Cytotoxic therapy with diphtheria toxin fusion proteins

Diphtheria toxin (DT) fusion proteins can selectively target malignant cells and induce cell death by a different mechanism than conventional chemotherapeutic drugs. Cytotoxic therapy with DT fusion proteins is a potential treatment option for relapsed/refractory cancers that are resistant to chemotherapeutic drugs. Due to the heterogeneity of chemical conjugates, the majority of DT fusion proteins used in clinical trials are recombinant DT fusion proteins. These consist of the catalytic and translocation domains of DT fused to tumor-selective ligands (single-chain antibody fragments [sFv], cytokines and growth factors). In this review, recent progress in DT fusion protein design and synthesis, clinical updates of DT fusion protein trials, and the challenges and perspectives for DT fusion proteins are discussed. Although DT fusion proteins have a unique mechanism of action toward tumor cells, their clinical use is limited by nonspecific cell toxicity, particularly endothelial damage. Immunogenicity also limits repeated dosing. New approaches to overcome these limitations are needed.