AU2016203578B2 - Focused Libraries of Genetic Packages - Google Patents

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.

Description

Australian Patents Act 1990 — Regulation 3.2A

Original Complete Specification, Standard Patent

Invention Title: Focused Libraries of Genetic Packages

The following statement is a full description of this invention, including the best method of performing it known to the applicant:

This application is a divisional of Australian Application No. 2013204439, which, in turn, is a divisional of Australian Patent Application No. 2011223997. Australian Patent Application No. 2011223997 is a divisional of Australian Application No. 2007214299, which, in turn, is a divisional of Australian Patent Application No. 2002249854, which claims priority to US Provisional Application No. 60/256,380, filed December 18 2000. All of the above referenced applications are hereby incorporated by reference in their entireties.

The present invention relates to focused libraries of genetic packages that each display, display and express, or comprise a member of a diverse family of peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. The focused diversity of the libraries of this invention comprises both sequence diversity and length diversity. In a preferred embodiment, the focused diversity of the libraries of this invention is biased toward the natural diversity of the selected family. In a more preferred embodiment, the libraries are biased toward the natural diversity of human antibodies and are characterized by variegation in their heavy chain and light chain complementarity determining regions ("CDRs").

The present invention further relates to vectors and genetic packages (e.g., cells, spores or viruses) for displaying, or displaying and expressing a focused diverse family of peptides, polypeptides or proteins. In a preferred embodiment the genetic packages are filamentous phage or phagemids or yeast. Again, the focused diversity of the family comprises diversity in sequence and diversity in length.

The present invention further relates to methods of screening the focused libraries of the invention and to the peptides, polypeptides and proteins identified by such screening.

BACKGROUND OF THE INVENTION

It is now common practice in the art to prepare libraries of genetic packages that individually display, display and express, or comprise a member of a diverse family of peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the amino acid diversity of the family. In many common libraries, the peptides, polypeptides or proteins are related to antibodies (e.g., single chain Fv (scFv), Fv, Fab, whole [Text continues on page 2] antibodies or minibodies (i.e., dimers that consist of VH linked to Vl))· Often, they comprise one or more of the CDRs and framework regions of the heavy and light chains of human antibodies.

Peptide, polypeptide or protein libraries have been produced in several ways in the prior art. See e.g., Knappik et al., J. Mol. Biol., 296, pp. 57-86 (2000), which is incorporated herein by references. One method is to capture the diversity of native donors, either naive or immunized. Another way is to generate libraries having synthetic diversity. A third method is a combination of the first two. Typically, the diversity produced by these methods is limited to sequence diversity, i.e., each member of the library differs from the other members of the family by having different amino acids or variegation at a given position in the peptide, polypeptide or protein chain. Naturally diverse peptides, polypeptides or proteins, however, are not limited to diversity only in their amino acid sequences. For example, human antibodies are not limited to sequence diversity in their amino acids, they are also diverse in the lengths of their amino acid chains.

For antibodies, diversity in length occurs, for example, during variable region rearrangements. See e.g., Corbett et al., J. Mol. Biol., 270, pp. 587-97 (1997). The joining of V genes to J genes, for example, results in the inclusion of a recognizable D segment in CDR3 in about half of the heavy chain antibody sequences, thus creating regions encoding varying lengths of amino acids. The following also may occur during joining of antibody gene segments: (i) the end of the V gene may have zero to several bases deleted or changed; (ii) the end of the D segment may have zero to many bases removed or changed; (iii) a number of random bases may be inserted between V and D or between D and J; and (iv) the 5' end of J may be edited to remove or to change several bases. These rearrangements result in antibodies that are diverse both in amino acid sequence and in length.

Libraries that contain only amino acid sequence diversity are, thus, disadvantaged in that they do not reflect the natural diversity of the peptide, polypeptide or protein that the library is intended to mimic. Further, diversity in length may be important to the ultimate functioning of the protein, peptide or polypeptide. For example, with regard to a library comprising antibody regions, many of the peptides, polypeptides, proteins displayed, displayed and expressed, or comprised by the genetic packages of the library may not fold properly or their binding to an antigen may be disadvantaged, if diversity both in sequence and length are not represented in the library.

An additional disadvantage of prior art libraries of genetic packages that display, display and express, or comprise peptides, polypeptides and proteins is that they are not focused on those members that are based on natural occurring diversity and thus on members that are most likely to be functional. Rather, the prior art libraries, typically, attempt to include as much diversity or variegation at every amino acid residue as possible. This makes library construction time-consuming and less efficient than possible. The large number of members that are produced by trying to capture complete diversity also makes screening more cumbersome than it needs to be. This is particularly true given that many members of the library will not be functional.

SUMMARY OF THE INVENTION

An embodiment of this invention is directed to focused libraries of vectors or genetic packages that encode members of a diverse family of peptides, polypeptides or proteins wherein the libraries encode populations that are diverse in both length and sequence. The diverse length comprising components that contain motifs that are likely to fold and function in the context of the parental peptide, polypeptide or protein.

Another embodiment of this invention is directed to focused libraries of genetic packages that display, display and express, or comprise a member of a diverse family of peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. These libraries are diverse not only in their amino acid sequences, but also in their lengths. And, their diversity is focused so as to more closely mimic or take into account the naturally-occurring diversity of the specific family that the library represents.

Another embodiment of this invention is directed to diverse, but focused, populations of DNA sequences encoding peptides, polypeptides or proteins suitable for display or display and expression using genetic packages (such as phage or phagemids) or other regimens that allow selection of specific binding components of a library. A further embodiment of this invention is directed to focused libraries comprising the CDRs of human antibodies that are diverse in both their amino acid sequence and in their length (examples of such libraries include libraries of single chain Fv (scFv), Fv, Fab, whole antibodies or minibodies (i.e., dimers that consist of VH linked to Vl)). Such regions may be from the heavy or light chains or both and may include one or more of the CDRs of those chains. More preferably, the diversity or variegation occurs in all of the heavy chain and light chain CDRs.

Another embodiment of this invention provides methods of making and screening the above libraries and the peptides, polypeptides and proteins obtained in such screening.

Among the preferred embodiments of this invention are the following: 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>iY2<1>3M4<1>5, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W, and Y; (2) (S/T)i(S/G/X)2(S/G/X)3Y4Y5W6(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, Η, I, K, L, Μ, N, P, Q, R, T, V, W, and Y; (3) ViS2G3G4S5l6S7<l>8<l>9<l>ioYiiYi2Wi3<l>i4, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, preferably in the ratio: HC CDRls (1):(2):(3)::0.80:0.17:0.02. 2. 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, Η, I, K, L, Μ, 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>< lxl ><G><5>< 1 >< 1 >< 1 >YADS VKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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><lxl>G<5>< 1 >< 1 >YNPSLKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and <4> and <5> are as defined above; (4) < 1 >I<8>S< 1 x 1 x 1 >GGYY < 1 >Y A AS VKG, wherein <1> is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, preferably in the ratio: HC CDR2s: (1)/(2) (equimolar): (3):(4)::0.54:0.43:0.03. 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 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, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, 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) YYCA2111CSG1 ICY 1YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (6) YYCA21 IS 1TIFG1 111 1YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, 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) YYCAR1111YC2231CY111 YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, preferably the HC CDR3s (1) through (8) are in the following proportions in the mixture: (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; and more preferably the HC CDR3s (1) through (8) are in the following proportions in the mixture: (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.

Preferably, 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, Η, I, K, L, Μ, N, P, Q, R, S, T, V, and W. 4. 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) R AS Q< 1 > V <2x2x3 >LA (2) R AS Q< 1 > V <2><2><2x3 >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, preferably in the ratio CDRls (1):(2)::0.68:0.32. 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 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. 6. 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, preferably in the ratio CDR3s (1):(2):(3)::0.65:0.1:0.25. 7. 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) T G< 1 >S S <2> V G< 1x3 ><2><3 > V S, 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 AEFGHIKFMPQRSTVWY, and <3> is 0.36 Y and 0.036 each of ADEFGHIKLMNPQRSTVW; (2) G<2x4>F<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, preferably in the ratio CDRls (1):(2)::0.67:0.33. 8. 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. 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 encode a lambda light chain CDR3 selected from the group consisting of: (1) <4x5 ><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<lx5>S<5xlx4>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, preferably in the ratio CDR3s (1):(2)::1:1. 10. A focused library comprising variegated DNA sequences that encode a heavy chain CDR selected from the group consisting of: (1) one or more of the heavy chain CDR Is of paragraph 1 above; (2) one or more of the heavy chain CDR2s of paragraph 2 above; (3) one or more of the heavy chain CDR3s of paragraph 3 above; and (4) mixtures of vectors or genetic packages characterized by (1), (2) and (3). 11. The focused library comprising one or more of the variegated DNA sequences that encodes a heavy chain CDR of paragraphs 1, 2 and 3 and 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 CDR Is of paragraph 4; (2) the kappa light chain CDR2 of paragraph 5; (3) one or more of the kappa light chain CDR3s of paragraph 6; (4) one or more of the kappa light chain CDR Is of paragraph 7; (5) the lambda light chain CDR2 of paragraph 8; (6) one or more of the lambda light chain CDR3s of paragraph 9; and (7) mixtures of vectors and genetic packages characterized by one or more of (1) through (6). 12. A population of variegated DNA sequences as described in paragraphs 1-11 above. 13. A population of vectors comprising the variegated DNA sequences as described in paragraphs 1-11 above. A definition of a specific embodiment of the invention claimed herein follows.

In a broad format, the invention provides an antibody library comprising a first set of variegated DNA molecules encoding a first collection of antibody light chains (LC), wherein each light chain comprises an LC CDR1 region, an LC CDR2 region and an LC CDR3 region, and wherein: (a) the first collection of antibody light chains are kappa light chains, which comprise a plurality of LCK CDR3 regions selected from the group consisting of: (1) QQ<3><lxl><l>P<l>T (SEQ ID NO:16), wherein <1> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y, and <3> is 0.2 Y and 0.044 each of A, D, E, F, G, Η, I, K, L, Μ, 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 0.2 S and 0.044 each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, T, V, W and Y; and (4) a mixture of any one of (1) to (3) as set forth above; or (b) the first collection of antibody light chains are lambda light chains, which comprise a plurality of LCx 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 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V and W, and <5> is 0.36 S and 0.0355 each of A, D, E, F, G, Η, I, K, L, Μ, 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 an equimolar mixture of A, D, E, F, G, Η, I, K, L, Μ, 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) as set forth above.

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Other embodiments of the invention as described herein are defined in the following paragraphs: 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>iY2<1>3M4<1>5, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, R, Q, R, S, T, V, W, and Y; (2) (S/T)i(S/G/X)2(S/G/X)3Y4Y5W6(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, Η, I, K, L, Μ, N, R, Q, R, T, V, W, and Y; (3) ViS2G3G4S5l6S7<l>8<l>9<l>ioYiiYi2Wi3<l>i4, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, R, 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 paragraph 1, wherein HC CDRls (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, Η, I, K, L, Μ, N, P, Q, R, S, L 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) <l>I<4xl><l><G><5><l><lxl>YADSVKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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><lxl>G<5>< 1 ><1>YNPSLKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and <4> and <5> are as defined above; (4) < 1 > 1 <8>S<lxlxl>GG Y Y <1> Y A AS VKG, wherein <1> is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; <8> is 0.27 R and 0.027 of each of A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, S, T, V, W, Y; and (5) mixtures of vectors or genetic packages characterized by any of the above DNA sequences. 4. The focused library according to paragraph 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, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (3) YYCA211111111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, 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) YYCA2111CSG11CY1 YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (6) YYCA21 IS 1TIFG1 111 1YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; 2 is an equimolar mixture of D and G; and 3 is an equimolar mixture of S and G; (8) YYCAR1111YC2231CY111 YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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 paragraph 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, Η, I, K, L, Μ, N, P, Q, R, S, T, V, and W. 7. The focused library according to paragraph 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. he focused library according to paragraph 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) R AS Q< 1 > V <2x2x3 >LA (2) R AS Q< 1 > V <2><2><2x3 >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 paragraph 9, wherein CDRls (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) QQ3311 IP, 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 paragraph 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>V G< 1 ><3><2><3>V S, 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<2x4>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 paragraph 14, where CDRls (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) <4x5 ><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<lx5>S<5xlx4>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 paragraph 17, wherein CDR3s (1) and (2) are present in the library in an equimolar mixture. 19. The focused library according to paragraph 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 paragraph 3 or 4; (2) one or more of the heavy chain CDR3s defined in paragraphs 5, 6, 7, or 8; and (3) mixtures of vectors or genetic packages characterized by (1) and (2). 20. The focused library according to paragraph 3 further comprising variegated DNA sequences that encodes one or more heavy chain CDR3s selected from the group defined in paragraphs 5, 6, 7 or 8. 21. The focused library according to paragraph 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 CDRls defined in paragraph 9 or 10; (2) the kappa light chain CDR2 defined in paragraph 11; (3) one or more of the kappa light chain CDR3s defined in paragraph 12 or 13; (4) one or more of the kappa light chain CDRls defined in paragraph 14 or 15; (5) the lambda light chain CDR2 defined in paragraph 16; (6) one or more of the lambda light chain CDR3s defined in paragraph 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>iY2<1>3M4<1>5, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W, and Y; (2) (S/T)i(S/G/X)2(S/G/X)3Y4Y5W6(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, Η, I, K, L, Μ, N, P, Q, R, T, V, W, and Y; (3) ViS2G3G4Ssl6S7<l>8<l>9<l>ioYiiYi2Wi3<l>i4, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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 paragraph 22, wherein HC CDRls (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<2x3>SGG<l>T<l>YADSVKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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 PandS; (2) <l>I<4xl><l><G><5><l><lxl>YADSVKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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) <l>I<4xl><l>G<5><lxl>YNPSLKG, wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and <4> and <5> are as defined above; (4) <l>I<8>S<lxlxl>GGYY<l>YAASVKG, wherein <1> is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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 paragraph 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, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (3) YYCA211111111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (4) YYCAR111S2S3111 YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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) YYCA2111CSG1 ICY 1 YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (6) YYCA211S1T1FG11111YFDYWG, wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, Η, I, K, L, Μ, 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, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; 2 is an equimolar mixture of D and G; 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, Η, I, K, F, Μ, 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 paragraph 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, Η, I, K, F, Μ, N, P, Q, R, S, T, V, and W. 28. The population of variegated DNA sequences according to paragraph 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 paragraph 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) R AS Q< 1 > V <2x2x3 >FA (2) R AS Q< 1 > V <2><2><2x3 >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 paragraph 30, wherein CDR1 s (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<3xlxlxl>P<l>T, wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <3> is 0.2 Y and 0.044 each of ADEFGHIKLMNPQRTVW ; (2) QQ3311 IP, 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 variegated DNA sequences characterized by any of the above DNA sequences. 34. The population of variegated DNA sequences according to paragraph 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) T G< 1 >S S <2> V G< 1x3 ><2><3 > V S, 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 variegated DNA sequences characterized by any of the above DNA sequences. 36. The population of variegated DNA sequences according to paragraph 35, where CDRls (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 acid residues ADEFGHIKLMNPQRSTVW. 38. A population of variegated mixture of amino DNA sequences that encode a lambda light chain CDR3 selected from the group consisting of: (1) <4><5><4><2><4>S<4><4><4x4>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<lx5>S<5xlx4>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 paragraph 38, wherein CDR3s (1) and (2) are present in the population in an equimolar mixture. 40. The population of variegated DNA sequences according to paragraph 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 paragraph 24 or 25; (2) one or more of the heavy chain CDR3s defined in paragraphs 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 paragraph 24 further comprising variegated DNA sequences that encodes one or more heavy chain CDR3s selected from the group defined in paragraphs 26, 27, 28 or 29. 42. The population of variegated DNA sequences according to paragraph 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 CDR Is defined in paragraph 30 or 31; (2) the kappa light chain CDR2 defined in paragraph 32; (3) one or more of the kappa light chain CDR3s defined in paragraph 33 or 34; (4) one or more of the kappa light chain CDRls defined in paragraph 35 or 36; (5) the lambda light chain CDR2 defined in paragraph 37; (6) one or more of the lambda light chain CDR3s defined in paragraph 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 paragraphs 22-42. A definition of the specific embodiment of the invention claimed herein follows.

In a broad format, the invention provides a focused library of vectors or genetic packages, each of which 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 comprising a synthetic heavy chain CDR1, CDR2 and CDR3, wherein the sequence encoding the heavy chain comprises the components V::nz::D::ny::JHn, wherein V is a v gene, nz is a series of bases that are essentially random, D is a D segment, ny is a series of bases that are essentially random, and JHn is one of the six JH segments.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Antibodies ("Ab") concentrate their diversity into those regions that are involved in determining affinity and specificity of the Ab for particular targets. These regions may be diverse in sequence or in length. Generally, they are diverse in both ways. However, within families of human antibodies the diversities, both in sequence and in length, are not truly random. Rather, some amino acid residues are preferred at certain positions of the CDRs and some CDR lengths are preferred. These preferred diversities account for the natural diversity of the antibody family.

According to this invention, and as more fully described below, libraries of vectors and genetic packages that more closely mirror the natural diversity, both in sequence and in length, of antibody families, or portions thereof are prepared and used.

