Marks, A.J.; (2005) Targeting of cytotoxic peptides to haematological malignancies. Doctoral thesis , University of London.

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Abstract

Amphipathic peptides with an a-helical structure disrupt membranes rich in negatively charged phospholipids and have antibiotic properties. They are toxic to eukaryotic cells if internalised by a suitable targeting mechanism. We have targeted one such peptide D(KLAKLAK)2 to haemopoetic cells by conjugating it to monoclonal antibodies which recognise lineage-specific cell-surface molecules. An anti-CD33: peptide conjugate was cytotoxic to one of three CD33-positive myeloid leukaemia lines, whereas an anti- CD 19: peptide conjugate efficiently killed three out of three B lymphoid lines with IC50 in the low nanomolar range. Cell lines which did not express the relevant antigen were resistant to the conjugates at the concentrations used. Peptide conjugated to anti-CD 19 and anti-CD33 antibodies had cytotoxic activity towards cells isolated from the peripheral blood of patients with chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) respectively. CLL cells isolated from heavily pre-treated patients or from poor risk category individuals, as determined by elevated expression of the ZAP-70 protein tyrosine kinase, were as sensitive to the conjugate as were untreated or good risk category patients. Cell death was shown to be by an apoptotic mechanism and independent of the level of expression of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP. In addition the conjugate acted synergistically with chlorambucil. The data here suggest that anti-CD 19 D(KLAKLAK)2 displays a highly selective and potent cytotoxic activity against CLL cells and may be of therapeutic value in the treatment of this incurable leukaemia. We also panned a phage display library in an attempt to isolate a peptide that would bind to CD33 and thereby create a peptide with both targeting and cytotoxic activity towards malignant myeloid cells.

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