Advances in Anticancer Immunotoxin Therapy

Alewine, Christine; Hassan, Raffit; Pastan, Ira

doi:10.1634/theoncologist.2014-0358

Cited by 163 publications

(170 citation statements)

References 79 publications

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“…injection (n ¼ 4 each) or i.v. injection via the tail vein for a total of 8 times on days 14,17,19,22,24,26,29, and 31. On day 36, the subcutaneous nodules were excised for weight measurements.…”

Section: Animal Models Of Pdacmentioning

confidence: 99%

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A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

Shimomura

Oda

Tateno

et al. 2018

Molecular Cancer Therapeutics

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Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL ¼ 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments.

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Section: Animal Models Of Pdacmentioning

confidence: 99%

“…2D). Because internalization into the cell cytoplasm is a key indispensable step for the cytocidal toxicity of PE toxin (19), the endocytosis of rBC2 lectins was observed. One hour after application of the conjugate, the cell surfaces of the Capan-1 cells were surrounded by rBC2 lectins (Fig.…”

Section: Construction Of Ldc and Its Cytocidal Activity In Vitromentioning

confidence: 99%

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

Shimomura

Oda

Tateno

et al. 2018

Molecular Cancer Therapeutics

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“…For instance, botulinum neurotoxins are currently used in many biomedical applications for various cosmetic and neurological disorders (1,2). Immunotoxins use specific receptor ligands to target and deliver toxin-derived cell-killing cargos to desired cell types, such as cancer cells (3). Toxins have also been used to deliver heterologous cargo in vaccine development, such as epitopes fused to diphtheria toxin (4), Bordetella adenylate cyclase (5) or anthrax toxin (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Modular domain swapping among the bacterial cytotoxic necrotizing factor (CNF) family for efficient cargo delivery into mammalian cells

Haywood

Wilson

2018

Journal of Biological Chemistry

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Modular AB-type bacterial protein toxins target mammalian host cells with high specificity and deliver their toxic cargo into the cytosol. Hence, these toxins are being explored as agents for targeted cytosolic delivery in biomedical and research applications. The cytotoxic necrotizing factor (CNF) family is unique among these toxins in that their homologous sequences are found in a wide array of bacteria, and their activity domains are packaged in various delivery systems. Here, to study how CNF cargo and delivery modules can be assembled for efficient cytosolic delivery, we generated chimeric toxins by swapping functional domains among CNF1, CNF2, CNF3 and CNFy. Chimeras with a CNFy delivery vehicle were more stably expressed, but were less efficient at cargo delivery into HEK293-T cells. We also found that CNFy cargo is the most universally compatible and that CNF3 delivery vehicle is the most flexible and efficient at delivering cargo. These findings suggest that domains within proteins can be swapped and accommodate each other for efficient function, and that an individual domain could be engineered for compatibility with multiple partner domains. We anticipate that our insights could help inform chemical biology approaches to develop toxin-based cargo-delivery platforms for cytosolic cargo delivery of therapeutics or molecular probes into mammalian cells.

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“…As a toxic module of the bifunctional recombinant proteins Pseudomonas exotoxin A fragment was used (PE40). This bacterial exotoxin is one of the most potent protein toxins known to date and has been successfully used for construction of a number of immunotoxins specific to different targets [2]. Two functional modules, targeting and toxic, were combined in a single recombinant protein by genetic engineering techniques.…”

Section: Research Resultsmentioning

confidence: 99%

Bifunctional Recombinant Protein Agent Based on Pseudomonas Exotoxin A Fragment for Targeted Therapy of HER2-Positive Tumors

Deyev

Kutova

Лебеденко

et al. 2017

Proceedings of the Scientific-Practical Conference "Research and Development - 2016"

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Four variants of bifunctional HER2-specific recombinant proteins (anti-HER2-toxins) were created composed of HER2-specific scFv antibody (4D5scFv) or HER2-specific DARPin (D29) as targeting module and Pseudomonas exotoxin A fragment (PE40) as toxic module, and distinguished by the way of bacterial expression (cytoplasmic or periplasmic). Physicochemical, immunochemical, and functional properties of the created recombinant proteins as well as their expression yields were analyzed and compared with the option of the most promising one, D29-PE40, for further implementation as an agent for targeted therapy of HER2-overexpressing tumors.

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Advances in Anticancer Immunotoxin Therapy

Cited by 163 publications

References 79 publications

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

Modular domain swapping among the bacterial cytotoxic necrotizing factor (CNF) family for efficient cargo delivery into mammalian cells

Bifunctional Recombinant Protein Agent Based on Pseudomonas Exotoxin A Fragment for Targeted Therapy of HER2-Positive Tumors

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