CHARACTERIZATION OF THE INCREASED CYTOTOXICITY OF GELONIN ANTI-T CELLIMMUNOCONJUGATES COMPARED WITH RICIN-A CHAIN IMMUNOCONJUGATES

Ribosomal inactivating proteins such as gelonin (Gel) and ricin A chai n (RTA) conjugated to MoAbs bind to specific target cells, and upon in ternalization inhibit protein synthesis, ultimately resulting in cell death. We report here that Gel anti-T cell MoAb conjugates are more cy totoxic than RTA conjugates when tested against human peripheral blood mononuclear cells (PBMC). This increased cytotoxicity is observed whe ther Gel is conjugated to the anti-T cell MoAb or to an anti-mouse imm unoglobulin Fab' fragment which then binds to the murine anti-human T cell MoAb. Gel conjugates are not only effective at lower concentratio ns, but also produce a greater extent of inhibition of cellular prolif eration. Moreover, a 10 min exposure to a Gel conjugate is as effectiv e as a 90h exposure to an RTA conjugate. When part of anti-T cell F(ab ')(2) or Fab' conjugates, Gel affects the early steps in cellular into xication more than RTA; Gel conjugates bind more avidly and accelerate the modulation of antigen. In contrast, when part of whole IgG conjug ates, Gel does not affect the binding to or modulation of surface anti gen compared with RTA, while it does increase conjugate cytotoxicity. These observations suggest that Gel may be delivered more efficiently into the cytosol than RTA. A divergent intracellular pathway for Gel i s also supported by the inability of chemical potentiators, which stro ngly enhance RTA potency, to affect Gel potency. These properties of G el might also be advantageous for targeted immunoconjugates made with other MoAbs or receptor-binding molecules.