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Immunotoxins in cancer therapy: Review and update
Bahman Akbari1,2,3, Safar Farajnia2, Shiva Ahdi Khosroshahi4
1a Department of Medical Laboratory Sciences , School of Paramedicine, Kermanshah University of Medical Sciences , Kermanshah , Iran.
Abstract:
Immunotoxins are a novel class of cancer therapeutics that contains a cytotoxic agent fused to a targeting moiety. Various toxic agents from different sources are used in immunotoxin development, including bacterial, plant and human origin cytotoxic elements. Although bacterial and plant-derived toxins are highly toxic and commonly used in immunotoxins, their immunogenicity for human restricted their application in cancer therapy. Here, we discuss the advantages and limitations of bacterial toxins such as Pseudomonas and Diphtheria toxins, plant toxins such as ricin and gelonin, and some endogenous protein of human origin such as RNases and Granzymes. This article will also review different generations of immunotoxins with special focus on immunotoxins which are under clinical trials or approved for clinical use. Finally, current deimmunization strategies for development of new less-immunogenic recombinant immunotoxins will be discussed.
Abbreviations:
mAbs: Monoclonal antibodies; EF2: elongation factor 2; ITs: Immunotoxins; DT: Diphtheria toxin; PE: Pseudomonas exotoxin; dgA: de-glycosylated A-chain of ricin; rGel: recombinant de-glycosylated form of gelonin; NKC: natural killer cells; HTR: human transferrin receptor; EGF: epidermal growth factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; DAB389: truncated Diphtheria toxin; B-CCL: B-cell chronic lymphocytic leukemia; RCC: renal cell carcinoma; GVHD: Graft-versus-host disease; EGFR: epidermal growth factor receptor; AML: acute myeloid leukemia; Fab: fragment antigen-binding; dsFv: disulfide-stabilized fragment variable; scFv: single-chain fragment variable; B-ALL: B-lineage Acute Lymphoblastic Leukemia; Fv: fragment variable; HCL: hairy cell leukemia; IL-2R: Interleukin-2 receptor; CR: complete response; CLL: chronic lymphocytic leukemia; ATL: adult T-cell leukemia; DARPins: designed Ankyrin repeat proteins; pmol: picomolar; HAMA: human-anti mouse antibody.
Insights
Immunotoxins, combining cytotoxic agents with targeting molecules, offer novel cancer therapy. This review explores toxin sources, immunogenicity challenges, and strategies for developing less immunogenic immunotoxins for improved cancer treatment.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Immunotoxins (ITs) are engineered therapeutics combining a cytotoxic agent with a targeting moiety for cancer treatment.
- Bacterial and plant-derived toxins are potent but often elicit immunogenicity, limiting their clinical application.
- Human endogenous proteins offer alternatives but require careful engineering for efficacy.
Purpose of the Study:
- To review the advantages and limitations of various cytotoxic agents used in immunotoxin development, including bacterial, plant, and human-derived toxins.
- To discuss different generations of immunotoxins, focusing on those in clinical trials or approved for use.
- To explore current deimmunization strategies for creating less immunogenic recombinant immunotoxins.
Main Methods:
- Review of literature on immunotoxin development, focusing on toxin sources, clinical applications, and deimmunization strategies.
- Analysis of the immunogenicity and efficacy of bacterial toxins (e.g., Diphtheria toxin, Pseudomonas exotoxin), plant toxins (e.g., ricin, gelonin), and human proteins (e.g., RNases, Granzymes).
- Examination of clinical trial data and approved immunotoxins, including different generations and targeting moieties.
Main Results:
- Bacterial and plant toxins show high potency but significant immunogenicity, whereas human proteins may be less immunogenic but require optimization.
- Several immunotoxins targeting various cancers (e.g., B-cell chronic lymphocytic leukemia, renal cell carcinoma) have progressed to clinical trials or gained approval.
- Deimmunization techniques are crucial for enhancing the therapeutic window and efficacy of novel immunotoxins.
Conclusions:
- Immunotoxin therapy holds significant promise for cancer treatment, with ongoing advancements in toxin selection and engineering.
- Addressing immunogenicity through deimmunization is key to unlocking the full potential of immunotoxins.
- Future research should focus on developing safer, more effective immunotoxins with improved targeting and reduced side effects.
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