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Title: Monoclonal antibody induced growth arrest and cell death in B-cell lymphoma cell lines
Author: Cragg, Mark Steven
ISNI:       0000 0001 2434 1625
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 1998
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The therapeutic efficacy of mAb has been shown to vary greatly with respect to both the antibody used and the antigen targeted. This observation has led to the notion that some surface antigens may transduce growth inhibitory signals when ligated. To investigate the role of signalling in therapy and to understand the mechanism by which such therapy is achieved with mAb, the following study was undertaken, using a variety of B-cell lymphoma lines. In particular, the ability of mAb directed to the IgM and CD79 components of BCR were assessed in these cell-lines. mAb targeting the CD20 antigen was similarly assessed. The data contained in this thesis demonstrate that the IgM region of the BCR is a potent inducer of growth inhibition in some cell-lines, and furthermore, that this effect is due almost entirely to the induction of apoptosis. The extent of cross-linking employed by the anti-IgM mAb was found to be of paramount importance and was correlated in part with the degree of signalling induced by these mAb. Growth inhibition and apoptosis were not induced by antibodies directed to the CD79 region of the BCR, although signalling as measured by changes in intracellular calcium (Ca²⁺i) and up-regulation of protein tyrosine phosphorylation (PTP), was demonstrated. Potent cross-linking of these mAb did not confer any increase in efficacy. Certain anti-CD20 mAb produced extremely potent growth inhibition. These effects were shown to be the result of extremely potent activation of the complement system. In high levels of serum (20-30%) the nuclear events undertaken during anti-CD20 death resembled apoptosis, although not all CD20 mAb were similarly efficacious. The DNA fragmentation observed under these conditions appeared to be due to a property of the serum. The data represented in this thesis help to explain why mAb directed to the BCR and CD20 antigen have been successful in therapy and indicate that at least two possible mechanisms exist for the destruction of tumour by mAb.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry