Rationale for the Clinical use of Immunotoxins: Monoclonal Antibodies Conjugated to Ribosome-Inactivating Proteins

Abstract

The use of chemotherapeutic drugs in combination with bone marrow transplantation to treat cancer patients has markedly improved the disease-free survival and cure rate. Part of the tumor cells, however, can escape from therapy due to resistance. Tumor-specific delivery of toxins that do not interfere with conventional drugs and are not cell cycle dependent seems to be a reasonable approach to overcome this problem. Natural ribosome-inhibiting-proteins (RIPs) from plants, bacteria and fungi which are extremely toxic inhibitors of protein synthesis are isolated and coupled to monoclonal antibodies (MoAbs) and receptor-specific ligands, immunotoxins (ITs), to fulfil this purpose. ITs are very suitable to eliminate malignant cells in vitro and in vivo.

RIPs contain two or three active sites: a binding site which can be absent in a part of the RIPs and can be replaced by the MoAb; a translocation site that facilitates transport into the cytosol after internalization, and a cytotoxic site that enzymatically inhibits protein synthesis. Binding site containing toxins induce strong nonspecific cytotoxicity when coupled to MoAbs. Recent developments in recombinant DNA techniques enable genetic elimination of the binding site to reduce nonspecific cytotoxicity of these toxins.

In this review the structures and mechanisms of action of RIPs as well as factors that influence cytotoxicity of immunotoxins are discussed. Moreover the problems dealing with in vivo application of ITs such as blood clearance by instability of the IT and hepatic entrapment, and production of antibodies directed against MoAb and toxin are reviewed.

Key Words:

• Cytotoxicity enhancers
• immunotherapy
• immunotoxins
• intracellular routing
• monoclonal antibodies
• ribosome-inactivating-proteins