Human Antibody Heavy Chain Sequence and Length Diversity (a) Framework

The heavy chain ("HC") Germ-Line Gene (GLG) 3-23 (also known as VP-47) accounts for about 12% of all human Abs and is preferred as the framework in the preferred embodiment of the invention. It should, however, be understood that other well-known frameworks, such as 4-34, 3-30, 3-30.3 and 4-30.1, may also be used without departing from the principles of the focused diversities of this invention.

In addition, JH4 (YFDYWGQGTLVTUSS) occurs more often than JH3 in native antibodies. Hence, it is preferred for the focused libraries of this invention. However, JH3 (AFDIWGQGTMVTVSS) could as well be used. (b) Focused Length Diversity: CDR1, 2 and 3 (i) CDR1

For CDR1, GLGs provide CDRls only of the lengths 5, 6, and 7. Mutations during the maturation of the V-domain gene, however, can lead to CDRls having lengths as short as 2 and as long as 16. Nevertheless, length 5 predominates. Accordingly, in the preferred embodiment of this invention, the preferred HC CDR1 is 5 amino acids, with less preferred CDRls having lengths of 7 and 14. In the most preferred libraries of this invention, all three lengths are used in proportions similar to those found in natural antibodies. (ii) CDR2 GLGs provide CDR2s only of the lengths 15-19, but mutations during maturation may result in CDR2s of lengths from 16 to 28 amino acids. The lengths 16 and 17 predominate in mature Ab genes. Accordingly, length 17 is the preferred length for HC CDR2 of the present invention. Less preferred HC CDR2s of this invention have lengths 16 and 19. In the most preferred focused libraries of this invention, all three lengths are included in proportions similar to those found in natural antibody families. (iii) CDR3 HC CDR3s vary in length. About half of human HCs consist of the components: V::nz::D::ny::JHn where V is a V gene, nz is a series of bases (mean 12) that are essentially random, D is a D segment, often with heavy editing at both ends, ny is a series of bases (mean 6) that are essentially random, and JH is one of the six JH segments, often with heavy editing at the 5' end. The D segments appear to provide spacer segments that allow folding of the IgG. The greatest diversity is at the junctions of V with D and of D with JH.

In the preferred libraries of this invention both types of HC CDR3s are used. In HC CDR3s that have no identifiable D segment, the structure is V::nz::JHn where JH is usually edited at the 5' end. In HC CDR3s that have an identifiable D segment, the structure is V::nz::D::ny::JHn. (c) Focused Sequence Diversity: CDR1, 2 and 3 (i) CDR1

In 5 amino acid length CDR1, examination of a 3D model of a humanized Ab showed that the side groups of residues 1,3, and 5 were directed toward the combining pocket. Consequently, in the focused libraries of this invention, each of these positions may be selected from any of the native amino acid residues, except cysteine ("C"). Cysteine can form disulfide bonds, which are an important component of the canonical Ig fold. Having free thiol groups could, thus, interfere with proper folding of the HC and could lead to problems in production or manipulation of selected Abs. Thus, in the focused libraries of this invention cysteine is excluded from positions 1, 3 and 5 of the preferred 5 amino acid CDRls. The other 19 natural amino acids residues may be used at positions 1, 3 and 5. Preferably, each is present in equimolar ratios in the variegated libraries of this invention. 3D modeling also suggests that the side groups of residue 2 in a 5 amino acid CDR1 are directed away from the combining pocket. Although this position shows substantial diversity, both in GLG and mature genes, in the focused libraries of this invention this residue is preferably Tyr (Y) because it occurs in 681/820 mature antibody genes. However, any of the other native amino acid residues, except Cys (C), could also be used at this position.

For position 4, there is also some diversity in GLG and mature antibody genes.

However, almost all mature genes have uncharged hydrophobic amino acid residues: A, G, L, P, F, M, W, I, V, at this position. Inspection of a 3D model also shows that the side group of residue 4 is packed into the innards of the HC. Thus, in the preferred embodiment of this invention which uses framework 3-23, residue 4 is preferably Met because it is likely to fit very well into the framework of 3-23. With other frameworks, a similar fit consideration is used to assign residue 4.

Thus, the most preferred HC CDR1 of this invention consists of the amino acid sequence <1>Y<1>M<1> where <1> can be any one of amino acid residues: A, D, E, F, G, H, I, K, L, Μ, N, P, Q, R, S, T, V, W, Y (not C), preferably present at each position in an equimolar amount. This diversity is shown in the context of a framework 3-23:JH4 in Table 1. It has a diversity of 6859-fold.

The two less preferred HC CDRls of this invention have length 7 and length 14. For length 7, a preferred variegation is (S/T)i(S/G/<1>)2(S/G/<1>)3Y4Y5W6(S/G/<1>)7; where (S/T) indicates an equimolar mixture of Ser and Thr codons; (S/G/<1>) indicates a mixture of 0.2025 S, 0.2025 G, and 0.035 for each of A, D, E, F, Η, I, K, L, Μ, N, P, Q, R, T, V, W, Y. This design gives a predominance of Ser and Gly at positions 2, 3, and 7, as occurs in mature HC genes. For length 14, a preferred variegation is VSGGSIS<lxlxl>YYW<l>, where <1> is an equimolar mixture of the 19 native amino acid residues, except Cys (C).

The DNA that encodes these preferred HC CDRls is preferably synthesized using trinucleotide building blocks so that each amino acid residue is present in essentially equimolar or other described amounts. The preferred codons for the <1> amino acid residues are get, gat, gag, ttt, ggt, cat, att, aag, ett, atg, aat, cct, cag, cgt, tet, act, gtt, tgg, and tat. Of course, other codons for the chosen amino acid residue could also be used.

The diversity oligonucleotide (ON) is preferably synthesized from BspEI to BstXI (as shown in Table 1) and can, therefore, be incorporated either by PCR synthesis using overlapping ONs or introduced by ligation of BspEI/BstXI-cut fragments. Table 2 shows the oligonucleotides that embody the specified variegations of the preferred length 5 HC CDRls of this invention. PCR using ON-RlVlvg, ON-Rltop, and ON-Rlbot gives a dsDNA product of 73 base pairs, cleavage with BspEI and BstXI trims 11 and 13 bases from the ends and provides cohesive ends that can be ligated to similarly cut vector having the 3-23 domain shown in Table 1. Replacement of ON-RlVlvg with either ONRlV2vg or ONRlV3vg (see Table 2) allows synthesis of the two alternative diversity patterns — the 7 residue length and the 14 residue length HC CDR1.

The more preferred libraries of this invention comprise the 3 preferred HC CDR1 length diversities. Most preferably, the 3 lengths should be incorporated in approximately the ratios in which they are observed in antibodies selected without reference to the length of the CDRs. For example, one sample of 1095 HC genes have the three lengths present in the ratio: L=5:L=7:L=14::820:175:23::0.80:0.17:0.02. This is the preferred ratio in accordance with this invention. (ii) CDR2

Diversity in HC CDR2 was designed with the same considerations as for HC CDR1: GLG sequences, mature sequences and 3D structure. A preferred length for CDR2 is 17, as shown in Table 1. For this preferred 17 length CDR2, the preferred variegation in accordance with the invention is: <2>I<2><3>SGG<1>T<1>YADSVKG, where <2> indicates any amino acid residue selected from the group of Y, R, W, V, G and S (equimolar mixture), <3> is P, S and G or P and S only (equimolar mixture), and <1> is any native amino acid residue except C (equimolar mixture). ON-R2Vlvg shown in Table 3 embodies this diversity pattern. It is preferably synthesized so that fragments of dsDNA containing the BstXI and Xbal site can be generated by PCR. PCR with ON-R2Vlvg, ON-R2top,and ONR2bot gives a dsDNA product of 122 base pairs. Cleavage with BstXI and Xbal removes about 10 bases from each end and produces cohesive ends that can be ligated to similarly cut vector that contains the 3-23 gene shown in Table 1.

In an alternative embodiment for a 17 length HC CDR2, the following variegation may be used: <l>I<4xlxl>G<5><l><l><l>YADSVKG, where <1> is as described above for the more preferred alternative of HC CDR2; <4> indicates an equimolar mixture of DINSWY, and <5> indicates an equimolar mixture of SGDN. This diversity pattern is embodied in ON-R2V2vg shown in Table 3. Preferably, the two embodiments are used in equimolar mixtures in the libraries of this invention.

Other preferred HC CDR2s have lengths 16 and 19. Length 16: < 1 >I<4><lxl>G<5< 1 >< 1 >YNPSLKG; Length 19: <l>I<8>S<lxlxl>GGYY<l>YAASVKG, wherein <1> is an equimolar mixture of all native amino acid residues except C; <4> is a equimolar mixture of DINSWY; <5> is an equimolar mixture of SGDN; and <8> is 0.27 R and 0.027 of each of residues ADEFGHIKLMNPQSTVWY. Table 3 shows ON-R2V3vg which embodies a preferred CDR2 variegation of length 16 and ON-R2V4vg which embodies a preferred CDR2 variegation of length 19. To prepare these variegations ON-R2V3vg may be PCR amplified with ON-R2top and ON-R2bo3 and ON-R2V4vg may be PCR amplified with ON-R2top and ON-R2-bo4. See Table 3. In the most preferred embodiment of this invention, all three HC CDR2 lengths are used. Preferably, they are present in a ratio 17:16:19::579:464:31::0.54:0.43:0.03. (iii) CDR3

The preferred libraries of this invention comprise several HC CDR3 components. Some of these will have only sequence diversity. Others will have sequence diversity with embedded D segments to extend the length, while also incorporating sequences known to allow Igs to fold. The HC CDR3 components of the preferred libraries of this invention and their diversities are depicted in Table 4: Components 1-8.

This set of components was chosen after studying the sequences of 1383 human HC sequences. The proposed components are meant to fulfill the following goals: 1) approximately the same distribution of lengths as seen in native Ab genes; 2) high level of sequence diversity at places having high diversity in native Ab genes; and 3) incorporation of constant sequences often seen in native Ab genes.

Component 1 represents all the genes having lengths 0 to 8 (counting from the YYCAR motif at the end of FR3 to the WG dipeptide motif near the start of the J region, i.e., FR4). Component 2 corresponds the all the genes having lengths 9 or 10. Component 3 corresponds to the genes having lengths 11 or 12 plus half the genes having length 13. Component 4 corresponds to those having length 14 plus half those having length 13. Component 5 corresponds to the genes having length 15 and half of those having length 16. Component 6 corresponds to genes of length 17 plus half of those with length 16. Component 7 corresponds to those with length 18. Component 8 corresponds to those having length 19 and greater. See Table 4.

For each HC CDR3 residue having the diversity <1>, equimolar ratios are preferably not used. Rather, the following ratios are used 0.095 [G and Y] and 0.048 [A, D, E, F, Η, I, K, L, Μ, N, P, Q, R, S, T, V, and W]. Thus, there is a double dose of G and Y with the other residues being in equimolar ratios. For the other diversities, e.g., KR or SG, the residues are present in equimolar mixtures.

In the preferred libraries of this invention the eight components are present in the following fractions: 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). See Table 4.

In the more preferred embodiment of this invention, the amounts of the eight components is adjusted because the first component is not complex enough to justify including it as 10% of the library. For example, if the final library were to have 1 x 109 members, then 1 x 108 sequences would come from component 1, but it has only 2.6 x 105 CDR3 sequences so that each one would occur in -385 CDR1/2 contexts. Therefore, the more preferred amounts of the eight components are 1(0.02), 2(0.14), 3(0.25), 4(0.14), 5(0.14), 6(0.12), 7(0.08), 8(0.11).

In accordance with the more preferred embodiment component 1 occurs in ~77 CDR1/2 contexts and the other, longer CDR3s occur more often.

Table 5 shows vgDNA that embodies each of the eight HC CDR3 components shown in Table 4. In Table 5, the oligonucleotides (ON) Ctop25, CtprmA, CBprmB, and CBot25 allow PCR amplification of each of the variegated ONs (vgDNA): Clt08, C2tl0, C3tl2, C4tl4, C5tl5, C6tl7, C7tl8, and C8tl9. After amplification, the dsDNA can be cleaved with AflTl and BstEII (or Kpnl) and ligated to similarly cleaved vector that contains the remainder of the 3-23 domain. Preferably, this vector already contains diversity in one, or both, of CDR1 and CDR2 as disclosed herein. Most preferably, it contains diversity in both the CDR1 and CDR2 regions. It is, of course, to be understood that the various diversities can be incorporated into the vector in any order.

Preferably, the recipient vector originally contains a stuffer in place of CDR1, CDR2 and CDR3 so that there will be no parental sequence that would then occur in the resulting library. Table 6 shows a version of the V3-23 gene segment with each CDR replaced by a short segment that contains both stop codons and restriction sites that will allow specific cleavage of any vector that does not have the stuffer removed. The stuffer can either be short and contain a restriction enzyme site that will not occur in the finished library, allowing removal of vectors that are not cleaved by both Aflll and BstEII (or Kpnl) and religated. Alternatively, the stuffer could be 200-400 bases long so that uncleaved or once cleaved vector can be readily separated from doubly cleaved vector.

Human Antibody Light Chain: Sequence and Length Diversity (i) Kappa Chain (a) Framework

In the preferred embodiment of this invention, the kappa light chain is built in an A27 framework with a JK1 region. These are the most common V and J regions in the native genes. Other frameworks, such as 012, L2, and All, and other J regions, such as JK4, however, may be used without departing from the scope of this invention. (b) CDR1

In native human kappa chains, CDRls with lengths of 11, 12, 13, 16, and 17 were observed with length 11 being predominant and length 12 being well represented. Thus, in the preferred embodiments of this invention LC CDRls of length 11 and 12 are used in an and mixture similar to that observed in native antibodies), length 11 being most preferred. Length 11 has the following sequence: RASQ<1>V<2><2><3>LA and Length 12 has the following sequence: RASQ<l>V<2x2x2x3>LA, wherein <1> is an equimolar mixture of all of the native amino acid residues, except C, <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY, and <3> is 0.2 Y and 0.044 each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, T, V, W and Y. In the most preferred embodiment of this invention, both CDR1 lengths are used. Preferably, they are present in a ratio of 11:12:: 154:73::0.68:0.32. (c) CDR2

In native kappa, CDR2 exhibits only length 7. This length is used in the preferred embodiments of this invention. It has the sequence <l>AS<2>R<4xl>, wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and O. 004 of each of ADEFGHIKLMNPQRTVWY; and <4> is 0.2 A and 0.044 of each of DEFGHIKLMNPQRS TUW Y. (d) CDR3

In native kappa, CDR3 exhibits lengths of 1, 4, 6, 7, 8, 9, 10, 11, 12, 13, and 19. While any of these lengths and mixtures of them can be employed in this invention, we prefer lengths 8, 9 and 10, length 9 being more preferred. For the preferred Length 9, the sequence is QQ<3xlxlxl>P<l>T, wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY and <3> is 0.2 Y and 0.044 each of ADEFGHIKLMNPQRSVW. Length 8 is preferably QQ33111P and Length 10 is preferably QQ3211PP1T, wherein 1 and 3 are as defined for Length 9 and 2 is S (0.2) and 0.044 each of ADEFGHIKLMNPQRTVWY. A mixture of all 3 lengths being most preferred (ratios as in native antibodies), i.e., 8:9:10::28:166:63::0.1:0.65:0.25.

Table 7 shows a kappa chain gene of this invention, including a PlacZ promoter, a ribosome-binding site, and signal sequence (Ml3 ΙΠ signal). The DNA sequence encodes the GLG amino acid sequence, but does not comprise the GLG DNA sequence. Restriction sites are designed to fall within each framework region so that diversity can be cloned into the CDRs. Xmal and EspI are in FR1, SexAI is in FR2, Rsrll is in FR3, and Kpnl (or Acc65I) are in FR4. Additional sites are provided in the constant kappa chain to facilitate construction of the gene.

Table 7 also shows a suitable scheme of variegation for kappa. In CDR1, the most preferred length 11 is depicted. However, most preferably both lengths 11 and 12 are used. Length 12 in CDR1 can be construed by introducing codon 51 as <2> (i.e. a Ser-biased mixture). CDR2 of kappa is always 7 codons. Table 7 shows a preferred variegation scheme for CDR2. Table 7 shows a variegation scheme for the most preferred CDR3 (length 9).

Similar variegations can be used for CDRs of length 8 and 10. In the preferred embodiment of this invention, those three lengths (8, 9 and 10) are included in the libraries of this invention in the native ratios, as described above.

Table 9 shows series of diversity oligonucleotides and primers that may be used to construct the kappa chain diversities depicted in Table 7. (ii) Lambda Chain (a) Framework

The lambda chain is preferably built in a 2a2 framework with an L2J region. These are the most common V and J regions in the native genes. Other frameworks, such as 31, 4b, la and 6a, and other J regions, such as L1J, L3J and L7J, however, may be used without departing from the scope of this invention. (b) CDR1

In native human lambda chains, CDRls with length 14 predominate, lengths 11, 12 and 13 also occur. While any of these can be used in this invention, lengths 11 and 14 are preferred. For length 11 the sequence is: TG<2><4>L<4><4><4><3><4><4> and for Length 14 the sequence is: 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; <3> is 0.36 Y and 0.0355 each of ADEFGHIKLMNPQRSTVW; and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY. Most preferably, mixtures (similar to those occurring in native antibodies) preferably, the ratio is 11:14::23:46::0.33: 0.67 of the three lengths are used. (c) CDR2

In native human lambda chains, CDR2s with length 7 are by far the most common. This length is preferred in this invention. The sequence of this Length 7 CDR2 is <4x4x4x2>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. (d) CDR3

In native human lambda chains, CDR3s of length 10 and 11 predominate, while length 9 is also common. Any of these three lengths can be used in the invention. Length 11 is preferred and mixtures of 10 and 11 more preferred. The sequence of Length 11 is <4><5><4><2><4>S<4x4x4x4>V, where <2> and <4> are as defined for the lambda CDR1 and <5> is 0.36 S and 0.0355 each of ADFFGHIKLMNPQRTVWY. The sequence of

Length 10 is <5>SY<l><5>S<5xl><4>V, wherein <1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and <4> and <5> are as defined for Length 11. The preferred mixtures of this invention comprise an equimolar mixture of Length 10 and Length 11. Table 8 shows a preferred focused lambda light chain diversity in accordance with this invention.

