Immunotoxins

Toxins, i.e., poisonous substances produced by living cells or organisms, constitute another class of highly cytotoxic agents suitable for mAb based tumor targeted therapy. Indeed, toxins or toxin subunits derived from plants, bacteria and fungi, such as diphtheria toxin, ricin, gelonin, saporin, pokeweed and Pseudomonas exotoxin A, have been conjugated to mAb and tested for anti-tumor therapy efficacy (Frankel 2005). Toxins are enzymes which exert their cytotoxic activity inside the cell and in most cases one single molecule is sufficient to kill the cell. In order to be used therapeutically, toxins have to be modified to remove their tissue binding sites (Frankel et al. 2000). In addition, deglycosylation of toxins avoids their rapid clearance by liver cells expressing mannose receptors. Toxins may be targeted to the tumor cells by conjugation to targeting moieties, which includes mAbs (immunotoxins) or growth factors, cytokines and peptide hormones (fusion protein toxins). For therapeutic efficacy the conjugates have to be internalized upon binding to susceptible cells. After endocytosis the released toxins cause cessation of protein synthesis, which results in subsequent cell death. Well defined biochemical properties determine the cytotoxic potency of immunotoxins. These properties include antigen-binding affinity, internalization rate, intracellular processing and the intrinsic potency of the toxin-domain (Hexham et al. 2001). It should be noted that since the uptake of the immunotoxins into the intracellular compartment seems rather inefficient, toxicities are not as high as would be expected from the toxicity of the toxin per se.

Several clinical trials addressed or are currently addressing the efficiency of toxin conjugates for therapy of hematological and solid tumors (Table 15.1), demonstrating an impressive clinical efficiency with response rates greater than 30%. Tested compounds include: (1) denileukin diftitox (Ontak) for the treatment of patients with therapy-refractory cutaneous T-cell lymphoma, which is approved by the FDA; (2) LMB-2 and (3) BL-22, both indicated for treatment of hairy cell leukemia; as well as (4) HN66000 for therapy of high grade glioma patients (Frankel et al. 2000). The FDA has approved denileukin diftitox, which consists of diphtheria toxin fragments fused to interleukin-2 (IL-2); the latter serves as a targeting device. Clinical cytotoxicity of targeted-toxin based therapies includes vascular leak syndrome and hepatocyte injury. Moreover, a major drawback of both immuno- and fusion protein toxins is their immunogenicity of the toxin; humoral immune responses to toxins can be observed as soon as after one treatment course (Posey et al. 2002). This immunological response not only reduces the serum half-life but also significantly inhibits the cytotoxic activity. These effects are particularly troublesome in cases where repeated treatment courses are necessary. Thus, several approaches have been pursued to decrease the immunogenicity of toxins, namely the co-administration of immunosuppressive agents or modifications of the toxin. To date, however, these concepts were either not effective in patients or have not yet been tested in clinical trials (Frankel 2004). PEGyla-tion of the toxin, i.e., its modification by conjugation with polyethylene glycol, and genetic engineering to generate humanized toxins, are promising approaches to overcoming this problem (Youn et al. 2005). The latter approach is exemplified by use of human RNase, which downregulates gene expression in the targeted cell; fusion proteins of RNase with humanized or fully human antibodies are expected to possess only limited immunogenicity. Two independent research groups generated fusion proteins consisting either of human pancreatic RNase and a fully human anti-ErbB-2 single chain Ab (De Lorenzo et al. 2004) or angiogenin and a humanized anti-CD22 single chain Ab (Arndt et al. 2005). Both constructs demonstrated specific binding to the cells expressing the respective antigen and exhibited cytotoxic/cytostatic activity towards these cells. For the anti-ErbB-2-human pancreatic RNase fusion protein, an anti-tumor effect could also be demonstrated in vivo, i.e., inhibition of tumor growth in a murine mammary carcinoma model (De Lorenzo et al. 2004). However, the expected low toxicity and any possible therapeutic effect awaits analysis in clinical trials.

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