Summary Pseudomonas exotoxin A (PE) is a highly toxic protein secreted by the opportunistic pathogen Pseudomonas aeruginosa. The modular structure and corresponding mechanism of action of PE make it amenable to extensive modifications that can redirect its potent cytotoxicity from disease to a therapeutic function. In combination with a variety of artificial targeting elements, such as receptor ligands and antibody fragments, PE becomes a selective agent for the elimination of specific cell populations. This review summarizes our current understanding of PE, its intoxication pathway, and ongoing efforts to convert this toxin into a treatment for cancer.
Immunotoxins based on Pseudomonas exotoxin A (PE) are promising anticancer agents that combine a variable fragment (Fv) from an antibody to a tumor-associated antigen with a 38-kDa fragment of PE (PE38). The intoxication pathway of PE immunotoxins involves receptor-mediated internalization and trafficking through endosomes/lysosomes, during which the immunotoxin undergoes important proteolytic processing steps but must otherwise remain intact for eventual transport to the cytosol. We have investigated the proteolytic susceptibility of PE38 immunotoxins to lysosomal proteases and found that cleavage clusters within a limited segment of PE38. We subsequently generated mutants containing deletions in this region using HA22, an anti-CD22 Fv-PE38 immunotoxin currently undergoing clinical trials for B-cell malignancies. One mutant, HA22-LR, lacks all identified cleavage sites, is resistant to lysosomal degradation, and retains excellent biologic activity. HA22-LR killed chronic lymphocytic leukemia cells more potently and uniformly than HA22, suggesting that lysosomal protease digestion may limit immunotoxin efficacy unless the susceptible domain is eliminated. Remarkably, mice tolerated doses of HA22-LR at least 10-fold higher than lethal doses of HA22, and these higher doses exhibited markedly enhanced antitumor activity. We conclude that HA22-LR advances the therapeutic efficacy of HA22 by using an approach that may be applicable to other PE-based immunotoxins. (Blood. 2009; 113:3792-3800) IntroductionMonoclonal antibodies, either alone or as immunoconjugates linked to other agents, have become valuable therapies for the targeted treatment of cancer. In recent years, several antibodybased therapies have progressed through regulatory approval by the Food and Drug Administration, and it is expected that many more will follow. 1 Immunotoxins are a category of immunoconjugate in which antibodies are joined to protein toxins. They exploit the precision of antibodies and the lethality of protein toxins to target and kill cancer cells expressing specific cell surface proteins. Any tumor-associated cell-surface antigen is a potential target for immunotoxins.A variety of plant, fungal, and bacterial toxins have been adapted for use with immunotoxins, including ricin, diphtheria toxin, and Pseudomonas exotoxin A (PE). 2,3 PE-based immunotoxins are currently in clinical trials for the treatment of CD22-expressing lymphomas and leukemias, as well as mesothelinexpressing solid tumors. 4,5 A phase 1 trial of the anti-CD22 PE immunotoxin BL22 had a high overall response rate of 81% but was particularly effective against drug-resistant hairy cell leukemia (HCL). 6 A phase 1 trial of the anti-CD25 PE immunotoxin LMB-2 showed a 23% response rate in patients with hematologic malignancies refractory to standard chemotherapy. 7 A phase 1 trial of the antimesothelin PE immunotoxin SS1P demonstrated minor but encouraging responses for treating solid tumors in patients with mesothelioma or ovarian cancer who had failed standard therapies....
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