Chemical Construction of Immunotoxins

Ghetie,; Vitetta, ES

doi:10.1385/1-59259-075-6:1

Cited by 9 publications

(11 citation statements)

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“…When the antibody is bound to the toxin through the RTB, the toxic A-chain can be released in the target cell by reduction of the interchain disulfide bond [28]. The antibodies that have been most widely used in immunotoxins are murine monoclonal antibodies (MAb) belonging to the IgG isotype [29]. In the 1990s instead of using single Fv fragment of antibodies, a new type of disulfide-stabilized Fv (dsFv) was designed in which the light and heavy chains were held together by a disulfide bond.…”

Section: Ricin-derived Immunotoxinsmentioning

confidence: 99%

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Słomińska-Wojewódzka

Sandvig

2013

Antibodies

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Ricin is a type II ribosome inactivating protein (RIP) isolated from castor beans. Its high toxicity classifies it as a possible biological weapon. On the other hand, ricin linked to specific monoclonal antibodies or used in other conjugates has powerful medical applications. Ricin consists of an A-chain (RTA) that damages ribosomes and inhibits protein synthesis, and a B-chain that plays a role in binding and cellular uptake. A number of recent studies have demonstrated that ricin-induced inhibition of protein synthesis is not the only mechanism responsible for cell death. It turns out that ricin is able to induce apoptosis in different cell lines and multiple organs in animals. However, the molecular link between protein synthesis inhibition and ricin-dependent triggering of apoptotic cell death is unclear. This review describes the intracellular transport of ricin and ricin-based immunotoxins and their mechanism of action in different non-malignant and cancer cell lines. Moreover, various ricin-containing immunotoxins, their composition, medical applications and side-effects will be described and discussed. Understanding the mechanism of action of ricin-based immunotoxins will facilitate construction of effectively acting immunotoxins that can be used in the clinic for cancer treatment

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Section: Ricin-derived Immunotoxinsmentioning

confidence: 99%

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Słomińska-Wojewódzka

Sandvig

2013

Antibodies

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“…The cytotoxic activity of the immunotoxin, assessed as cell viability [ 19 , 20 ], was performed as follows. Briefly, 96-well plates were seeded with 3 × 10 3 cells and 100 μL of culture medium per well.…”

Section: Methodsmentioning

confidence: 99%

“…Targeting endoglin over-expressed in tumor neovasculature has been used for therapeutic purposes with anti-endoglin antibodies [ 16 ], endoglin-targeted radioimmunotherapy [ 17 ], and anti-endoglin antibody–containing ITs [ 18 ]. Efficient conventional anti-endoglin ITs containing ricin A-chain [ 19 ] and the type 2 RIPs nigrin b [ 12 , 20 ] and ebulin l [ 21 ] have been constructed. In the present work, we report proof of the validity of the new IT (rMU1-44G4), containing rMU1 as a toxic moiety linked to an anti-human CD105 monoclonal antibody (44G4), on cultured mouse L929 fibroblasts transfected with the short form of CD105 [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Human Endoglin (hCD105) Immunotoxin—Containing Recombinant Single Chain Ribosome-Inactivating Protein Musarmin 1

Barriuso

Antolı́n

Arias

et al. 2016

Toxins

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Endoglin (CD105) is an accessory component of the TGF-β receptor complex, which is expressed in a number of tissues and over-expressed in the endothelial cells of tumor neovasculature. Targeting endoglin with immunotoxins containing type 2 ribosome-inactivating proteins has proved an effective tool to reduce blood supply to B16 mice tumor xenografts. We prepared anti-endoglin immunotoxin (IT)—containing recombinant musarmin 1 (single chain ribosome-inactivating proteins) linked to the mouse anti-human CD105 44G4 mouse monoclonal antibody via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The immunotoxin specifically killed L929 fibroblast mouse cells transfected with the short form of human endoglin with IC50 values in the range of 5 × 10−10 to 10−9 M.

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“…The main advantage of using SATA is the production of thiol by addition of a mild reagent (hydroxylamine) instead of a reducing agent (commonly dithiotreithol), which cannot react with native cysteine linkages [40]. …”

Section: Immunotoxinsmentioning

confidence: 99%

Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components

Dosio

Brusa

Cattel

2011

Toxins

145

123

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Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit conjugates’ therapeutic use, including inefficient cellular uptake, low cytotoxicity, and off-target effects. During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable in vivo but must afford efficient release of the toxic moiety when the target is reached. Vast efforts have been made, and the present article reviews strategies employed in developing immunoconjugates, focusing on the evolution of chemical linkers.

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Chemical Construction of Immunotoxins

Cited by 9 publications

References 0 publications

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Anti-Human Endoglin (hCD105) Immunotoxin—Containing Recombinant Single Chain Ribosome-Inactivating Protein Musarmin 1

Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components

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