Immunotoxins

Immunotoxins are targeted therapy agents composed of a toxin linked to a cell-binding domain, typically a monoclonal antibody or antibody fragment, designed to deliver the toxin selectively to cells that express a specific surface antigen. The toxin component is usually a truncated bacterial toxin such as Pseudomonas exotoxin A or diphtheria toxin, or a plant ribosome-inactivating protein. The targeting domain binds its antigen, the complex is internalized, and the toxin portion reaches the cytosol where it disrupts protein synthesis, leading to cell death. For example, PE-based toxins ADP-ribosylate elongation factor-2, while diphtheria toxin blocks protein synthesis through similar mechanisms. Efficacy depends on antigen expression and internalization efficiency, and toxic effects can occur in normal tissues expressing the target antigen or due to immunogenicity.

Components and design: The targeting domain is an antibody or fragment such as a single-chain variable fragment (scFv) directed at tumor-associated antigens (examples include CD22, mesothelin, CD25). The toxin domain is a truncated or modified fragment of a bacterial toxin, often linked by a protease-cleavable or engineered linker. Engineering strategies aim to improve stability, selectivity, and reduce immunogenicity.

Clinical status: Immunotoxins have seen limited approvals and widespread clinical use due to immunogenicity and toxicity. Notable examples include denileukin diftitox (Ontak), a IL-2–diphtheria toxin fusion, and moxetumomab pasudotox (Lumoxiti), a CD22-targeted PE-based immunotoxin approved for hairy cell leukemia. Ongoing research investigates new targets, alternative toxins, and strategies to minimize immune responses and enhance tumor penetration.