STRUCTURE BASED DESIGN OF PROTEIN LIGANDS: A STUDY OF ANTIBODY-LIKE SCAFFOLDS TARGETED AGAINST THE ANTHRAX TOXIN

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We have adopted structure-based approaches to enhance the affinities of two single chain antibodies, scFv1 and scFv4, that bind to two different epitopes on the Protective Antigen (PA), a toxin from Bacillus anthracis. In one approach, we have modified scFv4 and re-engineered a novel antibody-like scaffold in which we have placed V{sub L} on the N terminus and V{sub H} on the C-terminus and joined them by a 10 amino-acid-long linker. This scaffold preserves the native V{sub L}-V{sub H} contact interface and the dispositions of the CDR loops. It binds to PA with 10 fold higher affinity than scFv4. In ... continued below

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226 Kilobytes pages

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SHIFLETT, P.; HONG-GELLER, E. & AL, ET December 1, 2000.

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We have adopted structure-based approaches to enhance the affinities of two single chain antibodies, scFv1 and scFv4, that bind to two different epitopes on the Protective Antigen (PA), a toxin from Bacillus anthracis. In one approach, we have modified scFv4 and re-engineered a novel antibody-like scaffold in which we have placed V{sub L} on the N terminus and V{sub H} on the C-terminus and joined them by a 10 amino-acid-long linker. This scaffold preserves the native V{sub L}-V{sub H} contact interface and the dispositions of the CDR loops. It binds to PA with 10 fold higher affinity than scFv4. In a second approach, we have created a bispecific ligand by covalently joining scFv1 and scFv4 by a flexible linker that supports simultaneous and synergistic binding of the two scFvs to PA. This bispecific scFv1-linker-scFv4 binds to PA with 10 fold higher affinity than the individual scFvs. The newly re-engineered antibody-like scaffold of scFv4 and scFv1-linker-scFv4 are expected to be potent inhibitors of PA binding to the host cells.

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226 Kilobytes pages

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  • Report No.: LA-UR-00-6110
  • Grant Number: W-7405-ENG-36
  • Office of Scientific & Technical Information Report Number: 772829
  • Archival Resource Key: ark:/67531/metadc722472

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  • December 1, 2000

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  • Sept. 29, 2015, 5:31 a.m.

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  • March 23, 2016, 7:53 p.m.

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SHIFLETT, P.; HONG-GELLER, E. & AL, ET. STRUCTURE BASED DESIGN OF PROTEIN LIGANDS: A STUDY OF ANTIBODY-LIKE SCAFFOLDS TARGETED AGAINST THE ANTHRAX TOXIN, article, December 1, 2000; New Mexico. (digital.library.unt.edu/ark:/67531/metadc722472/: accessed September 19, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.