CYTO-TOXIC EFFECT OF ANTI-MR 67,000 PROTEIN IMMUNOTOXINS ON HUMAN-TUMORS IN A NUDE-MOUSE MODEL

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (3) , 1328-1336
Abstract
The potential use of immunotoxins (IT) for therapeutic treatment of human tumors was studied in an experimental model of human neoplasia. Intact ricin IT was tested for its antitumor activity against established tumors. CEM, a human T-cell leukemia line expressing an MW 67,000 cell surface antigen and Daudi, a human B-cell lymphoma line which does not express the antigen, were found to be consistently tumorigenic in nude mice. IT were synthesized using T101, a high-affinity monoclonal antibody reacting with the MW 67,000 protein determinanat and intact ricin. It was shown for the 1st time that established CEM solid tumors in nude mice will regress following intratumoral injection of T101-ricin IT, while Daudi tumors will not. Selective activity of T101-ricin IT is dependent on systemic i.v. administration of lactose and local intratumoral injection of the T101-ricin IT with lactose. Intact ricin IT require the presence of lactose to block native ricin binding and render them antigen specific when linked to monoclonal antibody. Killing of target was cell specific since nonspecific (irrelevant) IT did not cause the regression of CEM tumors and injection of large amounts of free T101 antibody prior to T101-ricin IT blocked antitumor activity. Selectivity was not absolute, since regression occurred in 1 of 6 animals given irrelevant IT and blocking was observed in 2 of 4 mice. Intratumoral IT treatment with 1 or 2 .mu.g of T101-ricin IT plus lactose was not harmful to mice in contrast to intratumoral ricin treatment, which killed all treated tumor-bearing mice at a dose of 0.3 .mu.g. Without i.v. injection of lactose, intratumoral injection of T101-ricin IT was also effective in eliminating established tumors. However, this treatment did not result in the selective elimination of tumor, since Daudi tumors also regressed following T101-ricin IT treatment. IT, made with ricin A chain only (T101-A chain IT), was also tested against established CEM tumors. High dosages of T101-A chain IT did not destroy CEM tumors when injected intratumorally, even in the presence of activating agents such as NH4Cl or the carboxylic ionophore X-537 A [lasalocid]. In vitro experiments demonstrated that T101-A chain IT plus activating agents had potent and selective cytotoxic effects against CEM cells.