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Anti‐tumor activity of a blocked ricin immunotoxin with specificity against the cluster‐5A antigen associated with human small‐cell lung cancer
Author(s) -
ZangemeisterWittke Uwe,
Collinson Albert R.,
Fisch Igor,
Jones Robert M. L.,
Waibel Robert,
Lehman HansPeter,
Stahel Rolf A.
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910540628
Subject(s) - immunotoxin , monoclonal antibody , antigen , antibody , microbiology and biotechnology , ricin , cancer research , chemistry , cell culture , radioimmunotherapy , biology , immunology , biochemistry , toxin , genetics
The monoclonal antibody (MAb) SEN3I, a mouse IgG 1 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 67 Ga‐labeled desferrioxamine moiety to the oligosaccharide side chains of the antibody in order to preserve the specific cell‐binding activity. 67 Ga‐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 clono‐genic 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.