A Textbook of Clinical Pharmacology and Therapeutics

CELL-BASED ANDRECOMBINANTDNA THERAPIES 93

soluble insulin, a real advance for some patients (see
Chapter 37). Other ‘designer’ insulins have longer actions or
other kinetic features that are advantageous in specific
circumstances.
In addition to producing recombinant human hormones
(see Table 16.2) and other recombinant proteins (e.g. hirudin,
the anticoagulant protein of the leech), recombinant mono-
clonal antibodies for treating human diseases have been pro-
duced originally in immortalized clones of mouse plasma
cells. Not surprisingly, the original murine antibodies induced
antibody responses in humans which in turn caused disease
or neutralizing antibodies, rendering the monoclonal antibod-
ies ineffective if used repeatedly (Table 16.3). Immunoglobulins
have been gradually humanized to reduce the risk of an
immune response on repeated treatments.
In cancer therapy, monoclonal antibodies have been devel-
oped against a tumour-associated antigen, e.g. trastuzumab
against the HER2 protein (over-expressed in certain breast

cancers in particular). Most facilitate the body’s immune sys-

tem in destroying the cancer cells or reduce the blood supply

to the tumour. Abciximab(see Chapter 30) inhibits platelet

aggregation by blocking the glycoprotein receptor that is a key

convergence point in different pathways of platelet aggrega-

tion. It is used as an adjunct to heparinandaspirinfor the

prevention of ischaemic complications in high-risk patients

undergoing percutaneous coronary intervention. It is a

murine monoclonal antibody and can only be used in an indi-

vidual patient once. Most recently developed monoclonal

antibodies have been fully humanized. In comparison to most

conventional ‘small molecule’ drugs, the antibodies’ activities

are very specific and toxicity is usually directly related to the

targeted effect either through excessive effect or a ‘down-

stream’ consequence of the effect. The effects are usually very

species-specific, so extrapolation from animal studies is more

difficult. The initial doses in humans should be a fraction of

the minimum anticipated biological effect level (MABEL, see

Figure 16.1) taking into account concentration, receptor occu-

pancy, relative potency, likely dose–response curve, and

effects of excessive pharmacology rather than just the ‘no

observable adverse effect level’ (NOAEL) which is the main-

stay of first dose calculation for conventional small molecule

drugs.

Recombinant techniques have also been of value in the

development of vaccines, thereby avoiding the use of intact

virus. Suspensions of hepatitis B surface antigen prepared

from yeast cells by recombinant DNA techniques are already

widely used to prevent hepatitis B infection in high-risk

groups in the UK. In comparison to traditional egg-based and

cell-based vaccines, DNA vaccines using plasmid DNA coding

for specific epitopes of influenza virus may be developed,

manufactured and distributed much more rapidly and effec-

tively. With the current likelihood of an influenza pandemic

caused by a new strain of virus predicted by the World Health

Organization (WHO), the ability to produce such DNA vac-

cines may save millions of lives.

Table 16.1:Recombinant proteins/enzymes licensed in the UK (examples)

Protein/enzyme Indication

Recombinant coagulation factors VIII Haemophilia

and VIIa

Imiglucerase Gaucher’s disease

Interferon alfa Hepatitis B and C, certain lymphomas and

solid tumours

Interferon beta Multiple sclerosis

Epoetin alfa and beta (recombinant human Anaemia of chronic renal failure. To increase

erythropoietin) yield of autologous blood, e.g. during

cancer chemotherapy

Drotrecogin alfa (activated) (recombinant Severe sepsis

activated protein C which reduces

microvascular dysfunction)

Table 16.2:Hormones/hormone antagonists (examples)

Mode of action Indication

Somatropin Synthetic human Growth hormone

growth hormone (hGH) deficiency

Pegvisomant Genetically modified Acromegaly

hGH that blocks hGH

receptors

Follitropin Recombinant human Infertility

alfa and follicle stimulating

beta hormone

Insulin aspart, Recombinant human Diabetes (helps

glulisine and insulin analogues, glucose control in

lispro faster onset of action some patients/

situations)