Anti-tumor activity of a blocked ricin immunotoxin with specificity against the cluster-5A antigen associated with human small-cell lung cancer

• Published in: International journal of cancer Vol. 54; no. 6; p. 1028
• Main Authors: Zangemeister-Wittke, U, Collinson, A R, Fisch, I, Jones, R M, Waibel, R, Lehman, H P, Stahel, R A
• Format: Journal Article
• Language: English
• Published: United States 30.07.1993
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - therapeutic use; Antigens, Neoplasm - immunology; Carcinoma, Small Cell - drug therapy; Carcinoma, Small Cell - immunology; Female; Humans; Immunotoxins - metabolism; Immunotoxins - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Mice; Mice, Inbred ICR; Mice, Nude; Ricin - pharmacokinetics; Ricin - therapeutic use; Tumor Cells, Cultured
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910540628

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.