Structure-based construction of human antibody library
OwnerPeizhi Luo, Mark Hsiehinventors
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Abstract
Methods and systems are provided for constructing recombinant antibody libraries based on three-dimensional structures of antibodies from various species including human. In one aspect, a library of antibodies with diverse sequences is efficiently constructed in silico to represent the structural repertoire of the vertebrate antibodies. Such a functionally representative library provides a structurally diverse and yet functionally more relevant source of antibody candidates which can then be screened for high affinity binding to a wide variety of target molecules, including but not limited to biomacromolecules such as protein, peptide, and nucleic acids, and small molecules.
Claims32
A method for constructing a library of recombinant antibodies, comprising the steps of:
- clustering variable regions of a collection of antibodies having known 3D structures into at least two families of structural ensembles, each family of structural ensemble comprising at least two different antibody sequences, wherein the root mean square difference of the main chain conformations of said different antibody sequences is less than 4 Å;
- selecting a representative structural template from each family of structural ensemble;
- profiling a tester polypeptide sequence onto the representative structural template within each family of structural ensemble;
- evaluating structural compatibility of the tester polypeptide sequence with the representative structural template based on a scoring function selected from the group consisting of electrostatic interactions, van der Waals interactions, electrostatic solvation energy, solvent-accessible surface solvation energy, and conformational entropy;
- selecting the tester polypeptide sequence that is compatible to the structural constraints of the representative structural template;
- and
- constructing a library of recombinant antibodies by combining the selected tester polypeptide sequences.
Dependencies are inferred from the claim text.