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

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.
Authors:
; ;
Publication Date:
OSTI Identifier:
772829
Report Number(s):
LA-UR-00-6110
TRN: AH200127%%217
DOE Contract Number:
W-7405-ENG-36
Resource Type:
Conference
Resource Relation:
Conference: Conference title not supplied, Conference location not supplied, Conference dates not supplied; Other Information: PBD: 1 Dec 2000
Research Org:
Los Alamos National Lab., NM (US)
Sponsoring Org:
US Department of Energy (US)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; AFFINITY; ANTIBODIES; ANTIGENS; BACILLUS; CHAINS; DESIGN; PROTEINS; TOXINS