US2020325469A1PendingUtilityA1

Focused libraries of genetic packages

70
Assignee: DYAX CORPPriority: Dec 18, 2000Filed: Feb 13, 2020Published: Oct 15, 2020
Est. expiryDec 18, 2020(expired)· nominal 20-yr term from priority
Inventors:Robert Charles Ladner
C40B 40/08C12N 15/1037C07K 16/00C40B 40/10C40B 40/02C07K 16/005C07K 2317/565
70
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Claims

Abstract

Focused libraries of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of antibody peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. The libraries have length and sequence diversities that mimic that found in native human antibodies.

Claims

exact text as granted — not AI-modified
1 - 43 . (canceled) 
     
     
         44 . A focused library of DNA plasmids or genetic packages comprising the DNA plasmids, the focused library comprising multiple different sets of variegated DNA molecules, each of which comprises a DNA sequence that encodes an antibody light chain variable domain having both frame work (FW) regions and complementary determining regions (CDR), wherein each light chain variable domain comprises antibody light chain FW1, antibody light chain CDR1, antibody heavy chain FW2, antibody light chain CDR2, antibody light chain FW3, antibody light chain CDR3, and antibody light chain FW4 in a DNA molecule arranged in the orientation of FW1-CDR1-FW2-CDR2-FW3-CDR3-FW4, and wherein:
 (a) a first collection of antibody light chains that are kappa light chains, which comprises a plurality of LC κ  CDR3 regions selected from the group consisting of:
 (1) QQ<3><1><1><1>P<1>T (SEQ ID NO:16), wherein <1> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y; and <3> is a mixture of amino acid residues Y, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, and W; 
 (2) QQ<3><3><1><1><1>P (SEQ ID NO:103), wherein <1> and <3> are as defined in (1) above; 
 (3) QQ<3><2><1><1>PP<1>T (SEQ ID NO:17), wherein <1> and <3> are as defined in (1) above and <2> is a mixture of amino acid residues S, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, and Y; and 
 (4) a mixture of any of (1) to (3) set forth above; or 
   (b) a second collection of antibody light chains that are lambda light chains, which comprise a plurality of LC λ  CDR3 regions selected from the group consisting of:
 (1) <4><5><4><2><4>S<4><4><4><4>V (SEQ ID NO:106), wherein <2> is a mixture of amino acid residues D, N, A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, and Y; <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and W; and <5> is a mixture of amino acid residues S, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, and Y; 
 (2) <5>SY<1><5>S<5><1><4>V (SEQ ID NO:19), wherein <1> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; and <4> and <5> are as defined in (1) above; and 
 (3) a mixture of (1) and (2) set forth above. 
   
     
     
         45 . The focused library of  claim 44 , wherein the first collection of antibody light chains are kappa light chains, which further comprise:
 (a) a plurality of LC K  CDR1 regions selected from the group consisting of:
 (1) RASQ<1>V<2><2><3>LA (SEQ ID NO:14), wherein <1> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; <2> is a mixture of amino acid residues S, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, Y; and <3> is a mixture of amino acid residues Y, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W and S; and 
 (2) RASQ<1>V<2><2><2><3>LA (SEQ ID NO:15); wherein <1>, <2>, and <3> are as defined in (1) above; and 
 (3) a mixture of (1) and (2) set forth above; 
   (b) a plurality of LCκ CDR2 regions <1>AS<2>R<4><1>(SEQ ID NO:102), wherein <1> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; <2> is a mixture of amino acid residues S, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, and Y; and <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; or   both (a) and (b).   
     
     
         46 . The focused library of  claim 44 , wherein the library is a library of DNA plasmids. 
     
     
         47 . The focused library of  claim 44 , wherein the library is a library of genetic packages comprising the DNA plasmids. 
     
     
         48 . The focused library of DNA plasmids of  claim 44 , wherein the DNA plasmids are in yeast cells. 
     
