Ultra high diversity factorizable libraries for efficient therapeutic discovery
Open Access
- 23 June 2022
- journal article
- research article
- Published by Cold Spring Harbor Laboratory in Genome Research
- Vol. 32 (9), 1787-1794
- https://doi.org/10.1101/gr.276593.122
Abstract
The successful discovery of novel biological therapeutics by selection requires highly diverse libraries of candidate sequences that contain a high proportion of desirable candidates. Here we propose the use of computationally designed factorizable libraries made of concatenated segment libraries as a method of creating large libraries that meet an objective function at low cost. We show that factorizable libraries can be designed efficiently by representing objective functions that describe sequence optimality as an inner product of feature vectors, which we use to design an optimization method we call Stochastically Annealed Product Spaces (SAPS). We then use this approach to design diverse and efficient libraries of antibody CDR-H3 sequences with various optimized characteristics.Keywords
This publication has 21 references indexed in Scilit:
- Synthetic DNA Synthesis and Assembly: Putting the Synthetic in Synthetic BiologyCold Spring Harbor Perspectives in Biology, 2017
- From selection hits to clinical leads: progress in aptamer discoveryMolecular Therapy - Methods & Clinical Development, 2016
- T Cell Receptor Engineering and Analysis Using the Yeast Display PlatformMethods in Molecular Biology, 2015
- A strategy for risk mitigation of antibodies with fast clearancemAbs, 2012
- High Affinity, Developability and Functional Size: The Holy Grail of Combinatorial Antibody Library GenerationMolecules, 2011
- Aptamers as therapeuticsNature Reviews Drug Discovery, 2010
- Golden Gate Shuffling: A One-Pot DNA Shuffling Method Based on Type IIs Restriction EnzymesPLOS ONE, 2009
- Directed evolution of human T-cell receptors with picomolar affinities by phage displayNature Biotechnology, 2005
- In vitroevolution of a T cell receptor with high affinity for peptide/MHCProceedings of the National Academy of Sciences of the United States of America, 2000
- Sequence logos: a new way to display consensus sequencesNucleic Acids Research, 1990