US2006257937A1PendingUtilityA1

Focused libraries of genetic packages

Assignee: DYAX CORP A DELAWARE CORPPriority: Dec 18, 2000Filed: May 1, 2006Published: Nov 16, 2006
Est. expiryDec 18, 2020(expired)· nominal 20-yr term from priority
C12N 15/1037C40B 40/10C07K 2317/565C40B 40/02C07K 16/005C07K 16/00C40B 40/08
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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 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR1 selected from the group consisting of: 
 (1) <1> 1 Y 2 <1> 3 M 4 <1> 5 , wherein <1> is an equimolar mixture of each 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) (S/T) 1 (S/G/X) 2 (S/G/X) 3 Y 4 Y 5 W 6 (S/G/X) 7 . wherein (S/T) is a 1:1 mixture of S and T residues, (S/G/X) is a mixture of 0.2025 S, 0.2025, G and 0.035 of each of amino acid residues A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, and Y;    (3) V 1 S 2 G 3 G 4 S 5 I 6 S 7 <<1> 8 <1> 9 <1> 10 Y 11 Y 12 W 13 <1> 14 , wherein <1> is an equimolar mixture of each 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) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         2 . The focused library according to  claim 1 , wherein HC CDR1s (1), (2) and (3) are present in the library in the ratio 0.80:0.17:0.02.  
     
     
         3 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody facility, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR2 selected from the group consisting of: 
 (1) <2>I<2><3>SGG<1>T<1>YADSVKG, wherein <1> is an equimolar mixture of each 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 an equimolar mixture of each of amino acid residues Y, R, W, V, G, and S; and <3> is an equimolar mixture of each of amino acid residues P, S, and G or an equimolar mixture of P and S;    (2) <1>I<4><1><1><G><5><1><1><1>YADSVKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; <4> is an equimolar mixture of residues D, I, N, S, W, Y; and <5> is an equimolar mixture of residues S, G, D and N;    (3) <1>I<4><1><1>G<5><1><1>YNPSLKG, wherein <1> is an equimolar mixture of each 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 above;    (4) <1>I<8>S<1><1><1>GGYY<1>YAASVKG, wherein <1> is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; <8> is 0.27 R and 0.027 of each of ADEFGHIKLMNPQSTVWY; and    (5) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         4 . The focused library according to  claim 3  wherein a mixture of HC CDR2s (1)/(2) (equimolar), (3) and (4) are present in the library in a ratio of 0.54:0.43:0.03.  
     
     
         5 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR3 selected from the group consisting of: 
 (1) YYCA21111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (2) YYCA2111111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (3) YYCA211111111YFDAYTG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (4) YYCAR111S2S3111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of S and G; and 3 is an equimolar mixture of Y and W;    (5) YYCA2111CSG11CY1YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (6) YYCA211S1TIFG11111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (7) YYCAR111YY2S3344111YFDYWG, wherein 1 is an equimolar mixture of each 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 an equimolar mixture of D and S; and 3 is an equimolar mixture of S and G;    (8) YYCAR1111YC2231CY111YFDYWG, wherein 1 is an equimolar mixture of each 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 an equimolar mixture of S and G; and 3 is an equimolar mixture of T, D and G; and    (9) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         6 . The focused library according to  claim 5 , wherein 1 in one or all of HC CDR3s (1) through (8) is 0.095 of each of G and Y and 0.048 of each of A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, and W.  
     
     
         7 . The focused library according to  claim 5  or  6 , wherein HC CDR3s (1) through (8) are present in the library in the following proportions: 
 (1) 0.10    (2) 0.14    (3) 0.25    (4) 0.13    (5) 0.13    (6) 0.11    (7) 0.04 and    (8) 0.10    
     
     
         8 . The focused library according to  claim 5  or  6 , wherein the HC CDR3s (1) through (8) are present in the library in the following proportions: 
 (1) 0.02    (2) 0.14    (3) 0.25    (4) 0.14    (5) 0.14    (6) 0.12    (7) 0.08 and    (8) 0.11    
     
     
         9 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encodes a kappa light chain CDR1 selected from the group consisting of: 
 (1) RASQ<1>V<2><2><3>LA    (2) RASQ<1>V<2><2><2><3>LA;    wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and <3> is 0.2Y and 0.044 each of ADEFGHIKLMNPQRTVW and Y; and    (3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         10 . The focused library of  claim 9 , wherein CDR1s (1) and (2) are present in the library in a ratio of 0.68:0.32.  
     
