Recombinant Immunotoxin: A New Tool for Cancer Therapy

Chemotherapy, radiotherapy, and surgery are the conventional treatment modalities for cancer. However, antimicrobial resistance (AMR), or drug resistance and toxicity may develop during chemotherapy. Radiotherapy kills cancer cells that are dividing, but it also affects dividing cells of normal tissues. And sometimes, the tumor cannot be completely removed with surgery. Therefore, monoclonal antibodies (mAbs) are selected as a new direction for cancer treatment because of their ability to specifically recognize and bind to target cells.

Since the advent of monoclonal antibodies (mAbs) in 1975, this technology has been widely used in the fields of diagnosis, prevention and treatment of clinical diseases as well as anti-tumor research, and has achieved encouraging results. Currently, 17 monoclonal antibodies have been approved by the US FDA for cancer treatment, and more than 100 monoclonal antibodies are in various stages of clinical research. Antibody therapy, while effective, does not completely eliminate tumor cells. Immunotoxin has emerged as a new approach to cancer treatment because it has specificity to target substances and also has the properties of toxic substances that kill tumor cells. It works by combining cytotoxic substances into monoclonal antibodies.

Traditional immunotoxins are created by chemically conjugating an antibody to a whole protein toxin, and this protein lacks its natural binding domain. Antitumor monoclonal antibodies are generally murine monoclonal antibodies with large molecules. Disadvantages such as strong immunogenicity, poor penetration, and difficulty in penetrating lesions, make their application limited.

Development of immunotoxins evolves with time and technology, but significant progress has been achieved in the past 20 years after introduction of recombinant DNA technique and generation of the first single-chain variable fragment (scFv) of monoclonal antibodies. Since then, more than 1,000 recombinant immunotoxins against cancer have been generated.

At present, recombinant immunotoxins (RITs) are produced in prokaryotic or eukaryotic cells by fusion of vector and gene fragment of toxin through gene recombination, which have the characteristics of low-molecular weight, strong penetration, weak immunogenicity and mass production. The best clinical success has been achieved in treating patients with refractory hairy cell leukemia. These patients were treated with recombinant immunotoxin targeting CD22 cell surface receptors on leukemic cells. In addition, many tumor cells in the blood and bone marrow, often with highly expressed surface markers, are in stable contact with drugs for a long time, making immunotoxin therapies more effective. There are some other RITs targeting hematologic malignancies in clinical application with different surface markers.

â» Interleukin-2 receptor (IL-2R)
Interleukin-2 (IL-2) is the major growth factor for activated T-lymphocytes and stimulates clonal expansion and maturation of these lymphocytes. IL-2R is overexpressed in hematologic malignancies such as adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), Hodgkin’s disease (HD), and other B- and T-cell leukemias and lymphomas. Thus, IL-2R has been broadly used to target leukemias and lymphomas.

⻠IL-2Rα (CD25)
The human IL-2Rα, also described as the Tac antigen or CD25, is a 55-kDa membrane glycoprotein (p55). The functional importance of IL-2Ra in hematopoietic cell systems is well known. However, the potential role that IL-2Ra plays in tumorigenesis is still not fully elucidated. Il-2Ra expression has been found in many types of cancers, including leukemia, lymphoma, lung, breast, head-and-neck and prostate. Recent evidence shows that high expression of IL-2Ra in tumors correlates with a poor prognosis for the patient.

â» CD19
CD19 is a biomarker for B cells. CD19 has been used to diagnose cancers caused by cells, especially B-cell lymphomas. Most experimental anti-CD19 drugs work by exploiting the presence of CD19 to treat B-cell cancers specifically. But another study indicated that CD19 plays an active role in driving the growth of these cancers, which suggests that CD19 and its downstream signaling may be a better therapeutic target.

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