Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

While pharmacokinetics issues and non-specific toxicity are common problems associated with the development of many drugs and particularly with the development of chemotherapeutic agents; immunogenicity is a major challenge distinguishing immunotoxins from small molecule-based therapy. Immunotoxins generally contain at least one non-human component which might be the bacterial/plant derived toxic moiety and/or an antibody from animal origin. Consequently, anti-drug antibody formation may be induced in immune-competent patients, resulting in a compromised treatment efficiency caused by the decrease in the level of circulating functional agent. The issue of human-anti mouse antibody (HAMA) formation against immunotoxins, in which the targeting moiety is a monoclonal antibody produced by hybridoma cells, has been overcome to a great extent by the development of chimeric, humanized and fully human antibodies using recombinant DNA technology (reviewed by [525, 526] ). Attempts to use polyethylene glycol ("PEGylation") [527] [528] [529] and immunosuppressive agents [105, 107, [530] [531] [532] ] have led to different success rates in reducing the immunogenic response against non-human components of immunotoxins. Deletion of B-cell and T-cell epitopes located on the surface of the toxic moieties is another option for reducing their immunogenicity. Recent studies conducted by Onda et al revealed seven major conformational B-cell epitopes on the PE38 molecule [533] . By mutation of specific large hydrophilic amino acids on the surface of the PE38 component in the immunotoxin BL22 (see above), most of the B cell epitopes were eliminated and a new fully functional immunotoxin which is significantly less immunogenic to mice was created [534] . Taking advantage of this knowledge, Oh et al have created a bispecific cytotoxic polypeptide in which human epidermal growth factor (EGF) and interleukin-4 (IL-4) are linked to the B-cell epitopes-deleted PE38. When administrated to a mouse model of metastatic breast carcinoma, immunogenicity was reduced by about 90% (in comparison to the non-mutated construct) with no apparent loss of anti-tumor activity [535] .