     
         11 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a kappa light chain CDR2 having the sequence: 
 <1>AS<2>R<4><1>,    wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and <4> is 0.2 A and) 0.044 each of DEFGHIKLMNPQRSTVWY.    
     
     
         12 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a kappa light chain CDR3 selected from the groups consisting of: 
 (1) QQ<3><1><1><1>P<1>T,    wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <3> is 0.2 Y and 0.044 each of ADEFGHIKLMNPQRTVW;    (2) QQ33111P, wherein 1 and 3 are as defined in (1) above;    (3) QQ3211PP1T, wherein 1 and 3 are as defined in (1) above and 2 is 0.2 S and 0.044 each of ADEFGHIKLMNPQRTVWY; and    (4) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         13 . The focused library according to  claim 12 , wherein CDR3s (1), (2) and (3) are present in the library in a ratio of 0.65:0.1:0.25.  
     
     
         14 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR1 selected from the group consisting of: 
 (1) TG<1>SS<2>VG<1><3><2><3>VS,    wherein <1> is 0.27 T, 0.27 G and 0.027 each of ADEFHIKLMNPQRSVWY, <2> is 0.27 D, 0.27 N and 0.027 each of AEFGHIKLMPQRSTVWY, and <3> is 0.36 Y and 0.036 each of ADEFGHIKLMNPQRSTVW;    (2) G<2><4>L<4><4><4><3><4><4>, wherein <2> is as defined in (1) above and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; and    (3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         15 . The focused library according to  claim 14 , where CDR1s (1) and (2) are present in the library in a ratio of 0.67:0.33.  
     
     
         16 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR2 has the sequence: 
 <4><4><4><2>RPS,    wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKLMPQRSTVWY and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVW.    
     
     
         17 . A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR3 selected from the group consisting of: 
 (1) <4><5><4><2><4>S<4><4><4><4>V,    wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKLMPQRSTVWY; <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVW; and <5> is 0.36 S and 0.0355 each of ADEFGHIKLMNPQRTVWY;    (2) <5>SY<1><5>S<5><1><4>V, wherein <1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and <4> and <5> are as defined in (1) above; and    (3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences.    
     
     
         18 . The focused library according to  claim 17 , wherein CDR3s (1) and (2) are present in the library in an equimolar mixture.  
     
     
         19 . The focused library according to  claim 1  or  2  further comprising variegated DNA sequences that encode a heavy chain CDR selected from the group consisting of: 
 (1) one or more of the heavy chain CDR2s defined in  claim 3  or  4 ;    (2) one or more of the heavy chain CDR3s defined in claims  5 ,  6 ,  7 , or 8; and    (3) mixtures of vectors or genetic packages characterized by (1) and (2).    
     
     
         20 . The focused library according to  claim 3  further comprising variegated DNA sequences that encodes one or more heavy chain CDR3s selected from the group defined in claims  5 ,  6 ,  7  or  8 .  
     
     
         21 . The focused library according to  claim 19  or  20 , further comprising variegated DNA sequences that encodes a light chain CDR selected from the group consisting of 
 (1) one or more the kappa light chain CDR1s defined in  claim 9  or  10 ;    (2) the kappa light chain CDR2 defined in  claim 11;     (3) one or more of the kappa light chain CDR3s defined in  claim 12  or  13 ;    (4) one or more of the kappa light chain CDR1s defined in  claim 14  or  15 ;    (5) the lambda light chain CDR2 defined in  claim 16;     (6) one or more of the lambda light chain CDR3s defined in  claim 17  or  18 ; and    (7) mixtures of vectors and genetic packages characterized by one or more of (1) through (6).    
     
     
         22 . A population of variegated DNA sequences that encode a heavy chain CDR1 selected from the group consisting of: 
 (1) <1> 1 Y 2 <1> 3 M 4 <1> 5 , wherein <1> is an equimolar mixture of each 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) (S/T) 1 (S/G/X) 2  (S/G/X) 3 Y 4 Y 5 W 6 (S/G/X) 7  wherein (S/T) is a 1:1 mixture of S and T residues, (S/G/X) is a mixture of 0.2025 S, 0.2025 G and 0.035 of each of amino acid residues A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, and Y;    (3) V 1 S 2 G 3 G 4 S 5 I 6 S 7 <1> 8 <1> 9 <1> 10 Y 11 Y 12 W 13 <1> 14 , wherein <1> is an equimolar mixture of each 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) mixtures of variegated DNA sequences characterized by any of the above DNA sequences.    
     
