Anti-tumor activity of a blocked ricin immunotoxin with specificity against the cluster-5A antigen associated with human small-cell lung cancer.
The monoclonal antibody (MAb SEN31, a mouse IgG1 which recognizes the cluster-5a antigen on small-cell lung cancer (SCLC) cells, was used to prepare a selective and potent blocked ricin immunotoxin. In a series of experiments in vitro and in a SCLC xenograft model in nude mice, the tumor localization potential of the radiolabeled antibody SEN31 and the anti-tumor activity of the immunotoxin SEN31-bR, the non-specific binding activity of which had been greatly reduced by blocking of the galactose binding domains of the B-chain, was determined. Radiolabeling of SEN31 was performed by linking a 67Ga-labeled desferrioxamine moiety to the oligosaccharide side chains of the antibody in order to preserve the specific cell-binding activity. 67Ga-SEN31 bound to the antigenic sites on cells of the SW2 SCLC cell line, with a dissociation constant of 3.5 nM and, when injected i.v., selectively localized at the site of s.c.-growing SW2 tumor xenografts in nude mice, with a tumor-to-blood ratio of 3.5. The immunotoxin SEN31-bR was potently and selectively active against SCLC cell lines both of classic and of variant morphologies. At a concentration of 300 pM the immunotoxin selectively eliminated 4.5 logs of clonogenic tumor cells. In nude mice, SEN31-bR was cleared from the blood with biphasic kinetics following i.v. injection and maintained a stable serum level during continuous i.p. infusion. The growth of s.c. SW2 solid-tumor xenografts was delayed following a single i.v. injection or a continuous i.p. infusion, each at a non-toxic dose.
Division of Oncology, University Hospital Zurich, Switzerland.
U
U
Zangemeister-Wittke
A R
AR
Collinson
I
I
Fisch
R M
RM
Jones
R
R
Waibel
H P
HP
Lehman
R A
RA
Stahel
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D012276:Ricin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000922:Immunotoxins; D012276:Ricin