearance mechanisms
as well as potentially exerting definitive therapeu-
tic effects. It is not surprising, therefore, that the
therapeutic targets for antibody therapy are extre-
mely broad, ranging from antitumor therapy to
specific immunological diseases, for example
rheumatoid arthritis.
Antibodies can be targeted more or less specifi-
cally, either against a single or avariety of antigens.
An example of a ‘broad-spectrum’ antibody ther-
apy is anti-Rhesus antigen antibody (WinRho)
which has been usedpostpartumfor many years
to prevent rhesus immunization of an Rhmother
by an Rhþneonate. There are at least 60 known
epitopes of the rhesus D antigen. The product is
made from pooled plasma of Rhmale volunteers
who have been deliberately challenged with small
Rhþ, ABO-compatible blood transfusions. The
resulting product binds to red cells from 99.7% of
all Rhþblood donors.
Specific targeting of single, infrequently
expressed antigens forms the basis of the large
number of monoclonal antibody therapies that
are either in development or in the market. These
are generally manufactured by mammalian cell
fermentation process, as described above (see
the chapter by Dr Reno for issues relating to the
manufacturing process and viral contamination
of these products). Rituximab (Rituxan; IDEC
Pharmaceuticals) is a highly targeted antibody
that binds principally with CD-20-positive B
lymphocytes that characterize one form of non-
Hodgkin lymphoma. More recently, clinical
trials on this agent have been conducted evaluating
its effects on other putatively B lymphocyte-
mediated diseases such as rheumatoid arthritis.
Another example of a specific therapeutic is
anMuromonab-CD3 (Orthoclone OKT3; Ortho
Pharmaceuticals) used to reverse acute rejection
of transplanted kidneys. The presence of single
antigen targets in or on tumor cells can be
further exploited by conjugating the antibody to a
radioactive or cytotoxic molecule. For example,
human milk fat globule I monoclonal antibody
complexed with^90 Yttrium (Theragyn) is under
development for the treatment of ovarian carci-
noma by Antisoma, PLC.
Antibody development radics can be learned by
reviewing the product labeling for some agents
mentioned. Antitumor necrosis factor alpha (inflix-
imab; Enbrel; Amgen, Inc., Wyeth, Inc.) has revo-
lutionized the treatment of rheumatoid arthritis,
even if its labeling, in small font, occupies both
sides of a small poster.Cytokines
Cytokine responses to infection or tumors are
thought phylogenetically to be the most ancient
form of immune response. Cytokines are generated
in response to antigen challenge and now have a
large impact in the clinical management of many
diseases. However, unlike antibodies, cytokine
responses are nonspecific, and their principal284 CH22 BIOTECHNOLOGY PRODUCTS AND DEVELOPMENT