Molecular and biological properties of an abrin A chain immunotoxin designed for therapy of human small cell lung cancer.
An immunotoxin (IT) comprising abrin A chain attached to the mouse monoclonal antibody SWA11, recognising a cell surface antigen highly associated with human small cell lung cancer (SCLC), was synthesised using a hindered disulphide crosslinker, N-succinimidyl 3-(2-pyridyldithio) butyrate (SPDB), and purified by Blue Sepharose CL-6B affinity chromatography. The IT preparation contained monomeric conjugate, composed of one abrin A chain molecule linked to one SWA11 molecule, and was free from unconjugated A chain or antibody. The IT fully retained the cell-binding capacity of the antibody component and the ribosome-inactivating activity of the A chain. In cytotoxicity assays using the SW2 SCLC cell line in tissue culture, SWA11-SPDB-abrin A chain inhibited the incorporation of 3H-leucine by 50% at a concentration of 10 pM and by 99% at a concentration of 1 nM. The anti-tumour efficacy of the IT was tested in nude mice bearing established s.c. solid SW2 tumour xenografts. A single i.v. injection of SWA11-SPDB-abrin A chain at a non-toxic dose induced a significant 7 to 10 day growth delay that could not be matched by administration of equivalent doses of either unconjugated SWA11 or abrin A chain alone. The results of this study indicate that the antigen recognised by SWA11 is an effective target for therapy of SCLC with A chain ITs in vivo.
Wawrzynczak
E J
EJ
Section of Immunology, Institute of Cancer Research, Sutton, Surrey, UK.
Zangemeister-Wittke
U
U
Waibel
R
R
Henry
R V
RV
Parnell
G D
GD
Cumber
A J
AJ
Jones
M
M
Stahel
R A
RA
D000036:Abrin / Q000627:therapeutic use* / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal; D018288:Carcinoma, Small Cell / Q000628:therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D000922:Immunotoxins / Q000302:isolation & purification / Q000627:therapeutic use* / Q000633:toxicity*; D007700:Kinetics; D008175:Lung Neoplasms / Q000628:therapy*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D046911:Macromolecular Substances; D000036:Abrin