Table 9 shows a series of diversity oligonucleotides and primers that may be used to construct the lambda chain diversities depicted in Table 7.

Method of Construction of the Genetic Package

The diversities of heavy chain and the kappa and lambda light chains are best constructed in separate vectors. First a synthetic gene is designed to embody each of the synthetic variable domains. The light chains are bounded by restriction sites for ApaLI (positioned at the very end of the signal sequence) and AscI (positioned afer the stop codon). The heavy chain is bounded by Sfil (positioned within the PelB signal sequence) and Notl (positioned in the linker between CHI and the anchor protein). Signal sequences other than PelB may also need, e.g., a M13 pin signal sequence.

The initial genes are made with "stuffer" sequences in place of the desired CDRs. A "Stuffer" is a sequence that is to be cut away and replaced by diverse DNA but which does not allow expression of a functional antibody gene. For example, the stuffer may contain several stop codons and restriction sites that will not occur in the correct finished library vector. For example, in Table 10, the stuffer for CDR1 of kappa A27 contains a StuI site. The vgDNA for CDR1 is introduced as a cassette from EspI, Xmal, or Aflll to either SexAI or Kasl. After the ligation, the DNA is cleaved with StuI; there should be no StuI sites in the desired vectors.

The sequences of the heavy chain gene with stuffers is depicted in Table 6. The sequences of the kappa light chain gene with stuffers is depicted in Table 10. The sequence of the lambda light chain gene with stuffers is depicted in Table 11.

In another embodiment of the present intention the diversities of heavy chain and the kappa or lambda light chains are constructed in a single vector or genetic packages (e.g., for display or display and expression) having appropriate restriction sites that allow cloning of these chains. The processes to construct such vectors are well known and widely used in the art. Preferably, a heavy chain and Kappa light chain library and a heavy chain and lambda light chain library would be prepared separately. The two libraries, most preferably, will then be mixed in equimolar amounts to attain maximum diversity.

Most preferably, the display is had on the surface of a derivative of M13 phage. The most preferred vector contains all the genes of Ml3, an antibiotic resistance gene, and the display cassette. The preferred vector is provided with restriction sites that allow introduction and excision of members of the diverse family of genes, as cassettes. The preferred vector is stable against rearrangement under the growth conditions used to amplify phage.

In another embodiment of this invention, the diversity captured by the methods of the present invention may be displayed and/or expressed in a phagemid vector (e.g., pCESl) that displays and/or expresses the peptide, polypeptide or protein. Such vectors may also be used to store the diversity for subsequent display and/or expression using other vectors or phage.

In another embodiment of this invention, the diversity captured by the methods of the present invention may be displayed and/or expressed in a yeast vector.

The foregoing embodiments are illustrative only of the principles of the invention, and various modifications and changes will readily occur to those skilled in the art. The invention is capable of being practiced and carried out in various ways and in other embodiments. It is also to be understood that the terminology employed herein is for the purpose of description and should not be regarded as limiting.

The term “comprise” and variants of the term such as “comprises” or “comprising” are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.

Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge.

Table 1: 3-23:JH4 CDR1/2 diversity = 1.78 x 108 FRl(VP47/V3-23)--------------- 20 21 22 23 24 25 26 27 28 29 30

AMA EVQLLESG ctgtctgaac cc atg gcc gaa|gtt|caa|ttg|tta|gag|tct|ggt|

Scab...... Ncol. . . . Mfel --------------FR1-------------------------------------------- 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 GGLVQPGGSLRLSCA Iggc|ggt|ctt|gtt|cag|cct|ggt|ggt|tct|tta|cgt|ctt|tct|tgc|get|

Sites of variegation <1> <1> <1> <1> 6859-fold diversity ----FRl-------- ------------> |.....CDR1....................|---FR2------ 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ASGFTFS-Y-M-WVR |get|tcc|gga|ttc|act|ttc|tct| - |tac| - |atg| - |tgg|gtt|ege|

BspEI BsiWI BstXI.

Sites of variegation-><2> <2> <3> -------FR2-------------------------------->| . . . CDR2......... 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 QAPGKGLEWVS-I--|caa|get|cct|ggt|aaa|ggt|ttg|gag|tgg|gtt|tct| - |atc| - | - |

...BstXI <1> <1> 25992-fold diversity in CDR2 .....CDR2............................................I---FR3--- 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 SGG-T-YADSVKGRF |tct|ggt|ggc| - |act| - |tat|get|gac|tec|gtt|aaa|ggt|ege|ttc| --------FR3-------------------------------------------------- 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 TISRDNSKNTLYLQM |act|ate|tct|aga|gac|aac|tct|aag|aat|act|etc|tac|ttg|cag|atg|

Xbal ---FR3-----------------------------------------------------> |

106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 N S LRAEDTAVYY CAK |aac|age|tta|agg|get|gag|gac|acc|get|gtc|tac|tac|tgc|gcc|aaa|

Aflll .......CDR3.................| Replaced by the various components!

121 122 123 124 125 126 127 D Y E G T G Y |gac|tat|gaa|ggt|act|ggt|tat| |-----FR4---(JH4 )----------------------------------------- YFDYWGQGTLVTVSS |tat|ttc|gat|tat|tgg|ggt|caa|ggt|acc|ctg|gtc|acc|gtc|tct|agt|...

Kpnl BstEII <1> = Codons for ADEFGHIKLMNPQRSTVWY (equimolar mixture) <2> = Codons for YRWVGS (equimolar mixture) <3> = Codons for PS or PS and G (equimolar mixture)

Table 2: Oligonucleotides used to variegate CDR1 of human HC CDR1 - 5 residues (ON-RlVlvg): 5'- ct|tcc|gga|ttc|act|ttc|tct|<1>|tac|<1>|atg|<1>|tgg|gtt|cgc|caa|get|cct|gg-3' <1> = Codons of ADEFGHIKLMNPQRSTVWY 1:1 (ON-Rltop): 5'-cctactgtct|tcc|gga|ttc|act|ttc|tct-3' (ON-Rlbot)[RC]: 5'-tgg|gtt|cgc|caa|get|cct|ggttgctcactc-3' CDR1 - 7 residues (0N-RlV2vg): 5'- ct|tcc|gga|ttc|act|ttc|tct|<6>|<7>|<7>|tac|tac|tgg|<7>|tgg|gtt|cgc|caa|get| cct|gg-3' <6> = Codons for ST, 1:1 <7> = 0.2025(Codons for SG) + 0.035(Codons for ADEFHIKLMNPQRTVWY) CDR1 -14 residues (ON-RlV3vg): 5'- ct|tcc|gga|ttc|act|ttc|tct|ate|age|ggt|ggt|tct|ate|tcc|<1>|<1>|<1>|-tac|tac|tgg|<1>|tgg|gtt|cgc|caa|get|cct|gg-3' <1> = Codons for ADEFGHIKLMNPQRSTVWY 1:1

Table 3: Oligonucleotides used to variegate CDR2 of human HC CDR2 -17 residues (0N-R2Vlvg): 5'- ggt|ttg|gag|tgg|gtt|tct|<2>|ate|<2>|<3>|tet|ggt|ggc|<1> |act|<1>|tat|get|-gac|tec|gtt|aaa|gg-3' (0N-R2top): 5'- ct|tgg|gtt|ege|caa|get|cct|ggt|aaa|ggt|ttg|gag|tgg|gtt|tct-3' (0N-R2bot)[RC]: 5'- tat|get|gac|tee|gtt|aaa|ggt|ege|ttc|act|ate|tct|aga|ttcctgtcac-3' <1> = Codons for A, D, E, F, G, Η, I, K, L,Μ, N, P, Q, R, S, T, V, W and Y (equimolar mixture) <2> = Codons for Y,R,W,V,G and S (equimolar mixture) <3> = Codons for P and S (equimolar mixture) or P,S and G (equimolar mixture) (ON-R2V2vg): 5'-ggt|ttg|gag|tgg|gtt|tct|<1>|ate|<4>|<1>|<1>|ggt| <5>|<1>|<1>|<1>|tat|get|-gac|tee|gtt|aaa|gg-3' <4> = Codons for DINSWY (equimolar mixture) <5> = Codons for SGDN, (equimolar mixture) CDR2 -16 residues (ON-R2V3vg): 5'-ggt|ttg|gag|tgg|gtt|tct|<1>|ate|<4>|<1>|<1>|ggt| <5>|<1>|<1>|tat|aac|cct|tee|ett|aag|gg-3' (ON-R2bo3)[RC]: 5'- tat|aac|cct|tee|ett|aag|ggt|ege|ttc|act|ate|tct|aga|ttcctgtcac-3' CDR2 -19 residues (ON-R2V4vg): 5'-ggt|ttg|gag|tgg|gtt|tct|<1>|ate|<8>|agt|<1>|<1>| <1> |ggt|ggt|act|act|<1>|tat|gee|get|tee|gtt|aag|gg-3' (ON-R2bo4)[RC]: 5'- tat|gee|get|tee|gtt|aag|ggt|ege|ttc|act|ate|tct|aga|ttcctgtcac-3'

<1>, <2>, <3>, <4> and <5> are as defined above <8> is 0.27 R and 0.027 each of ADEFGHIKLMNPQSTVWY

Table 4: Preferred Components of HC CDR3

Preferred

Fraction of Adjusted

Component Length Complexity Library____ Fraction 1 YYCA21111YFDYWG. 8 2.6 X 10s .10 .02 {l=any amino acid residue, except C; 2 - K and R) 2 YYGA2111111YFDYWG. 10 9.4 x 107 .14 .14 (l=any amino acid residue, except C; 2 ~ K and R ) 3 YYCA211111111YFDYWG. 12 3.4 x 1010 .25 .25 {l=any amino acid residue, except C; 2 = K and R ) 4 YYCAR111S2S3111YFDYWG. 14 1.9 X 108 .13 .14 (l»any amino acid residue, except C; 2 - S and G 3 = Y and W) 5 YYCA2111CSG11CY1YFDYWG. 15 9.4 X 107 .13 .14 (l=any amino acid residue, except C; 2 = K and R ) 6 YYCA211S1TIPG11111YFDYWG. 17 1.7 x 1G10 .11 .12 (l=any amino acid residue, except C; 2 - K and R ) 7 YYCAR111YY2S33YY111YFDYWG. 18 3.8 x 10® .04 .08 (l=any amino acid residue, except C; 2 = D or G; 3 = S and G) 8 YYCAR1111YC2231CY111YFDYWG. 19 2.0.x 10“ .10 .11 (l=any amino acid residue, except C; 2 « S and Gr 3 - T, D and G)

Table 5: Oligonucleotides used to variegate the eight components of HC CDR3 (Ctop25): 5'-gctctggtcaac|tta|agg|get|gag|g-3' (CtprmA): 5'-gctctggtcaac|tta|agg|get|gag|gac|acc|get|gtc|tac|tac|tgc|gcc-3'

Aflll... (CBprmB)[RC]: 5'—|tac|ttc|gat|tac|tgg|ggc|caa|ggt|acc|ctg|gtc|acc|tcgctccacc-3 '

BstEII. . . (CBot25)[RC]: 5'-|ggt|acc|ctg|gtc|acc|tcgctccacc-3'

The 20 bases at 3' end of CtprmA are identical to the most 5' 20 bases of each of the vgDNA molecules.

Ctop25 is identical to the most 5' 25 bases of CtprmA.

The 23 most 3' bases of CBprmB are the reverse complement of the most 3' 23 bases of each of the vgDNA molecules. CBot25 is identical to the 25 bases at the 5' end of CBprmB.

Component 1 (Clt08): 5'- cc|get|gtc|tac|tac|tgc|gcc|<2>|<1>|<1>|<1>|<1>|tac|ttc|gat|tac|tgg|ggc|caa|gg -3 ' <1> = 0.095 Y + 0.095 G + 0.048 each of the residues ADEFHIKLMNPQRSTVW, no C; <2> = K and R (equimolar mixture)

Component 2 (C2110) : 5'- cc|get|gtc|tac|tac|tgc|gcc|<2>|<1>|<1>|<1>|<1>|<1>|<1>|tac|ttc|gat|tac|tgg|gg c|caa|gg-3' <1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = K and R (equimolar mixture)

Component 3 (C3tl2) : 5'- cc|get|gtc|tac|tac|tgc|gccI<2>|<1>|<1>|<1>I<1>I<1>I<1>I<1>|<1>|tac|ttc|gat|ta c|-tgg|ggc|caa|gg-3' <1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = K and

R (equimolar mixture)

Component 4 (C4tl4 0) : 5'-cc|get|gtc|tac|tac|tgc|gcc|cgt|<1>|<1>|<1>|tet|<2>|tet|<3>|<1>|<1>|<1>

Itac|ttc|gat|-tac|tgg|ggc|caa|gg-3' <1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = S and G (equimolar mixture); <3> = Y and W (equimolar mixture)

Component 5 (C5tl5) : 5'-cc|gct|gtc|tac|tac|tgc|gcc|<2>|<l>|<l>|<l>|tgc|tct|ggt|<1>|<1>|tgc|tat|<1> |tac|-ttc|gat|tac|tgg|ggc|caa|gg-3'

<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = K and R (equimolar mixture)

Component 6 (C6tl7) : 5'- cc|gct|gtc|tac|tac|tgc|gcc|<2>|<l>|<l>|tct|<l>|act|atc|ttc|ggt|<1>|<1>|<1>|<1 >| -<1> |tac|ttc|gat|tac|tgg|ggc|caa|gg-3'

<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = K and R (equimolar mixture)

Component 7 (C7tl8) : 5'- cc|get|gtc|tac|tac|tgc|gcc|cgt|<1>|<1>|<1>|tat|tac|<2>|tet|<3>|<3>|tac|tat|-<1>|<1>|<1> |tac|ttc|gat|tac|tgg|ggc|caa|gg-3'

<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = D and G (equimolar mixture); <3> = S and G (equimolar mixture)

Component 8 (c8tl9) : 5 ' -cc | get|gtc|tac|tac|tgc|gcc|cgt|<1>|<1>|<1>|<1>|tat|tgc|<2>|<2>|<3>|<1> |tgc|tat|-<1>|<1>|<1>|tac|ttc|gat|tac|tgg|ggc|caa|gg-3'

<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; <2> = S and G (equimolar mixture); <3> = TDG (equimolar mixture);

Table 6: 3-23::JH4 Stuffers in place of CDRs FRl(DP47/V3-23)--------------- 20 21 22 23 24 25 26 27 28 29 30

AMA EVQLLESG ctgtctgaac cc atg gcc gaa|gtt|caa|ttg|tta|gag|tct|ggt|

Scab...... Ncol. . . . Mfel --------------FR1-------------------------------------------- 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 GGLVQPGGSLRLSCA |ggc|ggt|ctt|gtt|cag|cct|ggt|ggt|tct|tta|cgt|ctt|tct|tgc|get| ----FRl--------------------> | . . . CDR1 stuf f er . . . . |---FR2------ 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ASGFTFSSYA | |WVR |get|tcc|gga|ttc|act|ttc|tct|teg|tac|get|tag|taa|tgg|gtt|ege|

BspEI BsiWI BstXI. -------FR2-------------------------------->| . . . CDR2 stuffer. 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 QAPGKGLEWVS | pr | |caa|get|cct|ggt|aaa|ggt|ttg|gag|tgg|gtt|tct|taa|cct|agg|tag| ...BstXI AvrII.. .....CDR2 stuffer....................................|---FR3--- 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 TISRDNSKNTLYLQM |act|ate|tct|aga|gac|aac|tct|aag|aat|act|etc|tac|ttg|cag|atg|

Xbal ---FR3-----------..> CDR3 Stuffer------------->|

106 107 108 109 110 N S L R A |aac|age|tta|agg|get|tag taa agg cct taa Aflll StuI... |-----FR4---(JH4 )----------------------------------------- YFDYWGQGTLVTVS S |tat|ttc|gat|tat|tgg|ggt|caa|ggt|acc|ctg|gtc|acc|gtc|tct|agt|...

Kpnl BstEII

Table 7: A27:JH1 Human Kappa light chain gene gaggacc attgggcccc ctccgagact ctcgagcgca

Scab...... EcoO109I Xhol..

Apal. acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc ..-35.. Plac ..-10. cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg accatgatta cgccaagctt tggagccttt tttttggaga ttttcaac

PflMI.......

