Strategies to mitigate the on- and off-target toxicities of recombinant immunotoxins: an antibody engineering perspective

Abstract Targeted cancer therapies using immunotoxins have achieved remarkable efficacy in hematological malignancies. However, the clinical development of immunotoxins is also faced with many challenges like anti-drug antibodies and dose-limiting toxicity issues. Such a poor efficacy or safety ratio is also the major hurdle in the research and development of antibody-drug conjugates. From an antibody engineering perspective, various strategies were summarized or proposed to tackle the notorious on-target off-tumor toxicity issues, including passive strategy (XTENylation of immunotoxins) and active strategies (modulating the affinity and valency of the targeting moiety of immunotoxins, conditionally activating immunotoxins in the tumor microenvironments and reconstituting split toxin to reduce systemic toxicity, etc.). By modulating the functional characteristics of the targeting moiety and the toxic moiety of immunotoxins, selective tumor targeting can be augmented while sparing the healthy cells in normal tissues expressing the same target of interest. If successful, the improved therapeutic index will likely help to address the dose-limiting toxicities commonly observed in the clinical trials of various immunotoxins. Statement of Significance: Poor therapeutic index is the major hurdle in the development of targeted cancer therapies with immunotoxins and antibody-drug conjugates. In this review, from an antibody engineering perspective, various strategies to mitigate the on- and off-target toxicities of immunotoxins were reviewed. They may help to address the dose-limiting toxicities commonly observed in the clinical trials of various immunotoxins.