The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations

Rust, Aleksander; Partridge, Lynda J.; Davletov, Bazbek; Hautbergue, Guillaume M.

doi:10.3390/toxins9110344

Cited by 25 publications

(19 citation statements)

References 101 publications

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“…an ADC that was approved for the therapy of metastatic breast cancer in 2013) suggests that this route of delivery is effective. A different delivery route is exemplified by immunotoxins, which consist of an antibody linked to a toxin, often a protein of bacterial origin [73]. Similar to ADCs, the toxin has to be released from the antibody, which can be achieved by a cleavage site [74,75].…”

Section: Antibody Delivery Routes: Endosomes Lysosomes Er-associatementioning

confidence: 99%

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

et al. 2020

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To interfere with cell function, many scientists rely on methods that target DNA or RNA due to the ease with which they can be applied. Proteins are usually the final executors of function but are targeted only indirectly by these methods. Recent advances in targeted degradation of proteins based on proteolysis-targeting chimaeras (PROTACs), ubiquibodies, deGradFP (degrade Green Fluorescent Protein) and other approaches have demonstrated the potential of interfering directly at the protein level for research and therapy. Proteins can be targeted directly and very specifically by antibodies, but using antibodies inside cells has so far been considered to be challenging. However, it is possible to deliver antibodies or other proteins into the cytosol using standard laboratory equipment. Physical methods such as electroporation have been demonstrated to be efficient and validated thoroughly over time. The expression of intracellular antibodies (intrabodies) inside cells is another way to interfere with intracellular targets at the protein level. Methodological strategies to target the inside of cells with antibodies, including delivered antibodies and expressed antibodies, as well as applications in the research areas of neurobiology, viral infections and oncology, are reviewed here. Antibodies have already been used to interfere with a wide range of intracellular targets. Disease-related targets included proteins associated with neurodegenerative diseases such as Parkinson's disease (α-synuclein), Alzheimer's disease (amyloid-β) or Huntington's disease (mutant huntingtin [mHtt]). The applications of intrabodies in the context of viral infections include targeting proteins associated with HIV (e.g. HIV1-TAT, Rev, Vif, gp41, gp120, gp160) and different oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein-Barr virus, and they have been used to interfere with various targets related to different processes in cancer, including oncogenic pathways, proliferation, cell cycle, apoptosis, metastasis, angiogenesis or neo-antigens (e.g. p53, human epidermal growth factor receptor-2 [HER2], signal transducer and activator of transcription 3 [STAT3], RAS-related RHO-GTPase B (RHOB), cortactin, vascular endothelial growth factor receptor 2 [VEGFR2], Ras, Bcr-Abl). Interfering at the protein level allows questions to be addressed that may remain unanswered using alternative methods. This review addresses why direct targeting of proteins allows unique insights, what is currently feasible in vitro, and how this relates to potential therapeutic applications.Therapeutic antibodies are valuable drugs, which mostly act outside of cells.Reaching the numerous drug targets that reside inside cells by antibodies is possible in vitro and allows unique insights compared with other methods.Applying antibodies inside cells for therapeutic purposes has been explored in animal models and promises specific therapeutic benefits in neurobiology, virology and oncology.

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Section: Antibody Delivery Routes: Endosomes Lysosomes Er-associatementioning

confidence: 99%

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

et al. 2020

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“…Antigenic epitopes modification of RIPs is also applied. ITs can be used combining with other therapeutic agents to achieve synergic effect [44,45].…”

Section: Engineering Of Rips For Improving the Anti-hiv Efficacymentioning

confidence: 99%

Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties

Lü

Zhu

Zheng

et al. 2020

Toxins

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Ribosome-inactivating proteins (RIPs) are N-glycosidases, which depurinate a specific adenine residue in the conserved α-sarcin/ricin loop (α-SRL) of rRNA. This loop is important for anchoring elongation factor (EF-G for prokaryote or eEF2 for eukaryote) in mRNA translocation. Translation is inhibited after the attack. RIPs therefore may have been applied for anti-cancer, and anti-virus and other therapeutic applications. The main obstacles of treatment with RIPs include short plasma half-life, non-selective cytotoxicity and antigenicity. This review focuses on the strategies used to improve the pharmacological properties of RIPs on human immunodeficiency virus (HIV) and cancers. Coupling with polyethylene glycol (PEG) increases plasma time and reduces antigenicity. RIPs conjugated with antibodies to form immunotoxins increase the selective toxicity to target cells. The prospects for future development on the engineering of RIPs for improving their pharmacological properties are also discussed.

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“…Hemitoxins, or class I RIPs, include pokeweed antiviral protein (PAP), saporin, bryodin 1, bouganin, and gelonin. 84 Holotoxins contain both binding and catalytic domains, whereas hemitoxins contain only the catalytic domain. Both of holotoxins and hemitoxins exert their toxic effects by inactivating the cell's ribosomes, thus they can work only when their enzymatically active domains enter the cytosol.…”

Section: Plant Toxinsmentioning

confidence: 99%

Immunotoxins: Targeted Toxin Delivery for Cancer Therapy

Xin

Chen

Wang

et al. 2019

Pharmaceutical Fronts

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Immunotoxins are proteins that consist of a protein toxin conjugated to a specific targeting moiety. The targeting moiety is usually an antibody or ligand, such as monoclonal antibody, antibody fragment, a cytokine, or a growth factor. The toxins usually come from plant toxins, bacterial toxins, or human-origin cytotoxic elements. Nearly all toxins work by enzymatically inhibiting protein synthesis. After binding to antigens or receptors on target cell surfaces, immunotoxins are internalized and translocated to the cytosol where they can kill the cells. Immunotoxins have demonstrated high cytotoxicity to cancer cells and to date two immunotoxins have been approved by U.S. Food and Drug Administration on the markets for the treatment of hematological tumors: Lumoxiti and Ontak. Many other molecules are under development or clinical trials for different forms of cancer. Although immunotoxins exhibit great potency in xenograft model systems and early clinical trials, there are obstacles that limit successful treatments, including immunogenicity, nonspecific toxicity, and poor penetration. However, efforts are underway to address these problems. In this review, we summarize immunotoxins currently in clinical trials for either hematological tumors or solid tumors, outline the design of immunotoxins utilizing variety of components, and discuss the prominent examples of redesigned immunotoxins with reduced immunogenicity and nonspecific toxicity, as well as the strategies in manufacturing immunotoxins. With further improvements, it is anticipated that immunotoxins will play an increasing role in cancer therapy.

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The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations

Cited by 25 publications

References 101 publications

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties

Immunotoxins: Targeted Toxin Delivery for Cancer Therapy

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