Hind III M13 III signal sequence (AA seq)---------------------------> 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 MKKLLFAI PLVVPFY gtg aag aag etc eta ttt get ate ccg ett gtc gtt ccg ttt tac

Si gn a 1 > FR1-------------------------------------------> 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 SHSAQSVLTQSPGTL I age|cat|agt|gca|caa|tee|gtc|ett|act|caa|tet|cct|ggc|act|ett|

ApaLI... -----FR1------------------------------------->| CDR1------> 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 SLSPGERATLSCRAS |teg|eta|age|ccg|ggt|gaa|cgt|get|ace|tta|agt|tgc|cgt|get|tee|

EspI..... Aflll. . .

Xmal....

For CDR1: <1> ADEFGHIKLMNPQRSTVWY 1:1 <2> S ( 0.2) ADEFGHIKLMNPQRTVWY (0.044 each) <3> Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each) (CDR1 installed as AflII-(SexAI or KasI) cassette.) For the most preferred 11 length codon 51 (XXX) is omitted; for the preferred 12 length this codon is <2> -------CDR1--------------------->|---FR2---------------> <1> <2> <2> xxx <3> 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Q-V----LAWYQQKP Icag| - |gttI - I - I - | - |ctt|get|tgg|tat|caa|cag|aaa|cct|

SexAI...

For CDR2: <1> ADEFGHIKLMNPQRSTVWY 1:1 <2> S ( 0.2) ADEFGHIKLMNPQRTVWY (0.044 each) <4> A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each) CDR2 installed as (SexAI or KasI) to (BamHI or RsrII) cassette.) -----FR2 ------------------------->|-------CDR2----------> <1> <2> <4> 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 GQAPRLLIY-AS-R-Iggt|cag|geg|ccg|cgt|tta|ctt|att|tat| - |get|tet| - |ege| - | SexAI.... KasI.... CDR2 — >|---FR3-----------------------------------------------> <1> 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 -GIPDRFSGSGSGTD | - |ggg|ate|ccg|gac|cgt|ttc|tet|ggc|tet|ggt|tea|ggt|act|gac| BamHI...

RsrII..... ------FR3-------------------------------------------------> 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 FTLTI SRLEPEDFAV |ttt|acc|ctt|act|att|tet|aga|ttg|gaa|cct|gaa|gac|ttc|get|gtt|

Xbal...

For CDR3 (Length 9): <1> ADEFGHIKLMNPQRSTVWY 1:1 <3> Y(0.2) ADEFGHIKLMNPQRTVW (0.044 each)

For CDR3 (Length 8): QQ33111P 1 and 3 as defined for Length 9

For CDR3 (Length 10): QQ3211PP1T 1 and 3 as defined for Length 9

2 S ( 0.2) and 0.044 each of ADEFGHIKLMNPQRTVWY CDR3 installed as Xbal to (Styl or BsiWI) cassette. ----------->|----CDR3-------------------------->|-----FR4---> <3> <1> <1> <1> <1> 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 YYCQQ----P-TFGQ |tat|tat|tgc|caa|cag| - | - | - | - |cct| - |act|ttc|ggt|caa| BstXI........... -----I?R4------------------->| <-------Ckappa------------ 121 122 123 124 125 126 127 128 129 130 131 132 133 134

GTKVEIK RTVAAPS |ggt|acc|aag|gtt|gaa|ate|aag| |cgt|aeg|gtt|gcc|get|cct|agt|

Styl.... BsiWI.. 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 VFIFPPSDEQLKSGT |gtg|ttt|ate|ttt|cct|cct|tet|gac|gaa|caa|ttg|aag|tea|ggt|act|

Mf el... 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 ASVVCLLNNFYPREA |get|tet|gtc|gta|tgt|ttg|etc|aac|aat|ttc|tac|cct|cgt|gaa|get|

BssSI. . . 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 KVQWKVDNALQSGNS |aaa|gtt|cag|tgg|aaa|gtc|gat|aac|geg|ttg|cag|teg|ggt|aac|agt|

Mlul.... 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 QESVTEQDSKDSTYS |caa|gaa|tee|gtc|act|gaa|cag|gat|agt|aag|gac|tet|acc|tac|tet| 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 LS STLTLSKADYEKH |ttg|tee|tet|act|ett|act|tta|tea|aag|get|gat|tat|gag|aag|cat| 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 KVYACEVTHQGLS S P Iaag|gtc|tat|GCt|TGC|gaa|gtt|acc|cac|cag|ggt|ctg|age|tee|cct|

SacI.... 225 226 227 228 229 230 231 232 233 234 VTKSFNRGEC . . |gtt|acc|aaa|agt|ttc|aac|cgt|ggt|gaa|tgc|taa|tag ggcgcgcc

Dsal.... AscI....

BssHII acgcatctctaa gcggccgc aacaggaggag Notl....

Table 8: 2a2:JH2 Human lambda-chain gene gaggaccatt gggcccc ttactccgtgac

Scab...... EcoO109I

Apal.. -----------FR1--------------------------------------------> 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 SAQSALTQPASVSGSPG agt|gca|caa|tcc|get|etc|act|cag|cct|get|age|gtt|tee|ggg|tea|cct|ggt| ApaLI... Nhel... BstEII...

SexAI....

For CDR1 (length 14):

<1> = 0.27 T, 0.27 G, 0.027 each of ADEFHIKLMNPQRSVWY, no C <2> = 0.27 D, 0.27 N, 0.027 each of AEFGHIKLMPQRSTVWY, no C <3> = 0.36 Y, 0.0355 each of ADEFGHIKLMNPQRSTVW, no C

T G <1> S S <2> V G ------FR1------------------> |-----CDR1--------------------- 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 QSITISCTG-SS-VG |caa|agt|ate|act|att|tet|tgt|aca|ggt| - |tet|tet| - |gtt|ggc|

BsrGI.. <1> <3> <2> <3> V S = vg Scheme #1, length = 14 -----CDR1-------------> |--------FR2------------------------- 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 ----VSWYQQHPGKA I - I - I - I - |gtt|tet|tgg|tat|caa|caa|cac|ccg|ggc|aag|geg|

Xmal.... KasI.....

Aval.... A second Vg scheme for CDR1 gives segments of length 11: T22G<2><4>L<4><4><4><3><4><4> where <4> = equimolar mixture of each of ADEFGHIKLMNPQRSTVWY, no C <3> = as defined above for the alternative CDR1

For CDR2: <2> and <4> are the same variegation as for CDR1

<4> <4> <4> <2> R P S — FR2-----------------> |------CDR2--------------->|-----FR3- 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

PKLMIY----RPSGV

IccgIaagIttgIatgI ate ItacI - I - I - I - |cgt|cct|tet|ggt|gtt|

KasI.... -------FR3---------------------------------------------------- 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 SNRFSGSKSGNTASL |age|aat|cgt|ttc|tee|gga|tet|aaa|tee|ggt|aat|ace|gca|age|tta| BspEI.. Hindlll.

BsaBI........(blunt) -------FR3--------------------------------------------------> | 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 T I SGLQAEDEADYYC |act|ate|tet|ggt|ctg|cag|get|gaa|gac|gag|get|gac|tac|tat|tgt| PstI. . . CDR3 (Length 11) :

<2> and <4> are the same variegation as for CDR1 <5> = 0.36 S, 0.0355 each of ADEFGHIKLMNPQRTVWY no C

CDR3 (Length 10): <5> SY <1> <5> S <5> <1> <4> V <1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY, no C <4> and <5> are as defined for Length 11

<4> <5> <4> <2> <4> S <4> <4> <4> <4> V -----CDR3----------------------------------> |---FR4--------- 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105

-----S--- - VFGGG | | | | - I - |tet| - I - I - I - |gtc|ttc|ggc|ggt|ggt|

Kpnl... -------FR4--------------> 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 TKLTVLGQPKAAPSV |ace|aaa|ett|act|gtc|etc|ggt|caa|cct|aag|get|get|cct|tee|gtt| Kpnl... HincII..

Bsu36I... 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 TLFPPSSEELQANKA |act|etc|ttc|cct|cct|agt|tet|gaa|gag|ett|caa|get|aac|aag|get|

SapI..... 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 TLVCLI SDFYPGAVT |act|ctt|gtt|tgc|ttg|ate|agt|gac|ttt|tat|cct|ggt|get|gtt|act|

Bell.... 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 VAWKADS S PVKAGVE |gtc|get|tgg|aaa|gee|gat|tet|tet|cct|gtt|aaa|get|ggt|gtt|gag|

BsmBI... 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 TTTPSKQSNNKYAAS |aeg|acc|act|cct|tet|aaa|caa|tet|aac|aat|aag|tac|get|geg|age| BsmBI.... SacI.... 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 SYLSLTPEQWKSHKS |tet|tat|ctt|tet|etc|acc|cct|gaa|caa|tgg|aag|tet|cat|aaa|tee|

SacI... 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 YSCQVTHEGSTVEKT |tat|tee|tgt|caa|gtt|act|cat|gaa|ggt|tet|acc|gtt|gaa|aag|act|

BspHI... 211 212 213 214 215 216 217 218 219 V A P T E C S . |gtt|gee|cct|act|gag|tgt|tet|tag|tga|ggcgcgcc

Ascl....

BssHII aacgatgttc aag gcggccgc aacaggaggag Notl.... Scab.......

Table 9: Oligonucleotides For Kappa and Lambda Light Chain Variegation (Ctop25): 5'-gctctggtcaac|tta|agg|get|gag|g-3' (CtprmA): 5'-gctctggtcaac|tta|agg|get|gag|gac|acc|get|gtc|tac|tac|tgc|gee-3'

AfIII... (CBprmB)[RC]: 5'-|tac|ttc|gat|tac|ttg|ggc|caa|ggt|acc|ctg|gtc|acc|tcgctccacc-3 '

BstEII... (CBot25) [RC] : 5 '-|ggt|acc|ctg|gtc|acc|tcgctccacc-3'

Kappa chains: CDR1 ("1"), CDR2 ("2"), CDR3 ("3") CDR1 (KalTop610): 5'- ggtctcagttg|eta|age|ccg|ggt|gaa|cgt|get|acc|tta|agt|tgc|cgt|get|tee|cag-3' (KalSTp615): 5'-ggtctcagttg|eta|age|ccg|ggt|g-3' (KalBot62 0) [RC] : 5 ' - ett|get|tgg|tat|caa|cag|aaa|cct|ggt|cag|geg|ccaagtcgtgtc-3' (KalSB625) [RC]: 5'-cct|ggt|cag|geg|ccaagtcgtgtc-3' (Kalvg600): 5'-get|acc|tta|agt|tgc|cgt|get|tee|cag- I<1>|gtt|<2>|<2>|<3>|ett|get|tgg|tat|caa|cag|aaa|cc-3' (Kalvg600-12): 5'-get|acc|tta|agt|tgc|cgt|get|tee|cag- I<1>|gtt|<2>|<2>|<2>|<3>|ett|get|tgg|tat|caa|cag|aaa|cc-3' CDR2 (Ka2Tshort657): 5'-cacgagtccta|cct|ggt|cag|gc-3' (Ka2Tlong655): 5'-cacgagtccta|cct|ggt|cag|geg|ccg|cgt|tta|ett|att|tat-3' (Ka2Bshort660):[RC]: 5'-|gac|cgt|ttc|tet|ggt|tctcacc-3' (Ka2vg65 0) : 5'-cag|geg|ccg|cgt|tta|ett|att|tat|<1>|get|tet|<2 >| — |ege|<4>|<1>|ggg|ate|ccg|gac|cgt|ttc|tet|ggt|tctcacc-3' CDR3 (Ka3Tlon672): 5'- gacgagtccttct|aga|ttg|gaa|cct|gaa|gac|ttc|get|gtt|tat|tat|tgc|caa|c-3' (Ka3BotL682) [RC]: 5'- act|ttc|ggt|caa|ggt|acc|aag|gtt|gaa|ate|aag|cgt|aeg|tcacaggtgag-3' (Ka3Bsho694) [RC]: 5'-gaa|ate|aag|cgt|aeg|tcacaggtgag-3' (Ka3vg670): 5'-gac|ttc|get|gtt|- I tat|tat|tgc|caa|cag|<3>|<1>|<1>|<1>|cct|<1>|act|ttc|ggt|caa|-|ggt|acc|aag|gtt|g-3' (Ka3vg670-8): 5'-gac|ttc|get|gtt|- |tat|tat|tgc|caa|cag|<3>|<3>|<1>|<1>|<1>|cct|ttc|ggt|caa|-|ggt|acc|aag|gtt|g-3' (Ka3vg670-10): 5'-gac|ttc|get|gtt|tat|- |tat|tgc|caa|cag|<3>|<2>|<1>|<1>|cct|cct|<1>|act|ttc|ggt|caa|-|ggt|acc|aag|gtt|g-3'

Lambda Chains: CDR1 ("1"), CDR2 ("2"), CDR3 ("3") CDR1 (LmlTPri75): 5'-gacgagtcctgg|tea|cct|ggt|-3' (Lmltlo715): 5'-gacgagtcctgg|tea|cct|ggt|caa|agt|ate|act|att|tet|tgt|aca|ggt-3 ' (Lmlblo724) [re]: 5'- gtt|tet|tgg|tat|caa|caa|cac|ccg|ggc|aag|geg|agatcttcacaggtgag-3' (Lmlbsh737) [re]: 5'-gc|aag|geg|agatcttcacaggtgag-3' (Lmlvg710b):5'-gt|ate|act|att|tet|tgt|aca|ggt|<2>|<4>|etc|<4>|<4>|<4>|- I<3>|<4>|<4>|tgg|tat|caa|caa|cac|cc-3' (Lmlvg710): 5'-gt|ate|act|att|tet|tgt|aca|ggt|<1>|tet|tet|<2>|gtt|ggc|-|<1>|<3>|<2>|<3>|gtt|tet|tgg|tat|caa|caa|cac|cc-3' CDR2 (Lm2TSh757): 5'-gageagaggae|ccg|ggc|aag|gc-3' (Lm2TLo753): 5'-gageagaggae|ccg|ggc|aag|geg|ccg|aag|ttg|atg|ate|tac|-3' (Lm2BLo762) [RC]: 5'-cgt|cct|tet|ggt|gtc|age|aat|cgt|ttc|tee|gga|tcacaggtgag-3 ' (Lm2BSh765) [RC]: 5'-cgt|ttc|tee|gga|tcacaggtgag-3' (Lm2vg750): 5'-g|ccg|aag|ttg|atg|ate|tac|- <4>|<4>|<4>|<2>|cgt|cct|tet|ggt|gtc|age|aat|c-3' CDR3 (Lm3TSh822): 5'-ctg|cag|get|gaa|gac|gag|get|gac-3' (Lm3TLo819) : 5'-ctg|cag|get|gaa|gac|gag|get|gac|tac|tat|tgt|— 3' (Lm3BLo825) [RC]: 5'- gtc|ttc|ggc|ggt|ggt|acc|aaa|ett|act|gtc|etc|ggt|caa|cct|aag|g- acacaggtgag-3' (Lm3BSh832) [RC]: 5'-c|ggt|caa|cct|aag|gacacaggtgag-3' (Lm3vg817): 5'—gac|gag|get|gac|tac|tat|tgt|— |<4>|<5>|<4>|<2>|<4>|tet|<4>|<4>|<4>|<4>|—

Gtc|ttc|ggc|ggt|ggt|acc|aaa|ett|ac-3' (Lm3vg817-10): 5'- gac|gag|get|gac|tac|tat|tgt|- |<5>|age|tat|<1>|<5>|tet|<5>|<1>|<4>|gtc|ttc|ggc|ggt|ggt|-|ace|aaa|ett|ac-3'

Table 10: A27:JH1 Kappa light chain gene with stuffers in place of CDRs

Each stuffer contains at least one stop codon and a restriction site that will be unique within the diversity vector. gaggacc attgggcccc ctccgagact ctcgagcgca

Scab.....EcoO109I

Apal.

Xhol.. acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc . . -35. . Plac . .-10. cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatgac catgatta cgccaagctt tggagccttt tttttggaga ttttcaac

PflMI.......

Hind3. M13 III signal sequence (AA seq)---------------------------> 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 MKKLLFAI PLVVPFY gtg aag aag etc eta ttt get ate ccg ett gtc gtt ccg ttt tac — Signal — > FR1-------------------------------------------> 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 SHSAQSVLTQSPGTL |age|cat|agt|gca|caa|tcc|gtc|ett|act|caa|tet|cct|ggc|act|ett|

ApaLI... -----FR1--------------------------------->|-------Stuf f er-> 31 32 33 34 35 36 37 38 39 40 41 42 43 SLSPGERATLS | | |teg|eta|age|ccg|ggt|gaa|cgt|get|ace|tta|agt|tag|taa|get|ccc|

EspI..... Aflll. . .

Xmal.... - Stuffer for CDR1 — > FR2-------FR2------>|-----------Stuffer for CDR2 59 60 61 62 63 64 65 66

K P G Q A P R |agg|cct|ett|tga|tet|g|aaa|cct|ggt|cag|geg|ccg|cgt|taa|tga|aagcgctaatggccaaca gtg

StuI... SexAI... KasI.... Afel..

Ms cl. .

Stuffer-->|---FR3-----------------------------------------------> 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 TGIPDRFSGSGSGTD |act|ggg|ate|ccg|gac|cgt|ttc|tet|ggc|tet|ggt|tea|ggt|act|gac|

BamHI...

