Immunotoxin-mediated inhibition of chronic lymphocytic leukemia cell proliferation in humans.
We evaluated the cytotoxicity of the immunotoxin OKT1-SAP on fresh B-chronic lymphocytic leukemia (B-CLL) cells from 31 consecutive patients. OKT1-SAP comprised the OKT1 (CD5) monoclonal antibody disulfide linked to saporin-6 (SAP) ribosome-inactivating protein from the plant Saponaria officinalis. The effect of OKT1-SAP on target CD5-positive B-CLL cells was estimated using an in vitro proliferation inhibition assay in which control or OKT1-SAP-treated B-CLL cells were induced to proliferate by sequential stimulation with insolubilized anti-C3b receptor CB04 (CD35) antibody and low molecular weight B-cell growth factor. In 90% of patients, OKT1-SAP specifically suppressed B-CLL cell proliferation in a dose-related manner (50% inhibitory concentration, 4.0-6.8 nM). Taken together the findings reported in this article provide information relevant to the clinical development of immunotoxins because: (a) the in vitro conditions under which B-CLL cell proliferation is inhibited by OKT1-SAP are achievable in vivo without nonspecific toxicity according to our previous toxicology and pharmacokinetics studies in primates; and (b) the B-CLL cell proliferation inhibition assay described here provides a basis for future comparative studies.
Siena
S
S
Division of Medical Oncology, Istituto Nazionale Tumori, Milan, Italy.
Bregni
M
M
Formosa
A
A
Brando
B
B
Marenco
P
P
Lappi
D A
DA
Bonadonna
G
G
Gianni
A M
AM
D000368:Aged; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins