Complementarity Determining Regions; Immunoglobulin Fab Fragments; Immunoglobulin Heavy Chains; Lewis Blood Group Antigens; Lewis a oligosaccharide; Oligosaccharides; Peptide Library; Amino Acid Sequence; Animals; Antibody Diversity; Bacteriophage M13/chemistry; Bacteriophage M13/genetics; Bacteriophage M13/immunology; Binding Sites, Antibody; Carbohydrate Sequence; Complementarity Determining Regions/chemistry; Complementarity Determining Regions/genetics; Drug Design; Humans; Immunoglobulin Fab Fragments/chemistry; Immunoglobulin Fab Fragments/genetics; Immunoglobulin Heavy Chains/chemistry; Immunoglobulin Heavy Chains/genetics; Mice; Molecular Sequence Data; Oligosaccharides/chemistry; Oligosaccharides/genetics; Oligosaccharides/immunology; Protein Engineering/methods; Static Electricity; Immunology and Allergy; Immunology
Abstract :
[en] A number of small charged carbohydrate moieties have been associated with inflammation and cancer. However, the development of therapeutic Abs targeting these moieties has been hampered by their low immunogenicity and their structural relationship to self-Ag. We report the design of an Ab repertoire enriched in Abs binding to small charged carbohydrates and the construction of a human Fab phagemid library, "FAB-CCHO." This library combines L chain Ig sequences from human donors and H chain synthetic diversity constructed in key Ag contact sites in CDRs 1, 2, and 3 of the human framework V(H)3-23. The H chain CDR3 has been engineered to enrich the library in Abs that bind charged carbohydrates by the introduction of basic residues at specific amino acid locations. These residues were selected on the basis of anti-carbohydrate Ab sequence alignment. The success of this design is demonstrated by the isolation of phage Abs against charged carbohydrate therapeutic target Ags such as sulfated sialyl-Lewis X glycan and heparan sulfate.
Disciplines :
Immunology & infectious disease
Author, co-author :
Schoonbroodt, Sonia; Dyax SA, Liege, Belgium
Steukers, Mieke; Dyax SA, Liege, Belgium
Viswanathan, Malini; Dyax Corp., 300 Technology Square, Cambridge, MA 02139-3515, United States
Frans, Nicolas; Dyax SA, Liege, Belgium
Timmermans, Marie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique (CHR) ; Dyax SA, Liege, Belgium
Wehnert, Anita; Dyax SA, Liege, Belgium
Nguyen, Minh; Dyax SA, Liege, Belgium
Ladner, Robert Charles; Dyax Corp., 300 Technology Square, Cambridge, MA 02139-3515, United States
Hoet, René M; Dyax SA, Liege, Belgium ; Genmab, Netherlands
Language :
English
Title :
Engineering antibody heavy chain CDR3 to create a phage display Fab library rich in antibodies that bind charged carbohydrates.
Publication date :
01 November 2008
Journal title :
Journal of Immunology
ISSN :
0022-1767
eISSN :
1550-6606
Publisher :
American Association of Immunologists, United States
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