RsrII..... ------FR3----->----------------STUFFER for CDR3------------------> 91 92 93 94 95 96 97 F T L T I S R | | |ttt|ace|ett|act|att|tet|aga|taa|tga| gttaac tag ace taegta ace tag

Xbal... Hpal.. SnaBI. -----------------CDR3 stuffer------------------>|-----FR4---> 118 119 120 F G Q | ttc|ggt|caa| -----FR4------------------->| <-------Ckappa------------ 121 122 123 124 125 126 127 128 129 130 131 132 133 134

GTKVEIK RTVAAPS |ggt|ace|aag|gtt|gaa|ate|aag| |cgt|aeg|gtt|gee|get|cct|agt|

Styl.... BsiWI.. 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 VFIFPPSDEQLKSGT |gtg|ttt|ate|ttt|cct|cct|tet|gac|gaa|caa|ttg|aag|tea|ggt|act|

Mfel. . . acgcatctctaa gcggccgc aacaggaggag Notl....

EagI..

Table 11: 2a2:JH2 Human lambda-chain gene with stuffers in place of CDRs gaggaccatt gggcccc ttactccgtgac

Scab...... EcoO109I

Apal.. -----------FR1--------------------------------------------> 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 SAQSALTQPASVSGSPG agt|gca|caa|tcc|get|etc|act|cag|cct|get|age|gtt|tcc|ggg|tea|cct|ggt| ApaLI... Nhel... BstEII...

SexAI.... ------FR1------------------> |-----stuffer for CDR1--------- 16 17 18 19 20 21 22 23 QSITISCT |caa|agt|ate|act|att|tet|tgt|aca|tet tag tga etc

BsrGI.. -----Stuf fer--------------------------->-------FR2----------> 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

RS| | P | HPGKA aga tet taa tga ccg tag cac|ccg|ggc|aag|geg|

Bglll Xmal.... KasI.....

Aval.... -- |-------------Stuf fer for CDR2 ------------------------------------->

P |ccg|taa|tga|ate teg tac g ct|ggt|gtt|

KasI.... BsiWI. . . -------FR3---------------------------------------------------- 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 SNRFSGSKSGNTASL |age|aat|cgt|ttc|tcc|gga|tet|aaa|tcc|ggt|aat|acc|gca|age|tta|

BspEI.. Hindlll.

BsaBI........(blunt) -------FR3-------------> |--Stuf fer for CDR3----------------->| 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90

T I S G L Q |act|ate|tet|ggt|ctg|cag|gtt ctg tag ttc caattg ett tag tga ccc PstI... Mfel.. -----Stuffer------------------------------->|---FR4--------- 103 104 105 G G G |ggc|ggt|ggt|

Kpnl... -------FR4--------------> 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 TKLTVLGQPKAAPSV |acc|aaa|ctt|act|gtc|etc|ggt|caa|cct|aag|get|get|cct|tee|gtt| Kpnl... HincII..

Bsu36I... 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 TLFPPSSEELQANKA |act|etc|ttc|cct|cct|agt|tet|gaa|gag|ctt|caa|get|aac|aag|get|

SapI..... 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 TLVCLI SDFYPGAVT |act|ctt|gtt|tgc|ttg|ate|agt|gac|ttt|tat|cct|ggt|get|gtt|act| Bell....

Claims (22)

1. An antibody library comprising a first set of variegated DNA molecules encoding a first collection of antibody light chains (LC), wherein each light chain comprises an LC CDR1 region, an LC CDR2 region and an LC CDR3 region, and wherein: (a) the first collection of antibody light chains are kappa light chains, which comprise a plurality of LCK CDR3 regions selected from the group consisting of: (1) QQ<3>< 1 x 1 x 1 >P< 1 >T (SEQ ID NO: 16), wherein <1> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y, and <3> is 0.2 Y and 0.044 each of A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, T, V and W; (2) QQ<3x3xlxlxl>P (SEQ ID NO: 103), wherein <1> and <3> are as defined in (1) above; (3) QQ<3x2x 1 x 1 >PP< 1 >T (SEQ ID NO: 17), wherein <1> and <3> are as defined in (1) above and <2> is 0.2 S and 0.044 each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, T, V, W and Y; and (4) a mixture of any one of (1) to (3) as set forth above; or (b) the first collection of antibody light chains are lambda light chains, which comprise a plurality of LCx CDR3 regions selected from the group consisting of: (1) <4><5><4><2><4>S<4x4><4><4>V (SEQ ID NO: 106), wherein <2> is 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V and W, and <5> is 0.36 S and 0.0355 each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, T, V, W and Y; (2) <5>SY<lx5>S<5xl><4>V (SEQ ID NO:19), wherein <1> is an equimolar mixture of A, D, E, F, G, Η, I, K, L, Μ, 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) as set forth above.

2. The library of claim 1, wherein the first collection of antibody light chains are kappa light chains, which further comprise: (A) a plurality of LCK CDR1 regions selected from the group consisting of: (1) RASQ<l>V<2x2x3>LA (SEQ ID NO: 14), wherein <1> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y, <2> is 0.2 S and 0.044 of each of A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, T, V, W and Y, and <3> is 0.2Y and 0.044 each of A, D, E, F, G, Η, I, K, L, Μ, 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) as set forth above; (B) a plurality of LCK CDR2 regions comprising <1>AS<2>R<4><1> (SEQ ID NO: 102), wherein <1> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y, <2> is 0.2 S and 0.044 of each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, T, V, W and Y, and <4> is 0.2 A and 0.044 each of D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; or (C) both (A) and (B).

3. The library of claim 1 or claim 2, wherein the LCk CDR3s (1), (2) and (3) are present in the library in a ratio of 0.65:0.1:0.25.

4. The library of claim 2 or claim 3, wherein the LCK CDRls (1) and (2) are present in the library in a ratio of 0.68:0.32.

5. The library of any one of claims 2 to 4, 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 ΙΧλ 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 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V and W, and <5> is 0.36 S and 0.0355 each of A, D, E, F, G, Η, I, K, L, Μ, 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 an equimolar mixture of A, D, E, F, G, Η, I, K, L, Μ, 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) as set forth above.

6. The library of claim 5, wherein the second collection of antibody light chains further comprises: (A) a plurality of LC?. 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 0.27 T, 0.27 G and 0.027 each of A, D, E, F, Η, I, K, L, Μ, N, P, Q, R, S, V, W and Y, <2> is 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, and <3> is 0.36 Y and 0.036 each of A, D, E, F, G, Η, I, K, L, Μ, 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 0.36 Y and 0.0355 each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, S, T, V, W„ and <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and (3) a mixture of (1) and (2) as set forth above; (B) a plurality of LC>. CDR2 regions <4><4><4><2>RPS (SEQ ID NO: 105), wherein <2> is 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, and <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V and W; or (C) both (A) and (B).

7. The library of claim 6, wherein the ΕΟλ CDR3s (1) and (2) are present in the library in an equimolar mixture.

8. The library of claim 6 or claim 7, wherein the LO. CDRls (1) and (2) are present in the library in a ratio of 0.67:0.33.

9. The library of claim 1, wherein the first collection of antibody light chains are lambda chains, which comprise a plurality of LC>. 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 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V and W, and <5> is 0.36 S and 0.0355 each of A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, T, Y, W and Y; (2) <5>SY<1><5>S<5><1><4>V (SEQ ID NO: 19), wherein <1> is an equimolar mixture of A, D, E, F, G, Η, I, K, L, Μ, 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) as set forth above.

10. The library of claim 9, wherein the first collection of antibody light chains further comprises: (A) a plurality of LC>. 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 0.27 T, 0.27 G and 0.027 each of A, D, E, F, Η, I, K, L, Μ, N, P, Q, R, S, V, W and Y, <2> is 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, and <3> is 0.36 Y and 0.036 each of A, D, E, F, G, Η, I, K, L, Μ, 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 0.36 Y and 0.0355 each of A, D, E, F, G, Η, I, K, L, M, N, P, Q, R, S, T, V, W, and <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W and Y; and (3) a mixture of (1) and (2) as set forth above; (B) a plurality of LC* CDR2 regions <4><4><4><2>RPS (SEQ ID NO: 105), wherein <2> is 0.27 D, 0.27 N and 0.027 each of A, E, F, G, Η, I, K, L, Μ, P, Q, R, S, T, V, W and Y, and <4> is an equimolar mixture of amino acid residues A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V and W; or (C) both (A) and (B).

11. The library of claim 9 or claim 10, wherein the LC>. CDR3s (1) and (2) are present in the library in an equimolar mixture.

12. The library of claim 10 or claim 11, wherein the LCY CDRls (1) and (2) are present in the library in a ratio of 0.67:0.33.

13. The library of any one of claims 1 to 12, wherein the library is a library of vectors.

14. The library of claim 13, wherein the vectors are yeast vectors or phagemids.

15. The library of any one of claims 1 to 12, wherein the library is a library of genetic packages.

16. The library of claim 15, wherein the genetic packages are cells, spores or viral particles.

17. The library of claim 15 or claim 16, wherein the genetic packages are phage particles or yeast cells, which display the collection of antibody light chains encoded by the variegated DNA molecules in the library. <110> Ladner, Robert C. <120> FOCUSED LIBRARIES OF GENETIC PACKAGES <130> D0617.70025AU04 <140> PCT/US01/50297 <141> 2001-12-18 <160> 447 <170> Patentln version 3.5 <210> l <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (8)..(10) <223> A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (14)..(14) <223> A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W, or Y <400> 1 Val Ser Gly Gly Ser lie Ser Xaa Xaa Xaa Tyr Tyr Trp Xaa 15 10 <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MODRES <222> (1)..(1) <223> amino acid Y, R, W, V, G, or S <220> <221> MOD_RES <222> (3)..(3) <223> amino acid Y, R, W, V, G, or S <220> <221> MOD_RES <222> (4)..(4) <223> amino acid P, S, or G <220> <221> MOD_RES <222> (8)..(8) <223> amino acid E, F, G, H, I, K, L, M, N, P, 0, P, S, T, V, W, or Y <220> <221> MOD_RES <222> (10)..(10) <223> amino acid E, F, G, H, I, K, L, M, N, P, 0, P, S, T, V, W, or Y <400> 2 Xaa Ile Xaa Xaa Ser Gly Gly Xaa Thr Xaa Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 3 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H, I, K, L, M,N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (3)..(3) <223> amino acid D, I, N, S, W, or Y <220> <221> MOD_RES <222> (4)..(5) <223> amino acid A, D, E, F, G, H, I, K, L, M,N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (7)..(7) <223> amino acid S, G, D or N <220> <221> MOD_RES <222> (8)..(10) <223> amino acid A, D, E, F, G, H, I, K, L, M,N, P, Q, R, S, T, V, W, or Y <400> 3 Xaa Ile Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 4 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H, I, K, L, M, N; P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (3)..(3) <223> amino acid D, I, N, S, W, or Y <220> <221> MOD_RES <222> (4)..(5) <223> amino acid A, D, E, F, G, H, I, K, L, M, N; P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (7)..(7) <223> amino acid S, G, D or N <220> <221> MOD_RES <222> (8)..(9) <223> amino acid A, D, E, F, G, H, I, K, L, M, N; P, Q, R, S, T, V, W or Y <400> 4 Xaa Ile Xaa Xaa Xaa Gly Xaa Xaa Xaa Tyr Asn Pro Ser Leu Lys Gly 1 5 10 15 <210> 5 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or Y <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, V, W, or Y <220> <221> MOD_RES <222> (5)..(7) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or Y <220> <221> MOD_RES <222> (12)..(12) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or Y <400> 5 Xaa Ile Xaa Ser Xaa Xaa Xaa Gly Gly Tyr Tyr Xaa Tyr Ala Ala Ser 1 5 10 15 Val Lys Gly <210> 6 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (5)..(5) <223> amino acid K or R <220> <221> MOD_RES <222> (6)..(9) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <400> 6 Tyr Tyr Cys Ala Xaa Xaa Xaa Xaa Xaa Tyr Phe Asp Tyr Trp Gly 1 5 10 15 <210> 7 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (5)..(5) <223> amino acid K or R <220> <221> MOD_RES <222> (6)..(13) <223> amino acid A, D, E, F, G, Η, K, L, Μ, N, p, Q, R, S, τ, V, W on Y <400> 7 Tyn Tyn Cys Ala Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyn Phe Asp Tyr Tnp 15 10 15 Gly <210> 8 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (5)..(5) <223> amino acid K or R <220> <221> MOD_RES <222> (6)..(13) <223> amino acid A, D, E, F, G, H, 1, K, L, Μ, N, P, Q, R, S, T, V, W or Y <400> 8 Tyr Tyr Cys Ala Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Phe Asp 15 10 15 Tyr Trp Gly <210> 9 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (6)..(8) <223> amino acid A, D, E, G, Η, I, K, 1, Μ, N, P, Q, Rj S, T, V, W or Y <220> <221> MODRES <222> (10)..(10) <223> amino acid S on G <220> <221> MOD_RES <222> (11)..(11) <223> amino acid Y or W <220> <221> MOD_RES <222> (12)..(14) <223> amino acid A, D, E, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W or Y <220> <221> misc_featune <222> (15)..(15) <223> Xaa can be any naturally occurring amino acid <400> 9 Tyr Tyr Cys Ala Arg Xaa Xaa Xaa Ser Xaa Ser Xaa Xaa Xaa Xaa Tyr 15 10 15 Phe Asp Tyr Trp Gly 20 <210> 10 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (5)..(5) <223> amino acid K or R <220> <221> MOD_RES <222> (6)..(8) <223> amino acid A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (12)..(13) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (16)..(16) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <400> 10 Tyr Tyr Cys Ala Xaa Xaa Xaa Xaa Cys Ser Gly Xaa Xaa Cys Tyr Xaa 1 5 10 15 Tyr Phe Asp Tyr Trp Gly 20 <210> 11 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <220> <221> MOD_RES <222> (6)..(6) <223> amino acid K or R <220> <221> MOD_RES <222> (7)..(8) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <220> <221> misc_feature <222> (9)..(9) <223> Xaa can be any naturally occurring amino acid <220> <221> MOD_RES <222> (10)..(10) <223> amino acid A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W or Y <220> <221> misc_feature <222> (14)..(14) <223> Xaa can be any naturally occurring amino acid <220> <221> MODRES <222> (15)..(19) <223> amino acid A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W or Y <400> 11 Tyr Tyr Cys Ala Xaa Xaa Xaa Ser Xaa Thr lie Phe Gly Xaa Xaa Xaa 15 10 15 Xaa Xaa Tyr Phe Asp Tyr Trp Gly 20 <210> 12 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (6)..(8) <223> amino acid A, D, E, F, G, Η, I, K, L, Μ, N, P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (11)..(11) <223> amino acid D or S <220> <221> MOD_RES <222> (13)..(14) <223> amino acid S or G <220> <221> MOD_RES <222> (15)..(16) <223> any amino acid <220> <221> MOD_RES <222> (17)..(19) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <400> 12 Tyr Tyr Cys Ala Arg Xaa Xaa Xaa Tyr Tyr Xaa Ser Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Tyr Phe Asp Tyr Trp Gly 20 25 <210> 13 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (6)..(9) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (12)..(13) <223> amino acid S or G <220> <221> MOD_RES <222> (14)..(14) <223> amino acid T, D, or G <220> <221> MOD_RES <222> (15)..(15) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <220> <221> MOD_RES <222> (18)..(20) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y <400> 13 Tyr Tyr Cys Ala Arg Xaa Xaa Xaa Xaa Tyr Cys Xaa Xaa Xaa Xaa Cys 1 5 10 15 Tyr Xaa Xaa Xaa Tyr Phe Asp Tyr Trp Gly 20 25 <210> 14 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (5)..(5) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (7)..(8) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (9)..(9) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, or W <400> 14 Arg Ala Ser Gln Xaa Val Xaa Xaa Xaa Leu Ala 1 5 10 <210> 15 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (5)..(5) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (7)..(10) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <400> 15 Arg Ala Ser Gln Xaa Val Xaa Xaa Xaa Xaa Leu Ala 1 5 10 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, T, V, or W <220> <221> MOD_RES <222> (4)..(6) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (8)..(8) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <400> 16 Gln Gln Xaa Xaa Xaa Xaa Pro Xaa Thr 1 5 <210> 17 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, T, V, or W <220> <221> MOD_RES <222> (4)..(4) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (5)..(6) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (9)..(9) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <400> 17 Gln Gln Xaa Xaa Xaa Xaa Pro Pro Xaa Thr 1 5 10 <210> 18 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, D, E, F, R, I, K, L, M, N, P, Q, R, S, V, W, or Y <220> <221> MOD_RES <222> (6)..(6) <223> amino acid A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (9)..(9) <223> amino acid A, D, E, F, R, I, K, L, M, N, P, Q, R, S, V, W, or Y <220> <221> MOD_RES <222> (10)..(10) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (11)..(11) <223> amino acid A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (12)..(12) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or W <400>

18 Thr Gly Xaa Ser Ser Xaa Val Gly Xaa Xaa Xaa Xaa Val Ser 1 5 10 <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (4)..(4) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (5)..(5) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (7)..(7) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (8)..(8) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (9)..(9) <223> amino acid A, D, E, F, G, H, I, K, L, M, V, P, Q, R, S, T, V, or W <400>

19 Xaa Ser Tyr Xaa Xaa Ser Xaa Xaa Xaa Val 1 5 10 <210> 20 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400>

20 Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 15 <210> 21 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400>

21 Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 1 5 10 15 <210> 22 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (4)..(4) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (6)..(8) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (9)..(9) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (10)..(11) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <400>

