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Protection of the Furin Cleavage Site in Low-Toxicity Immunotoxins Based on Pseudomonas Exotoxin A.
Kaplan, Gilad; Lee, Fred; Onda, Masanori; Kolyvas, Emily; Bhardwaj, Gaurav; Baker, David; Pastan, Ira.
Afiliación
  • Kaplan G; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. gilad.kaplan@nih.gov.
  • Lee F; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. fred.lee@nih.gov.
  • Onda M; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. OndaM@mail.nih.gov.
  • Kolyvas E; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. emily.kolyvas@nih.gov.
  • Bhardwaj G; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Gauravb@uw.edu.
  • Baker D; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Gauravb@uw.edu.
  • Pastan I; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. dabaker@uw.edu.
Toxins (Basel) ; 8(8)2016 07 25.
Article en En | MEDLINE | ID: mdl-27463727
Recombinant immunotoxins (RITs) are fusions of an Fv-based targeting moiety and a toxin. Pseudomonas exotoxin A (PE) has been used to make several immunotoxins that have been evaluated in clinical trials. Immunogenicity of the bacterial toxin and off-target toxicity have limited the efficacy of these immunotoxins. To address these issues, we have previously made RITs in which the Fv is connected to domain III (PE24) by a furin cleavage site (FCS), thereby removing unneeded sequences of domain II. However, the PE24 containing RITs do not contain the naturally occurring disulfide bond around the furin cleavage sequence, because it was removed when domain II was deleted. This could potentially allow PE24 containing immunotoxins to be cleaved and inactivated before internalization by cell surface furin or other proteases in the blood stream or tumor microenvironment. Here, we describe five new RITs in which a disulfide bond is engineered to protect the FCS. The most active of these, SS1-Fab-DS3-PE24, shows a longer serum half-life than an RIT without the disulfide bond and has the same anti-tumor activity, despite being less cytotoxic in vitro. These results have significance for the production of de-immunized, low toxicity, PE24-based immunotoxins with a longer serum half-life.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Bacterianas / Región Variable de Inmunoglobulina / Diseño de Fármacos / Inmunotoxinas / ADP Ribosa Transferasas / Factores de Virulencia / Furina / Proliferación Celular / Disulfuros / Exotoxinas Tipo de estudio: Prognostic_studies Idioma: En Revista: Toxins (Basel) Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Bacterianas / Región Variable de Inmunoglobulina / Diseño de Fármacos / Inmunotoxinas / ADP Ribosa Transferasas / Factores de Virulencia / Furina / Proliferación Celular / Disulfuros / Exotoxinas Tipo de estudio: Prognostic_studies Idioma: En Revista: Toxins (Basel) Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza