ANTITUMOR-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 t o prepare a selective and potent blocked ricin immunotoxin. In a serie s of experiments in vitro and in a SCLC xenograft model in nude mice, the tumor localization potential of the radiolabeled antibody SEN31 an d the anti-tumor activity of the immunotoxin SEN31-bR, the non-specifi c binding activity of which had been greatly reduced by blocking of th e galactose binding domains of the B-chain, was determined. Radiolabel ing of SEN31 was performed by linking a Ga-67-labeled desferrioxamine moiety to the oligosaccharide side chains of the antibody in order to preserve the specific cell-binding activity. Ga-67-SEN31 bound to the antigenic sites on cells of the SW2 SCLC cell line, with a dissociatio n 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 tu mor-to-blood ratio of 3.5. The immunotoxin SEN31 -bR was potently and selectively active against SCLC cell lines both of classic and of vari ant morphologies. At a concentration of 300 pM the immunotoxin selecti vely eliminated 4.5 logs of clonogenic tumor cells. In nude mice, SEN3 1-bR was cleared from the blood with biphasic kinetics following i.v. injection and maintained a stable serum level during continuous i.p. i nfusion. The growth of s.c. SW2 solid-tumor xenografts was delayed fol lowing a single i.v. injection or a continuous i.p. infusion, each at a non-toxic dose. (C) 1993 Wiley-Liss, Inc.