Selective apoptotic killing of malignant hemopoietic cells by antibody-targeted delivery of an amphipathic peptide
Marks, A.J.; Cooper, M.S.; Anderson, R.J.; Orchard, K.H.; Hale, G.; North, J.M.; Ganeshaguru, K.; Steele, A.J.; Mehta, A.B.; Lowdell, M.W.; Wickremasinghe, R.G.
Cancer Research 65(6): 2373-2377
ISSN/ISBN: 0008-5472 PMID: 15781652 DOI: 10.1158/0008-5472.can-04-2594
The alpha-helical amphipathic peptide D-(KLAKLAK)2 is toxic to eukaryotic cells if internalized by a suitable targeting mechanism. We have targeted this peptide to malignant hemopoietic cells via conjugation to monoclonal antibodies, which recognize lineage-specific cell surface molecules. An anti-CD19/peptide conjugate efficiently killed 3/3 B lymphoid lines. However, an anti-CD33/peptide conjugate was cytotoxic to only one of three CD33-positive myeloid leukemia lines. The IC50 towards susceptible lines were in the low nanomolar range. Conjugates were highly selective and did not kill cells that did not express the appropriate cell surface cognate of the antibody moiety. Anti-CD19/peptide conjugates efficiently killed cells from patients with chronic lymphocytic leukemia but anti-CD33/peptide reagents were less effective against fresh acute myeloid leukemia cells. We therefore suggest that amphipathic peptides may be of value as targeted therapeutic agents for the treatment of a subset of hematologic malignancies.