22 Thr Gly Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 23 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 23 gactatgaag gtactggtta t 21 <210> 24 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 24 Asp Tyr Glu Gly Thr Gly Tyr 1 5 <210> 25 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 25 tatttcgatt attggggtca aggtaccctg gtcaccgtct ctagt 45 <210> 26 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 26 Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Sen Ser 15 10 15 <210> 27 <211> 46 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 27 cttccggatt cactttctct tacatgtggg ttcgccaagc tcctgg 46 <210> 28 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 28 cctactgtct tccggattca ctttctct 28 <210> 29 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 29 tgggttcgcc aagctcctgg ttgctcactc 30 <210> 30 <211> 49 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 30 cttccggatt cactttctct tactactggt gggttcgcca agctcctgg 49 <210> 31 <211> 70 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 31 cttccggatt cactttctct atcagcggtg gttctatctc ctactactgg tgggttcgcc 60 aagctcctgg 70 <210> 32 <211> 53 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 32 ggtttggagt gggtttctat ctctggtggc acttatgctg actccgttaa agg 53 <210> 33 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 33 cttgggttcg ccaagctcct ggtaaaggtt tggagtgggt ttct 44 <210> 34 <211> 49 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 34 tatgctgact ccgttaaagg tcgcttcact atctctagat tcctgtcac 49 <210> 35 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 35 ggtttggagt gggtttctat cggttatgct gactccgtta aagg 44 <210> 36 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 36 ggtttggagt gggtttctat tggttataac ccttccctta aggg 44 <210> 37 <211> 49 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 37 tataaccctt cccttaaggg tcgcttcact atctctagat tcctgtcac 49 <210> 38 <211> 56 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 38 ggtttggagt gggtttctat cagtggtggt actacttatg ccgcttccgt taaggg 56 <210> 39 <211> 49 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 39 tatgccgctt ccgttaaggg tcgcttcact atctctagat tcctgtcac 49 <210> 40 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 40 gctctggtca acttaagggc tgagg 25 <210> 41 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 41 gctctggtca acttaagggc tgaggacacc gctgtctact actgcgcc 48 <210> 42 <211> 46 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 42 tacttcgatt actggggcca aggtaccctg gtcacctcgc tccacc 46 <210> 43 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 43 ggtaccctgg tcacctcgct ccacc 25 <210> 44 <211> 43 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligonucleotide <400> 44 ccgctgtcta ctactgcgcc tacttcgatt actggggcca agg 43 <210> 45 <211> 42 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligonucleotide <400> 45 ccgctgtcta ctactgcgcc tacttcgatt actgggccaa gg 42 <210> 46 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 46 ccgctgtcta ctactgcgcc tacttcgatt actggggcca agg 43 <210> 47 <211> 52 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 47 ccgctgtcta ctactgcgcc cgttcttctt acttcgatta ctggggccaa gg 52 <210> 48 <211> 58 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 48 ccgctgtcta ctactgcgcc tgctctggtt gctattactt cgattactgg ggccaagg 58 <210> 49 <211> 58 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 49 ccgctgtcta ctactgcgcc tctactatct tcggttactt cgattactgg ggccaagg 58 <210> 50 <211> 61 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 50 cccctgtcta ctactgcgcc cgttattact cttactatta cttcgattac tggggccaag 60 g 61 <210> 51 <211> 58 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 51 ccgctgtcta ctactgcgcc cgttattgct gctattactt cgattactgg ggccaagg 58 <210> 52 <211> 234 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 52 gaagttcaat tgttagagtc tggtggcggt cttgttcagc ctggtggttc tttacgtctt 60 tcttgcgctg cttccggatt cactttctct tcgtacgctt agtaatgggt tcgccaagct 120 cctggtaaag gtttggagtg ggtttcttaa cctaggtaga ctatctctag agacaactct 180 aagaatactc tctacttgca gatgaacagc ttaagggctt agtaaaggcc ttaa 234 <210> 53 <211> 70 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 53 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser lie 35 40 45 Pro Arg Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 50 55 60 Met Asn Ser Leu Arg Ala 65 70 <210> 54 <211> 909 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 54 gaggaccatt gggccccctc cgagactctc gagcgcaacg caattaatgt gagttagctc 60 actcattagg caccccaggc tttacacttt atgcttccgg ctcgtatgtt gtgtggaatt 120 gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc caagctttgg 180 agcctttttt ttggagattt tcaacgtgaa gaagctccta tttgctatcc cgcttgtcgt 240 tccgttttac agccatagtg cacaatccgt ccttactcaa tctcctggca ctctttcgct 300 aagcccgggt gaacgtgcta ccttaagttg ccgtgcttcc caggttcttg cttggtatca 360 acagaaacct ggtcaggcgc cgcgtttact tatttatgct tctcgcggga tcccggaccg 420 tttctctggc tctggttcag gtactgactt tacccttact atttctagat tggaacctga 480 agacttcgct gtttattatt gccaacagcc tactttcggt caaggtacca aggttgaaat 540 caagcgtacg gttgccgctc ctagtgtgtt tatctttcct ccttctgacg aacaattgaa 600 gtcaggtact gcttctgtcg tatgtttgct caacaatttc taccctcgtg aagctaaagt 660 tcagtggaaa gtcgataacg cgttgcagtc gggtaacagt caagaatccg tcactgaaca 720 ggatagtaag gactctacct actctttgtc tctactctta ctttatcaaa ggctgattat 780 gagaagcata aggtctatgc ttgcgaagtt acccagcagg gtctgagctt ccctgttacc 840 aaaagtttca accgtggtga atgctaatag ggcgcgccac gcatctctaa gcggccgcaa 900 caggaggag 909 <210> 55 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 55 Met Lys Lys Leu Leu Phe Ala Ile Pro Leu Val Val Pro Phe Tyr Pro 1 5 10 15 His Ser Ala Gln Ser Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 20 25 30 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Val Leu 35 40 45 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 50 55 60 Ala Ser Arg Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 65 70 75 80 Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Pro Phe Ala Val 85 90 95 Tyr Tyr Cys Gln Gln Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 56 <211> 646 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 56 agtgcacaat ccgctctcac tcagcctgct agcgtttccg ggtcacctgg tcaaagtatc 60 actatttctt gtacaggttc ttctgttggc gtttcttggt atcaacaaca cccgggcaag 120 gcgccgaagt tgatgatcta ccgtccttct ggtgttagca atcgtttctc cggatctaaa 180 tccggtaata ccgcaagctt aactatctct ggtctgcagg ctgaagacga ggctgactac 240 tattgttctg tcttcggcgg tggtaccaaa cttactgtcc tcggtcaacc taaggctgct 300 ccttccgtta ctctcttccc tcctagttct gaagagcttc aagctaacaa ggctactctt 360 gtttgcttga tcagtgactt ttatcctggt gctgttactg tcgcttggaa agccgattct 420 tctcctgtta aagctggtgt tgagacgacc actccttcta aacaatctaa caataagtac 480 gctgcgagct cttatctttc tctcacccct gaacaatgga agtctcataa atcctattcc 540 tatcaagtta ctcatgaagg ttctaccgtt gaaaagactg ttgcccctac tgagtgttct 600 tagtgaggcg cgccaacgat gttcaaggcg gccgcaacag gaggag 646 <210> 57 <211> 200 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 57 Ser Ala Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro 1 5 10 15 Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Ser Ser Val Gly Val Ser 20 25 30 Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Arg 35 40 45 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 50 55 60 Ala Ser Leu Thr Ile Ser Gly Leu Gln Arg Glu Asp Glu Ala Asp Tyr 65 70 75 80 Tyr Cys Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 85 90 95 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 100 105 110 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 115 120 125 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Ala Ser Ser Phe Val Lys 130 135 140 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 145 150 155 160 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 165 170 175 Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 180 185 190 Thr Val Ala Pro Thr Glu Cys Ser 195 200 <210> 58 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 58 gctctggtca acttaagggc tgagg 25 <210> 59 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 59 gctctggtca acttaagggc tgaggacacc gctgtctact actgcgcc 48 <210> 60 <211> 46 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 60 tacttcaatt acttgggcca aggtaccctg gtcacctcgc tccacc 46 <210> 61 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 61 ggtaccctgg tcacctcgac cacc 24 <210> 62 <211> 56 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 62 ggtctcagtt gctaagcccg ggtgaacgtg ctaccttaag ttgccgtgct tcccag 56 <210> 63 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 63 ggtctcagtt gctaagcccg ggtg 24 <210> 64 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 64 cttgcttggt atcaacagaa acctggtcag gcgccaagtc gtgtc 45 <210> 65 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 65 cctggtcagg cgcaagtcgt gtc 23 <210> 66 <211> 53 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 66 gctaccttaa gttgccgtgc ttcccaggtt cttgcttggt atcaacagaa acc 53 <210> 67 <211> 53 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 67 gctaccttaa gttgccgtgc ttcccaggtt cttgcttggt atcaacagaa acc 53 <210> 68 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 68 cacgagtcct acctggtcag gc 22 <210> 69 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 69 cacgagtcct acctggtcag gcgccgcgtt tacttattta t 41 <210> 70 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 70 gaccgtttct ctggttctca cc 22 <210> 71 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 71 caggcgccgc gtttacttat ttatgcttct cgcgggatcc cggaccgttt ctctggttct 60 cacc 64 <210> 72 <211> 53 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 72 gacgagtcct tctagattgg aacctgaaga cttcgctgtt tattattgcc aac 53 <210> 73 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 73 actttcggtc aaggtaccaa ggttgaaatc aagcgtacgt cacaggtgag 50 <210> 74 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 74 gaaatcaagc gtacgtcaca ggtgag 26 <210> 75 <211> 55 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 75 gacttcgctg tttattattg ccaacagcct actttcggtc aaggtaccaa ggttg 55 <210> 76 <211> 52 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 76 gacttcgctg tttattattg ccaacagcct ttcggtcaag gtaccaaggt tg 52 <210> 77 <211> 58 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 77 gacttcgctg tttattattg ccaacagcct cctactttcg gtcaaggtac caaggttg 58 <210> 78 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 78 gacgagtcct ggtcacctgg t 21 <210> 79 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 79 gacgagtcct ggtcacctgg tcaaagtatc actatttctt gtacaggt 48 <210> 80 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 80 gtttcttggt atcaacaaca cccgggcaag gcgagatctt cacaggtgag 50 <210> 81 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 81 gcaaggcgag atcttcacag gtgag 25 <210> 82 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 82 gttatcatat ttcttgtaca ggtctctggt atcaacaaca ccc 43 <210> 83 <211> 58 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 83 gtatcactat ttcttgtaca ggttcttctg ttggcgtttc ttggtatcaa caacaccc 58 <210> 84 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 84 gagcagagga cccgggcaag gc 22 <210> 85 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 85 gagcagagga cccgggcaag gcgccgaagt tgatgatcta c 41 <210> 86 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 86 cgtccttctg gtgtcagcaa tcgtttctcc ggatcacagg tgag 44 <210> 87 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 87 cgtttctccg gatcacaggt gag 23 <210> 88 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 88 gccgaagttg atgatctacc gtccttctgg tgtcagcaat c 41 <210> 89 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 89 ctgcaggctg aagacgaggc tgac 24 <210> 90 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 90 ctgcaggctg aagacgaggc tgactactat tgt 33 <210> 91 <211> 57 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 91 gtcttcggcg gtggtaccaa acttactgtc ctcggtcaac ctaaggacac aggtgag 57 <210> 92 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 92 cggtcaacct aaggacacag gtga 24 <210> 93 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 93 gacgaggctg actactattg ttctgtcttc ggcggtggta ccaaacttac 50 <210> 94 <211> 56 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 94 gacgaggctg actactattg tagctattct gtcttcggcg gtggtaccaa acttac 56 <210> 95 <211> 618 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 95 gaggaccatt gggccccctc cgagactctc gagcgcaacg caattaatgt gagttagctc 60 actcattagg caccccaggc tttacacttt atgcttccgg ctcgtatgtt gtgtggaatt 120 gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc caagctttgg 180 agcctttttt ttggagattt tcaacgtgaa gaagctccta tttgctatcc cgcttgtcgt 240 tccgttttac agccatagtg cacaatccgt ccttactcaa tctcctggca ctctttcgct 300 aagcccgggt ggacgtgcta ccttaagtta gtaagctccc aggcctcttt gatctgaaac 360 ctggtcaggc gccgcgttaa tgaaagcgct aatggccaac agtgactggg atcccggacc 420 gtttctctgg ctctggttca ggtactgact ttacccttac tatttctaga taatgagtta 480 actagaccta cgtaacctag ggtaccaagg ttgaaatcaa gcgtacggtt gccgctccta 540 gtgtgtttat ctttcctcct tctgacgaac aattgaagtc aggtactacg catctctaag 600 cggccgcaac aggaggag 618 <210> 96 <211> 102 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 96 Met Lys Lys Leu Leu Phe Ala lie Pro Leu Val Val Pro Phe Tyr Ser 15 10 15 His Ser Ala Gin Ser Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu 20 25 30 Ser Pro Gly Glu Arg Ala Thr Leu Ser Lys Pro Gly Gin Ala Pro Arg 35 40 45 Thr Gly lie Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 50 55 60 Thr Leu Thr lie Ser Arg Phe Gly Gin Gly Thr Lys Val Glu lie Lys 65 70 75 80 Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 85 90 95 Gin Leu Lys Ser Gly Thr 100 <210> 97 <211> 404 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 97 gaggaccatt gggcccctta ctccgtgaca gtgcacaatc cgctctcact cagcctgcta 60 gcgtttccgg gtcacctggt caaagtatca ctatttcttg tacatcttag tgactcagat 120 cttaatgacc gtagcacccg ggcaaggcgc cgtaatgaat ctcgtacgct ggtgttagca 180 atcgtttctc cggatctaaa tccggtaata ccgcaagctt aactatctct ggtctgcagg 240 ttctgtagtt ccaattgctt tagtgaccca ccaaacttac tgtcctcggt caacctaagg 300 ctgctccttc cgttactctc ttccatccta gttctgaaga gattcaagct aacaaggcta 360 ctcctgtttg cttgatcagt gacttttatc ctggtgctgt tact 404 <210> 98 <211> 99 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 98 Ser Ala Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro 1 5 10 15 Gly Gln Ser Ile Thr Ile Ser Cys Thr Arg Ser Pro His Pro Gly Lys 20 25 30 Ala Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu 35 40 45 Thr Ile Ser Gly Leu Gln Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 50 55 60 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 65 70 75 80 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 85 90 95 Ala Val Thr <210> 99 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 99 ctgtctgaac ccatggcc 18 <210> 100 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H,I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, D, E, F, G, H,I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (5)..(5) <223> amino acid A, D, E, F, G, H,I, K, L, M, N, P, Q, R, S, T, V, W, or Y <400> 100 Xaa Tyr Xaa Met Xaa 1 5 <210> 101 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid S or T <220> <221> MOD_RES <222> (2)..(3) <223> amino acid S, G, or X <220> <221> MOD_RES <222> (7)..(7) <223> amino acid S, G, or X <400> 101 Xaa Xaa Xaa Tyr Tyr Trp Xaa 1 5 <210> 102 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (4)..(4) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (6)..(6) <223> amino acid D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (7)..(7) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y <400> 102 Xaa Ala Ser Xaa Arg Xaa Xaa 1 5 <210> 103 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (3)..(4) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, T, V, or W <220> <221> MOD_RES <222> (5)..(7) <223> amino acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <400> 103 Gln Gln Xaa Xaa Xaa Xaa Xaa Pro 1 5 <210> 104 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (2)..(2) <223> amnio acid A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (3)..(3) <223> amnio acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (5)..(7) <223> amnio acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (8)..(8) <223> amnio acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (9)..(10) <223> amnio acid A, D, E, F, G, H, I, K, I, M, N, P, Q, R, S, T, V, W, or Y <400> 104 Gly Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 105 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> amino acid A, D, E, F, G, H, I, K, L, O, N, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (4)..(4) <223> amino acid A, E, F, G, H, I, K, I, M, P, Q, R, S, T, V, W, or Y <400> 105 Xaa Xaa Xaa Xaa Arg Pro Ser 1 5 <210> 106 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid A, D, E, F, G, H, I, K, L, M, V, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (2)..(2) <223> amino acid A, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (3)..(3) <223> amino acid A, D, E, F, G, H, I, K, L, M, V, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (4)..(4) <223> amino acid A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (5)..(5) <223> amino acid A, D, E, F, G, H, I, K, L, M, V, P, Q, R, S, T, V, or W <220> <221> MOD_RES <222> (7)..(10) <223> amino acid A, D, E, F, G, H, I, K, L, M, V, P, Q, R, S, T, V, or W <400> 106 Xaa Xaa Xaa Xaa Xaa Ser Xaa Xaa Xaa Xaa Val 1 5 10 <210> 107 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> amino acid S or T <220> <221> MOD_RES <222> (2)..(3) <223> amino acid S or G, or A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <220> <221> MOD_RES <222> (7)..(7) <223> amino acid S or G, or A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, or Y <400> 107 Xaa Xaa Xaa Tyr Tyr Trp Xaa 1 5 <210> 108 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (8)..(10) <223> any amino acid except C <220> <221> MOD_RES <222> (14)..(14) <223> any amino acid except C <400> 108 Val Ser Gly Gly Ser Ile Ser Xaa Xaa Xaa Tyr Tyr Trp Xaa 1 5 10 <210> 109 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> any amino acid except C <220> <221> MOD_RES <222> (3)..(3) <223> any amino acid except C <220> <221> MOD_RES <222> (5)..(5) <223> any amino acid except C <400> 109 Xaa Tyr Xaa Met Xaa 1 5 <210> 110 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 110 Ser Gly Gly Tyr Tyr Trp Ser 1 5 <210> 111 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (4)..(6) <223> Xaa can be any naturally occurring amino acid <400> 111 Ser Ile Ser Xaa Xaa Xaa 1 5 <210> 112 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 112 Tyr Tyr Cys Ala Arg 1 5 <210> 113 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (4)..