     
         49 . The focused library of  claim 48 , wherein the yeast cells display the plurality of antibody light chain variable regions. 
     
     
         50 . The focused library of  claim 44 , wherein the DNA plasmids are yeast DNA plasmids. 
     
     
         51 . The focused library of  claim 44 , wherein the LC K  CDR3s (1), (2), and (3) are present in the library in a ratio of 0.65:0.1:0.25. 
     
     
         52 . The focused library of  claim 45 , wherein the LC κ  CDR1s (1) and (2) are present in the library in a ratio of 0.68:0.32. 
     
     
         53 . The focused library of  claim 52 , wherein the first collection of antibody light chains are kappa light chains, and wherein the library further comprises a second set of variegated DNA molecules encoding a second collection of antibody light chains, which are lambda light chains comprising a plurality of LC λ  CDR3 regions selected from the group consisting of:
 (1) <4><5><4><2><4>S<4><4><4><4>V (SEQ ID NO:106), wherein <2> is a mixture of amino acid residues D, N, A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, and Y; <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and W; and <5> is a mixture of amino acid residues S, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, and Y; 
 (2) <5>SY<1><5>S<5><1><4>V (SEQ ID NO:19), wherein <1> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; and <4> and <5> are as defined in (1) above; and 
 (3) a mixture of (1) and (2) set forth above. 
 
     
     
         54 . The focused library of  claim 53 , wherein the second collection of antibody light chains further comprises:
 (a) a plurality of LC λ  CDR1 regions selected from the group consisting of:
 (1) TG<1>SS<2>VG<1><3><2><3>VS (SEQ ID NO:18), wherein <1> is a mixture of amino acid residues T, G, A, D, E, F, H, I, K, L, M, N, P, Q, R, S, V, W, and Y, <2> is a mixture of amino acid residues D, N, A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, and Y, and <3> is a mixture of amino acid residues Y, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and W; 
 (2) G<2><4>L<4><4><4><3><4><4>; (SEQ ID NO:104), wherein <2> is as defined in (1) above, <3> is a mixture of amino acid residues Y, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; and 
   (b) a plurality of LCλ CDR2 regions <4><4><4><2>RPS (SEQ ID NO:105), wherein <2> is a mixture of amino acid residues D, N, A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, and Y, and <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and W; or   both (a) and (b)   
     
     
         55 . The focused library of  claim 54 , wherein the LCλ CDR3s (1) and (2) are present in the library in an equimolar mixture. 
     
     
         56 . The focused library of  claim 54 , the LCλ CDR1s (1) and (2) are present in the library in a ratio of 0.67:0.33. 
     
     
         57 . The focused library of  claim 44 , wherein the first collection of antibody light chains are lambda chains, which further comprise
 (a) a plurality of LC λ  CDR1 regions selected from the group consisting of:
 (1) TG<1>SS<2>VG<1><3><2><3>VS (SEQ ID NO:18), wherein <1> is a mixture of amino acid residues T, G, A, D, E, F, H, I, K, L, M, N, P, Q, R, S, V, W, and Y, <2> is a mixture of amino acid residues D, N and, A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, and Y, and <3> is a mixture of amino acid residues Y, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and W; 
 (2) G<2><4>L<4><4><4><3><4><4>; (SEQ ID NO:104), wherein <2> is as defined in (1) above, <3> is a mixture of amino acid residues Y, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; and 
 (3) a mixture of (1) and (2) set forth above; 
   (b) a plurality of LCλ CDR2 regions <4><4><4><2>RPS (SEQ ID NO:105), wherein <2> is a mixture of amino acid residues D, N, A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, and Y and <4> is a mixture of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and W; or   both (a) and (b).   
     
     
         58 . The focused library of  claim 57 , wherein the LCλ CDR3s (1) and (2) are present in the library in an equimolar mixture. 
     
     
         59 . The focused library of  claim 57 , wherein the LCλ CDR1s (1) and (2) are present in the library in a ratio of 0.67:0.33.

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