Biomedical Engineering Reference
In-Depth Information
In some instances, binding of antibody results in immediate shedding of Ab-TSA from the cell
surface.
TSA expression can be transitory. For many tumours, only a proportion (albeit a large one) of
the tumour cells express TSAs at any given time.
13.3.5 Antigenicity of murine monoclonals
Antibody immunogenicity remains one of the inherent therapeutic limitations associated with
administration of murine monoclonals to human subjects. In most instances, a single injec-
tion of the murine monoclonal will elicit an immune response in 50-80 per cent of patients.
Human anti-mouse antibodies (HAMA) will generally be detected within 14 days of antibody
administration. Repeated administration of the monoclonal (usually required if the monoclonal is
used for therapeutic purposes) will increase the HAMA response signifi cantly. It will also induce
an HAMA response in the majority of individuals who display no such response after the initial
injection. The HAMA response will effectively and immediately destroy subsequent doses of
monoclonal administered. In practice, therefore, therapeutic effi cacy of murine monoclonals is
limited to the fi rst and, at most, the second dose administered.
An obvious strategy for overcoming the immunogenicity problem would be the generation and
use of monoclonal antibodies of human origin. This is possible but diffi cult. Human antibody-
producing lymphocytes can potentially be rendered immortal by:
transformation by Epstein-Barr virus infection;
fusion with murine monoclonals;
fusion with human lymphoblastoid cell lines.
However, a number of technical hurdles remain that prevent routine production of human mon-
oclonal preparations. These include:
source of antibody-producing cell;
reliable methods for lymphocyte immortalization;
stability and antibody-producing capacity of resulting immortalized cells.
Initial stages in the production of murine monoclonals entail administration of the antigen of
interest to a mouse. This is followed by sacrifi ce and recovery of activated B-lymphocytes from
the spleen. A similar approach to the production of human monoclonals would be unethical. Ad-
ministration of some antigens to humans could endanger their health. Although B-lymphocytes
could be obtained from the peripheral circulation, the majority of these are unstimulated, and
recovery of (stimulated) B-lymphocytes from the spleen is impractical.
Although Epstein-Barr virus is capable of inducing cellular transformation, few antibody-
producing B-lymphocytes display the viral cell surface receptor. Most, therefore, are immune
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