(5) <223> any amino acid <400> 113 Tyr Tyr Cys Xaa Xaa 1 5 <210> 114 <211> 519 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 114 atggactgga cctggaggtt cctctttgtg gtggcagcag ctacaggtgt ccagtcccag 60 gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120 tgcaaggctt ctggaggcac cttcagcagc tatgctatca gctgggtgcg acaggcccct 180 ggacaagggc ttgagtggat gggagggatc atccctatct ttggtacagc aaactacgca 240 cagaagttcc agggcagagt cacgattacc gcggacgaat ccacgagcac agcctacatg 300 gagctgagca gcctgagatc tgaggacacg gccgtgtatc actgtgcgag tgagggatgg 360 gagagttgta gtggtggtgg ctgctacgac ggtatggacg tctggggcca agggaccacg 420 gtcaccgtct cctcagcttc caccaagggc ccatcggtct tccccctggc gccctgctcc 480 aggagcacct ctgggggcac agcggccctg ggctgcctg 519 <210> 115 <211> 518 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 115 atggactgga cctggaggtt cctctttgtg gtggcagcag ctacaggtgt ccagtcccag 60 gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120 tgcaaggctt ctggaggcac cttcagcagc tatgctatca gctgggtgcg acaggcccct 180 ggacaagggc ttgagtggat gggagggatc atccctatct ttggtacagc aaactacgca 240 cagaagttcc agggcagagt cacgattacc gcggacgaat ccacgagcac agcctacatg 300 gagctgagca gcctgagatc tgaggacacg gccgtgtatc actgtgcgag tgagggatgg 360 gagagttgta gtggtggtgg ctgctacgac ggtatggacg tctggggcca agggaccacg 420 gtcaccgtct cctcagcttc caccaagggc catcggtctt ccccctggcg ccctgctcca 480 ggagcacctc tgggggcaca gcggccctgg gctgcctg 518 <210> 116 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 116 Tyr His Cys Ala Ser 1 5 <210> 117 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 117 Asp Arg Gly Gly Lys Tyr Gln Leu Ala Pro Lys Gly Gly Met 1 5 10 <210> 118 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 118 Asp Arg Gly Gly Lys Tyr Gln Leu Ala Pro Lys Gly Gly Met Asp Val 1 5 10 15 <210> 119 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 119 tatgatagta gtgggtcata ctccgactac tgggggcag 39 <210> 120 <211> 52 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 120 gctgaatact tccagcactg gggccagggc accctggtca ccgtctcctc ag 52 <210> 121 <211> 53 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 121 ctactggtac ttcgatctct ggggccgtgg caccctggtc actgtctcct cag 53 <210> 122 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 122 tgatgctttt gatatctggg gccaagggac aatggtcacc gtctcttcag 50 <210> 123 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 123 actactttga ctactggggc cagggaaccc tggtcaccgt ctcctcag 48 <210> 124 <211> 51 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 124 acaactggtt cgacccctgg ggccagggaa ccctggtcac cgtctcctca g 51 <210> 125 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 125 attactacta ctactacggt atggacgtct ggggccaagg gaccacggtc accgtctcct 60 cag 63 <210> 126 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 126 tatgatagta gtgggtcata ctccgactac tgggggcag 39 <210> 127 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 127 Tyr Asp Ser Ser Gly Ser Tyr Ser Asp Tyr Trp Gly Gin 15 10 <210> 128 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 128 actactttga ctactggggc cagggaaccc tggtcaccgt ctcctcag 48 <210> 129 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 129 Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 15 <210> 130 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 130 gtattactat gatagtagtg gttattacta c 31 <210> 131 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 131 gatcgccaca attactatga tagtagtggg tcatactcc 39 <210> 132 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 132 Val Gin Leu Glu Arg Xaa 1 5 <210> 133 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 133 Gly Thr Thr Gly Thr Xaa 1 5 <210> 134 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 134 Tyr Asn Trp Asn Asp 1 5 <210> 135 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <400> 135 Val Leu Glu Leu Xaa l 5 <210> 136 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 136 Gly lie Thr Gly Thr Xaa l 5 <210> 137 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 137 Tyr Asn Trp Asn Tyr l 5 <210> 138 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <400> 138 Val Leu Glu Arg Xaa l 5 <210> 139 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 139 Gly lie Thr Gly Thr Xaa l 5 <210> 140 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 140 Tyr Asn Trp Asn Asp l 5 <210> 141 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_featune <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 141 Val Trp Glu Leu Leu Xaa l 5 <210> 142 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 142 Gly lie Val Gly Ala Thr Xaa 1 5 <210> 143 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 143 Tyr Ser Gly Ser Tyr Tyr 1 5 <210> 144 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 144 Gly Tyn Cys Sen Ser Thr Ser Cys Tyr Thr 15 10 <210> 145 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (9)..(9) <223> Xaa can be any naturally occurring amino acid <400> 145 Arg lie Leu Tyr Gin Leu Leu Tyr Xaa 1 5 <210> 146 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 146 Asp He Val Val Val Pro Ala Ala lie Xaa 15 10 <210> 147 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 147 Gly Tyr Cys Thr Asn Gly Val Cys Tyr Thr 15 10 <210> 148 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 148 Arg lie Leu Tyr Trp Cys Met Leu Tyr Xaa 15 10 <210> 149 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 149 Asp lie Val Leu Met Val Tyr Ala lie Xaa 15 10 <210> 150 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 150 Gly Tyr Cys Ser Gly Gly Ser Cys Tyr Ser 15 10 <210> 151 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (9)..(9) <223> Xaa can be any naturally occurring amino acid <400> 151 Arg lie Leu Trp Trp Leu Leu Leu Xaa 1 5 <210> 152 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 152 Asp Ile Val Val Val Val Ala Ala Thr Xaa 1 5 10 <210> 153 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 153 Ala Tyr Cys Gly Gly Asp Cys Tyr Ser 1 5 <210> 154 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (9)..(9) <223> Xaa can be any naturally occurring amino acid <400> 154 Ser Ile Leu Trp Trp Leu Leu Phe Xaa 1 5 <210> 155 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (9)..(9) <223> Xaa can be any naturally occurring amino acid <400> 155 His lie Val Val Val Thr Ala lie Xaa l 5 <210> 156 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 156 Tyr Tyr Asp Phe Trp Ser Gly Tyr Tyr Thr 15 10 <210> 157 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (11)..(11) <223> Xaa can be any naturally occurring amino acid <400> 157 Val Leu Arg Phe Leu Glu Trp Leu Leu Tyr Xaa 15 10 <210> 158 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_featune <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 158 lie Thr lie Phe Gly Val Val lie He Xaa 15 10 <210> 159 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 159 Tyr Tyr Asp lie Leu Thr Gly Tyr Tyr Asn 15 10 <210> 160 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 160 Val Leu Arg Tyr Phe Asp Trp Leu Leu Xaa 15 10 <210> 161 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (9)..(9) <223> Xaa can be any naturally occurring amino acid <400> 161 lie Thr lie Phe Leu Val lie lie Xaa l 5 <210> 162 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 162 Tyr Tyr Tyr Gly Ser Gly Ser Tyr Tyr Asn 15 10 <210> 163 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 163 Val Leu Leu Trp Phe Gly Glu Leu Leu Xaa 15 10 <210> 164 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 164 lie Thr Met Val Arg Gly Val lie lie Xaa 15 10 <210> 165 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 165 Tyr Tyr Asp Tyr Val Trp Gly Ser Tyr Arg Tyr Thr 15 10 <210> 166 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (12)..(12) <223> Xaa can be any naturally occurring amino acid <400> 166 Val Leu Leu Arg Leu Gly Glu Leu Ser Leu Tyr Xaa 15 10 <210> 167 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_featune <222> (12)..(12) <223> Xaa can be any naturally occurring amino acid <400> 167 lie Met lie Thr Phe Gly Gly Val lie Val lie Xaa 15 10 <210> 168 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 168 Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr 15 10 <210> 169 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (8)..(8) <223> Xaa can be any naturally occurring amino acid <400> 169 Val Leu Leu Trp Leu Leu Leu Xaa 1 5 <210> 170 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (10)..(10) <223> Xaa can be any naturally occurring amino acid <400> 170 lie Thr Met lie Val Val Val lie Thr Xaa 15 10 <210> 171 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 171 Asp Tyr Ser Asn Tyr 1 5 <210> 172 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (4)..(4) <223> Xaa can be any naturally occurring amino acid <400> 172 Leu Gin Leu Xaa l <210> 173 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <400> 173 Thr Thr Val Thr Xaa 1 5 <210> 174 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 174 Asp Tyr Gly Asp Tyr 1 5 <210> 175 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (4)..(4) <223> Xaa can be any naturally occurring amino acid <400> 175 Leu Arg Leu Xaa l <210> 176 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <400> 176 Thr Thr Val Thr Xaa 1 5 <210> 177 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 177 Asp Tyr Gly Gly Asn Ser 1 5 <210> 178 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <400> 178 Leu Arg Trp Leu Xaa 1 5 <210> 179 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 179 Thr Thr Val Val Thr Xaa l 5 <210> 180 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 180 Trp lie Gin Leu Trp Leu Xaa 1 5 <210> 181 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 181 Val Asp Thr Ala Met Val Xaa l 5 <210> 182 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 182 Gly Tyr Ser Tyr Gly Tyr 1 5 <210> 183 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 183 Trp lie Trp Leu Arg Leu Xaa 1 5 <210> 184 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (8)..(8) <223> Xaa can be any naturally occurring amino acid <400> 184 Val Asp He Val Ala Thr lie Xaa l 5 <210> 185 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 185 Gly Tyr Ser Gly Tyr Asp Tyr 1 5 <210> 186 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 186 Arg Trp Leu Gin Leu Xaa 1 5 <210> 187 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_featune <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 187 Val Glu Met Ala Thr lie Xaa l 5 <210> 188 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 188 Arg Asp Gly Tyr Asn Tyr 1 5 <210> 189 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 189 Ser lie Ala Ala Arg Xaa 1 5 <210> 190 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 190 Glu Tyr Ser Ser Ser Ser l 5 <210> 191 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (5)..(5) <223> Xaa can be any naturally occurring amino acid <400> 191 Val Gin Leu Val Xaa 1 5 <210> 192 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 192 Gly lie Ala Ala Ala Gly Xaa 1 5 <210> 193 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 193 Gly Tyr Ser Ser Ser Trp Tyr 1 5 <210> 194 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 194 Val Gin Gin Leu Val Xaa 1 5 <210> 195 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <22l> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 195 Gly lie Ala Val Ala Gly Xaa 1 5 <210> 196 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 196 Gly Tyr Ser Ser Gly Trp Tyr l 5 <210> 197 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (6)..(6) <223> Xaa can be any naturally occurring amino acid <400> 197 Val Gin Trp Leu Val Xaa 1 5 <210> 198 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (4)..(4) <223> Xaa can be any naturally occurring amino acid <400> 198 Leu Thr Gly Xaa 1 <210> 199 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (11)..(13) <223> any amino acid <400> 199 Xaa Xaa Xaa Tyr Cys Ser Ser Thr Ser Cys Xaa Xaa Xaa 1 5 10 <210> 200 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (11)..(13) <223> any amino acid <400> 200 Xaa Xaa Xaa Xaa Tyr Val Trp Gly Ser Tyr Xaa Xaa Xaa 1 5 10 <210> 201 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(7) <223> any amino acid <220> <221> MOD_RES <222> (11)..(13) <223> any amino acid <400> 201 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ser Gly Tyr Xaa Xaa Xaa 1 5 10 <210> 202 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (12)..(13) <223> any amino acid <400> 202 Xaa Xaa Xaa Tyr Asp Ile Leu Thr Gly Tyr Tyr Xaa Xaa 1 5 10 <210> 203 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (10)..(13) <223> any amino acid <400> 203 Xaa Xaa Xaa Val Val Val Pro Ala Ala Xaa Xaa Xaa Xaa 1 5 10 <210> 204 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (11)..(12) <223> any amino acid <400> 204 Xaa Xaa Xaa Tyr Tyr Asp Ser Ser Gly Tyr Xaa Xaa 1 5 10 <210> 205 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (9)..(12) <223> any amino acid <400> 205 Xaa Xaa Xaa Asp Phe Trp Ser Gly Xaa Xaa Xaa Xaa 1 5 10 <210> 206 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (9)..(12) <223> any amino acid <400> 206 Xaa Xaa Xaa Thr Ile Phe Gly Val Xaa Xaa Xaa Xaa 1 5 10 <210> 207 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (9)..(12) <223> any amino acid <400> 207 Xaa Xaa Xaa Xaa Ile Val Ala Thr Xaa Xaa Xaa Xaa 1 5 10 <210> 208 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (11)..(11) <223> any amino acid <400> 208 Xaa Xaa Xaa Tyr Gly Ser Gly Ser Tyr Tyr Xaa 1 5 10 <210> 209 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (9)..(11) <223> any amino acid <400> 209 Xaa Xaa Xaa Xaa Tyr Ser Tyr Gly Xaa Xaa Xaa 1 5 10 <210> 210 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (7)..(8) <223> any amino acid <220> <221> MOD_RES <222> (11)..(11) <223> any amino acid <400> 210 Xaa Xaa Xaa Cys Ser Gly Xaa Xaa Cys Tyr Xaa 1 5 10 <210> 211 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (9)..(11) <223> any amino acid <400> 211 Xaa Xaa Xaa Xaa Ala Ala Ala Gly Xaa Xaa Xaa 1 5 10 <210> 212 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(1) <223> any amino acid <220> <221> MOD_RES <222> (3)..(5) <223> any amino acid <220> <221> MOD_RES <222> (9)..(11) <223> any amino acid <400> 212 Xaa Gly Xaa Xaa Xaa Gly Gly Asn Xaa Xaa Xaa 1 5 10 <210> 213 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (8)..(10) <223> any amino acid <400> 213 Xaa Xaa Xaa Ser Gly Ser Tyr Xaa Xaa Xaa 1 5 10 <210> 214 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (8)..(10) <223> any amino acid <400> 214 Xaa Xaa Xaa Ser Ser Ser Trp Xaa Xaa Xaa 1 5 10 <210> 215 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (10)..(10) <223> any amino acid <400> 215 Xaa Xaa Xaa Xaa Thr Thr Val Thr Thr Xaa 1 5 10 <210> 216 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (5)..(5) <223> amino acid S or G <220> <221> MOD_RES <222> (8)..(8) <223> any amino acid <220> <221> MOD_RES <222> (10)..(10) <223> any amino acid <400> 216 Xaa Xaa Xaa Cys Xaa Gly Asp Xaa Cys Xaa 1 5 10 <210> 217 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (4)..(4) <223> amino acid I or V <220> <221> MOD_RES <222> (9)..(10) <223> any amino acid <400> 217 Xaa Xaa Xaa Xaa Ala Val Ala Gly Xaa Xaa 1 5 10 <210> 218 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(2) <223> any amino acid <220> <221> MOD_RES <222> (9)..(10) <223> any amino acid <400> 218 Xaa Xaa Leu Trp Phe Gly Glu Leu Xaa Xaa 1 5 10 <210> 219 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (2)..(3) <223> any amino acid <220> <221> MOD_RES <222> (6)..(9) <223> any amino acid <400> 219 Gly Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Phe 1 5 10 <210> 220 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (6)..(6) <223> any amino acid <220> <221> MOD_RES <222> (9)..(10) <223> any amino acid <400> 220 Xaa Xaa Xaa Asp Thr Xaa Met Val Xaa Xaa 1 5 10 <210> 221 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(5) <223> any amino acid <220> <221> MOD_RES <222> (8)..(10) <223> any amino acid <400> 221 Xaa Xaa Xaa Xaa Xaa Gly Glu Xaa Xaa Xaa 1 5 10 <210> 222 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (8)..(9) <223> any amino acid <400> 222 Xaa Xaa Xaa Xaa Ser Gly Trp Xaa Xaa 1 5 <210> 223 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(4) <223> any amino acid <220> <221> MOD_RES <222> (8)..(9) <223> any amino acid <400> 223 Xaa Xaa Xaa Xaa Gly Tyr Asn Xaa Xaa 1 5 <210> 224 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (8)..(9) <223> any amino acid <400> 224 Xaa Xaa Xaa Val Arg Gly Val Xaa Xaa 1 5 <210> 225 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (7)..(9) <223> any amino acid <400> 225 Xaa Xaa Xaa Ile Ala Ala Xaa Xaa Xaa 1 5 <210> 226 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(2) <223> any amino acid <220> <221> MOD_RES <222> (4)..(4) <223> any amino acid <220> <221> MOD_RES <222> (7)..(9) <223> any amino acid <400> 226 Xaa Xaa Tyr Xaa Trp Asn Xaa Xaa Xaa 1 5 <210> 227 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (7)..(8) <223> any amino acid <400> 227 Xaa Xaa Xaa Tyr Gly Asp Xaa Xaa 1 5 <210> 228 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(2) <223> any amino acid <220> <221> MOD_RES <222> (7)..(8) <223> any amino acid <400> 228 Xaa Xaa Val Gly Ala Thr Xaa Xaa 1 5 <210> 229 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (1)..(3) <223> any amino acid <220> <221> MOD_RES <222> (8)..