Introduction: Cancer is recognized as a major contributor to global mortality rates. Despite the availability of diverse treatment options, numerous forms of cancer persist without a cure or develop resistance to the therapies employed. In addition, nearly all chemotherapeutic agents induce various side effects as they impact not only cancerous cells but also healthy cells. Consequently, it is essential to develop new therapeutic agents that specifically target cancer cells. Immunotoxins (ITs) offer a novel strategy in targeted cancer treatment by utilizing the precision of antibodies to transport powerful toxins directly to malignant cells. ITs are a type of fusion protein that is engineered to selectively target tumor cells, consisting of a moiety for targeting and a moiety that delivers toxicity. The targeting component typically consists of an antibody, an antibody fragment, or a ligand from the immune system, which is capable of binding to an antigen or receptor that is exclusively expressed or overexpressed in cancer cells, while remaining absent in normal cells, and the toxic agent is often a protein toxin, or its derivative, derived from animal, plant, insect, or bacterial origins. The process of receptor-mediated endocytosis is responsible for the uptake of ITs, which promote the delivery of toxic substances into the cytoplasm, and inhibit protein synthesis in targeted cells, ultimately leading to the destruction of cancer cells. This method improves the effectiveness of the therapy while reducing harm to healthy tissues. ITs development is enhanced by breakthroughs in recombinant DNA technology, which provide the means for precise targeting and contribute to better therapeutic, and combining them with other targeted therapies, including monoclonal antibodies and small molecule inhibitors, can enhance the overall efficacy of treatment. Recent clinical trials indicate that recombinant ITs can generate significant therapeutic responses in patients whose cancers are resistant to conventional treatment options. Currently, the Food and Drug Administration (FDA) has approved for human use three ITs: denileukin diftitox, tagraxofusp, and moxetumomab pasudotox, as well as the list of ITs under preclinical or clinical evaluation is expanding significantly
Methods: In this review, we will present a comprehensive overview of the targets and toxins utilized in the formulation of ITs. It will also highlight the significant advancements in applications of Pseudomonas exotoxin A (PE) protein and its derivatives in generating ITs and their role in targeted cancer therapy. Our review will be confined to investigational treatments that have entered clinical trials and remain under active clinical assessment.
Results: Although ITs exhibit significant promise, there are still challenges to overcome encompassing both off-target and on-target toxicities, human cytotoxic proteins, immunogenicity, the selection of antigen targets, the efficacy of cytosolic delivery, and targeting of solid tumors.
Conclusion: Hence, there is a need for additional research to enhance their application and tackle possible resistance mechanisms in cancer cells.
Keywords: Immunotoxin, Cancer targeted therapy, Immunogenicity