Immunotoxins kill target cells by:
Immunotoxins constitute chimeric fusion therapeutics coupling targeting domain, typically single-chain variable fragment scFv or Fab derived from monoclonal antibody recognizing tumor-associated antigen like CD22 or HER2, to potent catalytic toxin of bacterial or plant origin including Pseudomonas exotoxin A fragment PE38, diphtheria toxin DT390, ricin A chain, saporin or gelonin. Mechanism begins with antigen-specific binding, internalization via clathrin-mediated endocytosis into early endosome, pH-dependent furin cleavage between targeting and toxin domains, retrograde transport via KDEL receptor to Golgi then endoplasmic reticulum in case of PE, translocation to cytosol through Sec61 channel. Once cytosolic, catalytic domain irreversibly inactivates protein synthesis: Pseudomonas and diphtheria toxins ADP-ribosylate diphthamide-modified histidine 715 of elongation factor-2 blocking translocation, while ricin depurinates adenine 4324 of 28S rRNA sarcin-ricin loop preventing EF-2 binding, halting translation elongation. Single toxin molecule can inactivate thousands of ribosomes achieving IC50 in picomolar range, triggering ribotoxic stress, JNK activation and apoptosis. First-generation chemically conjugated constructs suffered off-target toxicity and immunogenicity; second and third generation recombinant de-immunized versions with deleted B cell epitopes improve therapeutic window for hematologic malignancies.
Ref: Pastan et al. Nature Reviews Cancer 2006 Immunotoxins; Weldon & Pastan FEBS J 2011 mechanism; PubMed PMID 16794637.