The development of immunotoxins for the therapy of cancer, AIDS, and immune dysfunctions

Abstract

Immunotoxins (ITs) consist of cell-reactive ligands coupled to toxins or their toxic subunits. The ligands are usually antibodies, hormones, or growth factors and the toxins are of bacterial or plant origin. In the case of the plant toxin, ricin, its structure consists of a ribosome-inactivating A chain of 32 Kd linked by a disulfide bond to a galactose-specific lectin (B chain) of approximately 30 Kd. The A and B chains of ricin can be separated following reduction and the A chain can then be purified and chemically linked to different ligands to generate a cell-reactive conjugate. Studies using A chain-containing ITs to specifically delete tumor cells, or regulatory cells of the immune system began a decade ago. Initial in vitro experiments were successful and led to further experiments in vivo. However, in vivo studies carried out over the past five years in both animals and humans have demonstrated that the efficacy of ITs or conjugates in vivo is often poor due to problems involving instability of the conjugate, inferior potency, inaccessibility of tumor cells, nonspecific binding to cells other than the target cells, and the survival of antigen-negative mutants. In addition, immune responses against both the ligand and the A chain are usually elicited, precluding repeated therapy. During the past several years, there have been attempts to solve these problems and thereby develop more effective ITs. By analogy with conventional chemotherapeutic agents, it could be predicted that immunotoxins will require many years of study to optimize their construction and therapeutic regimens.(ABSTRACT TRUNCATED AT 250 WORDS)