Editorial [Hot Topic: Recombinant Immunotoxins - The Next Generation (Executive Editor: Stefan Barth)]

Immunotoxins are anticancer agents with at least two functional components, one of which binds to a tumor-specific, internalizing cell-surface antigen and one that confers cellular toxicity. The two components may be joined covalently in vitro by chemical conjugation or they may be expressed as a fusion protein generated by recombinant DNA technology. The binding moiety is usually a monoclonal antibody derivative or a cytokine, ultimately of mammalian origin, whereas the cytotoxic moiety is an enzyme that may originate from any source, including plants and bacteria as well as mammals. After selective binding to a tumor-specific receptor, immunotoxins are internalized and translocated into the cytosol. The cytotoxic component then induces cell death through its catalytic activity. Beyond the first recombinant immunotoxins to undergo clinical studies were based on Pseudomonas exotoxin A, a format pioneered by Pastan and colleagues. One of the major challenges with this format was its immunogenicity - treated patients produced neutralizing antibodies against the toxin, reducing the effectiveness of multiple treatment cycles. This special issue of Current Pharmaceutical Design considers recent developments in immunotoxin technology that aim to overcome this difficulty by incorporating modified or novel cytotoxic components into immunotoxins. The new generation of recombinant immunotoxins includes molecules that incorporate cytotoxic human enzymes, or non-human enzymes with reduced immunogenicity. In the first review, RJ Kreitman [1] summarizes results from recent clinical studies with immunotoxins based on Pseudomonas exotoxin A. These studies involved immunotoxins targeting CD25 (LMB-2) and CD22 (BL22 and HA22) in patients with hematologic malignancies, and showed promising results against a range of leukemias and lymphomas. The review considers recent strategies to reduce the immunogenicity of the bacterial toxin, e.g. by removing immunodominant epitopes or by suppressing the patient's immune system nonspecifically. Several research groups have investigated the possibility of replacing immunogenic bacterial toxins with human enzymes, to generate fully human immunotoxins. Rybak et al. [2] were the first to consider this approach, using human ribonucleases (RNases) as the cytotoxic component. Their review discusses the most recent developments in the field of immunoRNase fusion proteins, focusing on the results of pre-clinical studies featuring immunoRNases targeting CD22 and CD30.