Selective apoptotic killing of malignant hemopoietic cells by antibody-targeted delivery of an amphipathic peptide.
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.
Marks
Alexandra J
AJ
Department of Haematology, Royal Free and University College Medical School, London, United Kingdom.
Cooper
Margaret S
MS
Anderson
Robert J
RJ
Orchard
Kim H
KH
Hale
Geoffrey
G
North
Janet M
JM
Ganeshaguru
Kanagasabai
K
Steele
Andrew J
AJ
Mehta
Atul B
AB
Lowdell
Mark W
MW
Wickremasinghe
R Gitendra
RG
D000208:Acute Disease; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000276:immunology; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage*; D063268:Sialic Acid Binding Ig-like Lectin 3
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D000922:Immunotoxins; D010455:Peptides; D063268:Sialic Acid Binding Ig-like Lectin 3