     
         23 . The population of variegated DNA sequences according to  claim 22 , wherein HC CDR1s (1), (2) and (3) are present in the population in the ratio 0.80:0.17:0.02.  
     
     
         24 . A population of variegated DNA sequences that encode a heavy chain CDR2 selected from the group consisting of: 
 (1) <2>I<2><3>SGG<1>T<1>YADSVKG, wherein <1> is an equimolar mixture of each 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 an equimolar mixture of each of amino acid residues Y, R, W, V, G, and S; and <3> is an equimolar mixture of each of amino acid residues P, S, and G or an equimolar mixture of P and S;    (2) <1>I<4><1><1><G><5><1><1><1>YADSVKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; <4> is an equimolar mixture of residues D, I, N, S, W, Y; and <5> is an equimolar mixture of residues S, G, D and N;    (3) <1>I<4><1><1>G<5><1><1>YNPSLKG, wherein <1> is an equimolar mixture of each 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 above;    (4) <1>I<8>S<1><1><1>GGYY<1>YAASVKG, wherein <1> is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; <8> is 0.27 R and 0.027 of each of ADEFGHIKLMNPQSTVWY; and    (5) mixtures of variegated DNA sequences characterized by any of the above DNA sequences.    
     
     
         25 . The population of variegated DNA sequences according to  claim 24 , wherein a mixture of HC CDR2s (1)/(2) (equimolar), (3) and (4) are present in the population in a ratio of 0.54:0.43:0.03.  
     
     
         26 . A population of variegated DNA sequences that encode a heavy chain CDR3 selected from the group consisting of: 
 (1) YYCA21111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (2) YYCA2111111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (3) YYCA211111111YFDAYTG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (4) YYCAR111S2S3111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of S and G; and 3 is an equimolar mixture of Y and W;    (5) YYCA2111CSG11CY1YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (6) YYCA211S1TIFG11111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;    (7) YYCAR111YY2S3344111YFDYWG, wherein 1 is an equimolar mixture of each 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 an equimolar mixture of D and S; and 3 is an equimolar mixture of S and G;    (8) YYCAR1111YC2231CY111YFDYWG, wherein 1 is an equimolar mixture of each 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 an equimolar mixture of S and G; and 3 is an equimolar mixture of T, D and G; and    (9) mixtures of variegated DNA sequences characterized by any of the above DNA sequences.    
     
     
         27 . The population of variegated DNA according to  claim 26 , wherein 1 in one or all of HC CDR3s (1) through (8) is 0.095 of each of G and Y and 0.048 of each of A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, and W.  
     
     
         28 . The population of variegated DNA sequences according to  claim 26  or  27 , wherein HC CDR3s (1) through (8) are present in the population in the following proportions: 
 (1) 0.10    (2) 0.14    (3) 0.25    (4) 0.13    (5) 0.13    (6) 0.11    (7) 0.04 and    (8) 0.10    
     
     
         29 . The population of variegated DNA sequences according to  claim 26  or  27 , wherein the HC CDR3s (1) through (8) are present in the population in the following proportions: 
 (1) 0.02    (2) 0.14    (3) 0.25    (4) 0.14    (5) 0.14    (6) 0.12    (7) 0.08 and    (8) 0.11    
     
     
         30 . A population of variegated DNA sequences that encode a kappa light chain CDR1 selected from the group consisting of: 
 (1) RASQ<1>V<2><2><3>LA    (2) RASQ<1>V<2><2><2><3>LA;    wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and <3> is 0.2Y and 0.044 each of ADEFGHIKLMNPQRTVW and Y; and    (3) mixtures of variegated DNA sequences characterized by any of the above DNA sequences.    
     
     
         31 . The population of variegated DNA sequences of  claim 30 , wherein CDR1s (1) and (2) are present in the population in a ratio of 0.68:0.32.  
     
