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Construction of Synthetic Phage Displayed Fab Library with Tailored Diversity
Published on: May 1, 2018
Structural guided scaffold phage display libraries as a source of bio-therapeutics
Y K Stella Man1, Danielle DiCara, Nicole Chan
1Centre for Tumour Biology, Barts Cancer Institute, Queen Mary's University of London, London, United Kingdom.
Plos One
|August 17, 2013
Summary
We developed a new method to create targeted cancer therapies by designing protein fragments that mimic natural ligands. This approach successfully identified novel therapeutics for integrin alpha-v-beta-6 (αvβ6), a key target in solid tumors.
Area of Science:
- Biotechnology
- Structural Biology
- Drug Discovery
Background:
- Integrin αvβ6 is a tumor-specific surface receptor and a promising target for cancer imaging and therapy.
- Developing effective therapeutics targeting αvβ6 requires understanding its ligand-binding structure.
Purpose of the Study:
- To develop a structurally-guided phage display strategy for identifying novel ligand mimetic biotherapeutics.
- To engineer human single chain fragment variable (scFv) libraries targeting integrin αvβ6.
Main Methods:
- Utilized NMR structure analysis to determine optimal RGD-helix structures for αvβ6 interaction.
- Designed algorithms to generate scFv libraries with synthetic VH-CDR3 encoding RGD-helix hairpins.
- Tested lead scFv clones (D25scFv, D34scFv) and derived peptides (D25p, D34p) for binding, inhibition, and in vivo retention.
Main Results:
- Identified scFv clones and peptides (D25p, D34p) with specific binding to αvβ6.
- Demonstrated inhibition of αvβ6-dependent cell adhesion and internalization.
- Showed selective retention of therapeutics by αvβ6-expressing xenografts in vivo.
- Confirmed retention of RGD-helix structures in the identified peptides via NMR.
Conclusions:
- Structurally-guided phage display is effective for developing potent biotherapeutics.
- Engineering scFv libraries based on ligand structural motifs enhances the discovery of targeted therapies.
- This strategy holds promise for developing novel imaging and therapeutic agents for solid cancers targeting αvβ6.
