Biomedical Engineering Reference
In-Depth Information
Box 13.3
Product case study: Avastin
Avastin (tradename, also known as bevacizumab) is a 149 kDa recombinant humanized mono-
clonal IgG1 antibody fi rst approved for medical use in the USA in 2004, and subsequently in the
EU in 2005. It is indicated for fi rst-line treatment of patients with metastatic colorectal cancer,
in combination with specifi ed (5-fl uorouricil-based) small molecule chemotherapeutic drugs.
The antibody brings about its effect by inhibiting angiogenesis (the formation of new blood
vessels), a process required to support tumour growth. Specifi cally, the antibody binds human
vascular endothelial growth factor. This prevents the latter from binding to its cell surface re-
ceptor, a process central to triggering new blood vessel formation in both normal and diseased
tissue.
The engineered antibody is produced in a CHO cell line using 12 000 l bioreactors. Purifi ca-
tion is achieved mainly by protein A affi nity chromatography, followed by sequential anion and
cation ion-exchange chromatography. It is formulated as a sterile solution in single-use vials
containing either 100 or 400 mg active substance. Excipients include phosphate buffer com-
ponents, trehalose and polysorbate 20. The product is generally administered by i.v. infusion
(5 mg kg
1
) once every 2 weeks.
Pharmacokinetic studies in patients yielded an estimated product half-life of approximately
20 days (11-50 days range) and the product clearance was found to be variable according to
body weight, gender and tumour burden. Safety and effi cacy were established by three rand-
omized, controlled trials. The fi rst study was a randomized double-blind trial involving 813
patients. The primary end-point measured was overall survival, which was extended from a
median of 15.6 months to 20.3 months.
Serious, sometimes fatal, side effects reported included gastrointestinal perforation, wound
healing complications and haemorrhage, and the product should not be administered for at least
28 days following major surgery. Avastin was developed by Genentech.
13.3.7 Antibodyfragments
One limitation to antibody-mediated treatment of solid tumours relates to their poor penetration of
tumour mass. Antibody-based tumour therapy (e.g. using radiolabelled murine monoclonals) has
proved more effective in treating disseminated cancers (e.g. leukaemias and lymphomas) as opposed
to solid tumours. The physical size of the intact antibody likely hinders tumour penetration. As a
result, recent interest has focused upon using antibody fragments that retain their antigen-binding
capabilities. Fragments, such as F(ab), F(ab)
2
and F
v
(Box 13.2), can be easily generated, mainly
via recombinant DNA technology. These have been labelled with, for example, radioactive tags
with the intention of using them as diagnostic and therapeutic agents. Although their lower mo-
lecular mass may aid more effective tumour penetration, whole chimaeric/humanized antibodies
may be more effective, particularly if used for therapeutic purposes. Fragments generally display
greatly reduced serum half-lives (Table 13.4) and cannot initiate effector functions. Radiolabelled
fragments may be better suited to diagnostic imaging purposes.
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