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.
- Research Organization:
- Los Alamos National Lab., NM (US)
- Sponsoring Organization:
- US Department of Energy (US)
- DOE Contract Number:
- W-7405-ENG-36
- OSTI ID:
- 772829
- Report Number(s):
- LA-UR-00-6110
- Country of Publication:
- United States
- Language:
- English
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