Rationally Designed, Synthetic Antibody Libraries and Uses Therefor
First Claim
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1. A library of synthetic polynucleotides, wherein said polynucleotides encode at least 106 unique antibody CDRH3 amino acid sequences comprising:
- (i) an N1 amino acid sequence of 0 to about 3 amino acids, wherein each amino acid of the N1 amino acid sequence is among the 12 most frequently occurring amino acids at the corresponding position in N1 amino acid sequences of CDRH3 amino acid sequences that are functionally expressed by B cells;
(ii) a non-human CDRH3 DH amino acid sequence, N- and C-terminal truncations thereof, or a sequence of at least about 80% identity to any of them;
(iii) an N2 amino acid sequence of 0 to about 3 amino acids, wherein each amino acid of the N2 amino acid sequence is among the 12 most frequently occurring amino acids at the corresponding position in N2 amino acid sequences of CDRH3 amino acid sequences that are functionally expressed by B cells; and
(iv) a human CDRH3H3-JH amino acid sequence, N-terminal truncations thereof, or a sequence of at least about 80% identity to any of them.
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Abstract
The present invention overcomes the inadequacies inherent in the known methods for generating libraries of antibody-encoding polynucleotides by specifically designing the libraries with directed sequence and length diversity. The libraries are designed to reflect the preimmune repertoire naturally created by the human immune system, with or without DH segments derived from other species, and are based on rational design informed by examination of publicly available databases of antibody sequences.
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Citations
18 Claims
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1. A library of synthetic polynucleotides, wherein said polynucleotides encode at least 106 unique antibody CDRH3 amino acid sequences comprising:
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(i) an N1 amino acid sequence of 0 to about 3 amino acids, wherein each amino acid of the N1 amino acid sequence is among the 12 most frequently occurring amino acids at the corresponding position in N1 amino acid sequences of CDRH3 amino acid sequences that are functionally expressed by B cells; (ii) a non-human CDRH3 DH amino acid sequence, N- and C-terminal truncations thereof, or a sequence of at least about 80% identity to any of them; (iii) an N2 amino acid sequence of 0 to about 3 amino acids, wherein each amino acid of the N2 amino acid sequence is among the 12 most frequently occurring amino acids at the corresponding position in N2 amino acid sequences of CDRH3 amino acid sequences that are functionally expressed by B cells; and (iv) a human CDRH3H3-JH amino acid sequence, N-terminal truncations thereof, or a sequence of at least about 80% identity to any of them. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
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Specification