     
         32 . A population of variegated DNA sequences that encode a kappa light chain CDR2 having the sequence: 
 <1>AS<2>R<4><1>,    wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and <4> is 0.2 A and) 0.044 each of DEFGHIKLMNPQRSTVWY.    
     
     
         33 . A population of variegated DNA sequences that encode a kappa light chain CDR3 selected from the groups consisting of: 
 (1) QQ<3><1><1><1>P<1>T,    wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <3> is 0.2 Y and 0.044 each of ADEFGHIKLMNPQRTVW;    (2) QQ33111P, wherein 1 and 3 are as defined in (1) above;    (3) QQ3211PPlT, wherein 1 and 3 are as defined in (1) above and 2 is 0.2 S and 0.044 each of ADEFGHIKLMNPQRTVWY; and    (4) mixtures of variegated DNA sequences characterized by any of the above DNA sequences.    
     
     
         34 . The population of variegated DNA sequences according to  claim 33 , wherein CDR3s (1) , (2) and (3) are present in the population in a ratio of 0.65:0.1:0.25.  
     
     
         35 . A population of variegated DNA sequences that encode a lambda light chain CDR1 selected from the group consisting of: 
 (1) TG<1>SS<2>VG<1><3><2><3>VS,    wherein <1> is 0.27 T, 0.2.7 G and 0.027 each of ADEFHIKLMNPQRSVWY, <2> is 0.27 D, 0.27 N and 0.027 each of AEFGHIKLMPQRSTVWY, and <3> is 0.36 Y and 0.036 each of ADEFGHIKLMNPQRSTVW;    (2) G<2><4>L<4><4><4><3><4><4>,    wherein <2> is as defined in (1) above and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; and    (3) mixtures of variegated DNA sequences characterized by any of the above DNA sequences.    
     
     
         36 . The population of variegated DNA sequences according to  claim 35 , where CDR1s (1) and (2) are present in the population in a ratio of 0.67:0.33.  
     
     
         37 . A population of variegated DNA sequences that encode a lambda light chain CDR2 has the sequence: 
 <4><4><4><2>RPS,    wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKLMPQRSTVWY and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVW.    
     
     
         38 . A population of variegated DNA sequences that encode a lambda light chain CDR3 selected from the group consisting of: 
 (1) <4><5><4><2><4>S<4><4><4><4>V,    wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKLMPQRSTVWY; <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVW; and <5> is 0.36 S and 0.0355 each of ADEFGHIKLMNPQRTVWY;    (2) <5>SY<1><5>S<5><1><4>V, wherein <1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and <4> and <5> are as defined in (1) above; and    (3) mixtures of variegated. DNA sequence characterized by any of the above DNA sequences.    
     
     
         39 . The population of variegated DNA sequences according to  claim 38 , wherein CDR3s (1) and (2) are present in the population in an equimolar mixture.  
     
     
         40 . The population of variegated DNA sequences according to  claim 22  or  23  further comprising variegated DNA sequences that encode a heavy chain CDR selected from the group consisting of: 
 (1) one or more of the heavy chain CDR2s defined in  claim 24  or  25 ;    (2) one or more of the heavy chain CDR3s defined in claims  26 ,  27 ,  28  or  29 ; and    (3) mixtures of variegated DNA sequence characterized by (1) and (2).    
     
     
         41 . The population of variegated DNA sequences according to  claim 24  further comprising variegated DNA sequences that encodes one or more heavy chain CDR3s selected from the group defined in claims  26 ,  27 ,  28  or  29 .  
     
     
         42 . The population of variegated DNA sequences according to  claim 40  or  41  further comprising variegated DNA sequences that encodes a light chain CDR selected from the group consisting of (1) one or more the kappa light chain CDR1s defined in  claim 30  or  31 ; 
 (2) the kappa light chain CDR2 defined in  claim 32;     (3) one or more of the kappa light chain CDR3s defined in  claim 33  or  34 ;    (4) one or more of the kappa light chain CDR1s defined in  claim 35  or  36 ;    (5) the lambda light chain CDR2 defined in  claim 37;     (6) one or more of the lambda light chain CDR3s defined in  claim 38  or  39 ; and    (7) mixtures of variegated DNA sequences characterized by one or more of (1) through (6).    
     
     
         43 . A population of vectors comprising the variegated DNA sequences of any one of claims  22 - 42 .

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