(8) <223> any amino acid <400> 229 Xaa Xaa Xaa Tyr Ser Ser Ser Xaa 1 5 <210> 230 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 230 Gly Tyr Tyr Met His 1 5 <210> 231 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 231 Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 232 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 232 Ser Tyr Ala Met His 1 5 <210> 233 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 233 Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe Gln 1 5 10 15 Gly <210> 234 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 234 Ser Tyr Asp Ile Asn 1 5 <210> 235 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 235 Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 236 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 236 Ser Tyr Gly Ile Ser 1 5 <210> 237 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 237 Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln 1 5 10 15 Gly <210> 238 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 238 Glu Leu Ser Met His 1 5 <210> 239 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 239 Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 240 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 240 Tyr Arg Tyr Leu His 1 5 <210> 241 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 241 Trp Ile Thr Pro Phe Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Asp <210> 242 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 242 Ser Tyr Tyr Met His 1 5 <210> 243 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 243 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 244 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 244 Ser Ser Ala Val Gln 1 5 <210> 245 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 245 Trp Ile Val Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Glu <210> 246 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 246 Ser Tyr Ala Ile Ser 1 5 <210> 247 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 247 Gly lie lie Pro lie Phe Gly Thn Ala Asn Tyn Ala Gin Lys Phe Gin 15 10 15 Gly <210> 248 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 248 Ser Tyr Ala lie Ser l 5 <210> 249 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 249 Gly lie lie Pro lie Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe Gin 15 10 15 Gly <210> 250 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 250 Asp Tyr Tyr Met His 1 5 <210> 251 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 251 Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe Gln 1 5 10 15 Gly <210> 252 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 252 Thr Ser Gly Val Gly Val Gly 1 5 <210> 253 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 253 Leu Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser Leu Lys Ser 1 5 10 15 <210> 254 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 254 Asn Ala Arg Met Gly Val Ser 1 5 <210> 255 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 255 His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser 1 5 10 15 <210> 256 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 256 Thr Ser Gly Met Arg Val Ser 1 5 <210> 257 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 257 Arg Ile Asp Trp Asp Asp Asp Lys Phe Tyr Ser Thr Ser Leu Lys Thr 1 5 10 15 <210> 258 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 258 Ser Tyr Trp Met Ser 1 5 <210> 259 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 259 Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly <210> 260 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 260 Asp Tyr Ala Met His 1 5 <210> 261 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 261 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 262 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 262 Asp Tyr Tyr Met Ser 1 5 <210> 263 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 263 Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 264 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 264 Ser Tyr Asp Met His 1 5 <210> 265 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 265 Ala Ile Gly Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys Gly 1 5 10 15 <210> 266 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 266 Asn Ala Trp Met Ser 1 5 <210> 267 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 267 Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala Pro 1 5 10 15 Val Lys Gly <210> 268 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 268 Asp Tyr Gly Met Ser 1 5 <210> 269 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 269 Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 270 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 270 Ser Tyr Ser Met Asn 1 5 <210> 271 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 271 Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 272 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 272 Ser Tyr Ala Met Ser 1 5 <210> 273 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 273 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 274 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 274 Ser Tyr Gly Met His 1 5 <210> 275 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 275 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 276 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 276 Ser Tyr Ala Met His 1 5 <210> 277 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 277 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 278 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 278 Ser Tyr Gly Met His 1 5 <210> 279 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 279 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 280 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 280 Ser Tyr Gly Met His 1 5 <210> 281 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 281 Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 282 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 282 Asp Tyr Thr Met His 1 5 <210> 283 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 283 Leu Ile Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 284 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 284 Ser Tyr Ser Met Asn 1 5 <210> 285 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 285 Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 286 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 286 Asp Tyr Ala Met Ser 1 5 <210> 287 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 287 Phe Ile Arg Ser Lys Ala Tyr Gly Gly Thr Thr Glu Tyr Thr Ala Ser 1 5 10 15 Val Lys Gly <210> 288 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 288 Ser Asn Tyr Met Ser 1 5 <210> 289 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 289 Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 290 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 290 Ser Tyr Ala Met His 1 5 <210> 291 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 291 Ala Ile Ser Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asn Ser Val Lys 1 5 10 15 Gly <210> 292 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 292 Ser Asn Tyr Met Ser 1 5 <210> 293 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 293 Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 294 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 294 Asp His Tyr Met Asp l 5 <210> 295 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 295 Arg Thr Arg Asn Lys Ala Asn Ser Tyr Thr Thr Glu Tyr Ala Ala Ser 15 10 15 Val Lys Gly <210> 296 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 296 Gly Ser Ala Met His 1 5 <210> 297 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 297 Arg He Arg Ser Lys Ala Asn Ser Tyr Ala Thr Ala Tyr Ala Ala Ser 15 10 15 Val Lys Gly <210> 298 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 298 Ser Tyr Trp Met His 1 5 <210> 299 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 299 Arg Ile Asn Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 300 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 300 Ser Asn Glu Met Ser 1 5 <210> 301 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 301 Ser Ile Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Arg Lys Gly 1 5 10 15 <210> 302 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 302 Ser Ser Asn Trp Trp Ser 1 5 <210> 303 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 303 Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 304 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 304 Ser Ser Asn Trp Trp Gly 1 5 <210> 305 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 305 Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 306 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 306 Ser Gly Gly Tyr Tyr Trp Ser 1 5 <210> 307 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 307 Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 308 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 308 Ser Gly Gly Tyr Ser Trp Ser 1 5 <210> 309 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 309 Tyr Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 310 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 310 Ser Gly Asp Tyr Tyr Trp Ser 1 5 <210> 311 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 311 Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 312 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 312 Ser Gly Gly Tyr Tyr Trp Ser 1 5 <210> 313 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 313 Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 314 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 314 Gly Tyr Tyr Trp Ser 1 5 <210> 315 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 315 Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 316 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 316 Ser Ser Ser Tyr Tyr Trp Gly 1 5 <210> 317 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 317 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 318 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 318 Ser Tyr Tyr Trp Ser 1 5 <210> 319 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 319 Tyn lie Tyn Tyr Sen Gly Ser Thr Asn Tyn Asn Pro Sen Leu Lys Sen 15 10 15 <210> 320 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 320 Sen Gly Sen Tyn Tyn Trp Ser 1 5 <210> 321 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 321 Tyn lie Tyn Tyn Sen Gly Sen Thn Asn Tyn Asn Pro Sen Leu Lys Sen 15 10 15 <210> 322 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 322 Sen Gly Tyn Tyn Tnp Gly 1 5 <210> 323 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 323 Sen lie Tyr His Ser Gly Ser Thr Tyn Tyn Asn Pro Sen Leu Lys Sen 15 10 15 <210> 324 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 324 Sen Tyn Tnp lie Gly 1 5 <210> 325 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 325 lie lie Tyn Pro Gly Asp Ser Asp Thr Arg Tyn Sen Pro Ser Phe Gin 15 10 15 Gly <210> 326 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 326 Sen Tyn Trp lie Ser 1 5 <210> 327 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 327 Ang lie Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe Gin 15 10 15 Gly <210> 328 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 328 Ser Asn Ser Ala Ala Trp Asn l 5 <210> 329 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 329 Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Val Ser Val 15 10 15 Lys Ser <210> 330 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 330 Ser Tyr Ala Met Asn 1 5 <210> 331 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 331 Trp Ile Asn Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Gly Phe Thr 1 5 10 15 Gly <210> 332 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 332 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 1 5 10 <210> 333 <211> 75 <212> DNA <213> Artificial Sequence <220> <223> Synthetic oligonucleotide <400> 333 gttaccaaaa gtttcaaccg tggtgaatgc taatagggcg cgccacgcat ctctaagcgg 60 ccgcaacagg aggag 75 <210> 334 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 334 Gly Arg Asp Tyr Tyr Asp Ser Gly Gly Tyr Phe Thr 15 10 <210> 335 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 335 Gly Arg Asp Tyr Tyr Asp Ser Gly Gly Tyr Phe Thr Val Ala Phe Asp 15 10 15 He <210> 336 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 336 Asp Arg His Asn Tyr Tyr Asp Ser Ser Gly Ser Tyr Ser 1 5 10 <210> 337 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 337 Asp Arg His Asn Tyr Tyr Asp Ser Ser Gly Ser Tyr Ser Asp Tyr 1 5 10 15 <210> 338 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 338 Asp Cys Pro Ala Pro Ala Lys Met Tyr Tyr Tyr Gly Ser Gly Ile Cys 1 5 10 15 Thr <210> 339 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 339 Asp Cys Pro Ala Pro Ala Lys Met Tyr Tyr Tyr Gly Ser Gly Ile Cys 1 5 10 15 Thr Phe Asp Tyr 20 <210> 340 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 340 Ala Phe Tyr Asp Ser Ala Asp 1 5 <210> 341 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 341 Ala Phe Tyr Asp Ser Ala Asp Asp Tyr 1 5 <210> 342 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 342 Arg Asp Tyr Tyr Asp Ser Ser Gly Pro Glu Ala Gly 1 5 10 <210> 343 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 343 Arg Asp Tyr Tyr Asp Ser Ser Gly Pro Glu Ala Gly Phe Asp Ile 1 5 10 15 <210> 344 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 344 Asp Gly Thr Leu Ile Asp Thr Ser Ala Tyr Tyr Tyr Leu 1 5 10 <210> 345 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 345 Asp Gly Thr Leu Ile Asp Thr Ser Ala Tyr Tyr Tyr Leu Tyr 1 5 10 <210> 346 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 346 Asn Ser Ser Asp Ser Ser 1 5 <210> 347 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 347 Asn Sen Ser Asp Ser Ser Val Leu Asp Val 15 10 <210> 348 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 348 Asp Gin Val Phe Asp Ser Gly Gly Tyr Asn His Arg 15 10 <210> 349 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 349 Asp Gin Val Phe Asp Ser Gly Gly Tyr Asn His Arg Phe Asp Ser 15 10 15 <210> 350 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 350 Asp Leu Glu Tyr Tyr Tyr Asp Ser Gly Gly His Tyr Ser Pro 15 10 <210> 351 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 351 Asp Leu Glu Tyr Tyr Tyr Asp Ser Gly Gly His Tyr Ser Pro Phe His 1 5 10 15 Tyr <210> 352 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 352 Asp Asp Ser Ser Gly Tyr 1 5 <210> 353 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 353 Asp Asp Ser Ser Gly Tyr Tyr Tyr Ile Asp Tyr 1 5 10 <210> 354 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 354 Gly His Tyr Tyr Asp Ser Pro Gly Gln Tyr Ser Tyr Ser 1 5 10 <210> 355 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 355 Gly His Tyr Tyr Asp Ser Pro Gly Gln Tyr Ser Tyr Ser Glu Tyr 1 5 10 15 <210> 356 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 356 Gly Gly Phe Arg Pro Pro Pro Tyr Asp Tyr Glu Ser Ser Ala Tyr Arg 1 5 10 15 Thr Tyr Arg <210> 357 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 357 Gly Gly Phe Arg Pro Pro Pro Tyr Asp Tyr Glu Ser Ser Ala Tyr Arg 1 5 10 15 Thr Tyr Arg Leu Asp Phe 20 <210> 358 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 358 Asp Ser Asp Thr Arg Ala Tyr 1 5 <210> 359 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 359 Asp Ser Asp Thr Arg Ala Tyr Tyr Trp Tyr Phe Asp Leu 1 5 10 <210> 360 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 360 Gly Arg His Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser Thr Pro Glu 1 5 10 15 <210> 361 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 361 Gly Arg His Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser Thr Pro Glu Asn 1 5 10 15 Tyr Phe Asp Tyr 20 <210> 362 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 362 Asp Pro Ser Tyr Tyr Tyr Asp Ser Ser Gly Leu Pro Leu 1 5 10 <210> 363 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 363 Asp Pro Ser Tyr Tyr Tyr Asp Ser Ser Gly Leu Pro Leu His Gly Met 1 5 10 15 Asp Val <210> 364 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 364 Thr Tyr Tyr Tyr Asp Sen Ser Gly Tyn Leu Leu Thr Arg 15 10 <210> 365 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 365 Thr Tyn Tyn Tyn Asp Sen Sen Gly Tyn Leu Leu Thr Ang Tyn Phe Gin 15 10 15 His <210> 366 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 366 Asn Ala Pro His Tyn Asp Sen Sen Gly Tyn Tyn Gin Thr 15 10 <210> 367 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 367 Asn Ala Pro His Tyn Asp Ser Sen Gly Tyn Tyn Gin Thr Phe Asp Tyn 15 10 15 <210> 368 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 368 Gly Tyr His Ser Ser Ser Tyr Ala 1 5 <210> 369 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 369 Gly Tyr His Ser Ser Ser Tyr Ala Asp Ala Phe Asp Ile 1 5 10 <210> 370 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 370 Pro Ile Gly Tyr Cys Ser Gly Gly Ser Cys 1 5 10 <210> 371 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 371 Pro Ile Gly Tyr Cys Ser Gly Gly Ser Cys Tyr Ser Phe Asp Tyr 1 5 10 15 <210> 372 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 372 Thr His Gly Thr Tyr Val Thr Ser Gly Tyr Tyr Pro Lys Ile 1 5 10 <210> 373 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 373 Thr His Gly Thr Tyr Val Thr Ser Gly Tyr Tyr Pro Lys Ile 1 5 10 <210> 374 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 374 Gly Ala Thr Tyr Tyr Tyr Glu Ser Ser Gly Asn Tyr Pro 1 5 10 <210> 375 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 375 Gly Ala Thr Tyr Tyr Tyr Glu Ser Ser Gly Asn Tyr Pro Asp Tyr 1 5 10 15 <210> 376 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 376 Ala Phe Tyr His Tyr Asp Ser Thr Gly Tyr Pro Asn Arg Arg Tyr 1 5 10 15 <210> 377 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 377 Ala Phe Tyr His Tyr Asp Ser Thr Gly Tyr Pro Asn Arg Arg Tyr Tyr 1 5 10 15 Phe Asp Tyr <210> 378 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 378 Ser Tyr Ser Tyr Tyr Tyr Asp Ser Ser Gly Tyr Trp Gly Gly 1 5 10 <210> 379 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 379 Ser Tyr Ser Tyr Tyr Tyr Asp Ser Ser Gly Tyr Trp Gly Gly Tyr Phe 1 5 10 15 Asp Tyr <210> 380 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 380 Leu Ser Pro Tyr Tyr Tyr Asp Ser Ser Ser Tyr His 1 5 10 <210> 381 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 381 Leu Ser Pro Tyr Tyr Tyr Asp Ser Ser Ser Tyr His Asp Ala Phe Asp 1 5 10 15 Ile <210> 382 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 382 Glu Glu Asp Tyr Tyr Asp Ser Ser Gly Gln Ala Ser 1 5 10 <210> 383 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> misc_feature <222> (17)..(17) <223> Xaa can be any naturally occurring amino acid <400> 383 Glu Glu Asp Tyr Tyr Asp Ser Ser Gly Gln Ala Ser Tyr Asn Trp Phe 1 5 10 15 Xaa Pro <210> 384 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 384 Glu Thr Asn Tyr Tyr Asp Ser Gly Gly Tyr Pro Gly 1 5 10 <210> 385 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 385 Glu Thr Asn Tyr Tyr Asp Ser Gly Gly Tyr Pro Gly Phe Asp Phe 1 5 10 15 <210> 386 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 386 Gly Asp His Tyr Tyr Asp Arg Ser Gly Tyr Arg His 1 5 10 <210> 387 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 387 Gly Asp His Tyr Tyr Asp Arg Ser Gly Tyr Arg His Ser Tyr Tyr Tyr 1 5 10 15 Tyr Ala Met Asp Val 20 <210> 388 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 388 Asp Arg Ser Ser Gly Asn 1 5 <210> 389 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 389 Asp Arg Ser Ser Gly Asn Tyr Phe Asp Gly Met Asp Val 1 5 10 <210> 390 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 390 Gly Arg Ser Arg Tyr Ser Gly Tyr Gly 1 5 <210> 391 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 391 Gly Arg Ser Arg Tyr Ser Gly Tyr Gly Phe Tyr Ser Gly Met Asp Val 1 5 10 15 <210> 392 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 392 Asp Asp Thr Ser Gly Tyr Gly Pro 1 5 <210> 393 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 393 Asp Asp Thr Ser Gly Tyr Gly Pro Tyr Tyr Phe Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 394 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 394 Arg Ala Tyr Tyr Asp Thr Ser Phe Tyr Phe Glu Tyr 1 5 10 <210> 395 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 395 Arg Ala Tyr Tyr Asp Thr Ser Phe Tyr Phe Glu Tyr Tyr 1 5 10 <210> 396 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 396 Asp Arg Ile Asp Tyr Tyr Lys Ser Gly Tyr Tyr Leu Gly Ser Ala 1 5 10 15 <210> 397 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 397 Asp Arg Ile Asp Tyr Tyr Lys Ser Gly Tyr Tyr Leu Gly Ser Ala Asp 1 5 10 15 Ser <210> 398 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 398 Asp Thr Asp Ser Ser Ser His Tyr Gly 1 5 <210> 399 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 399 Asp Thr Asp Sen Ser Ser His Tyr Gly Arg Phe Asp Pro 15 10 <210> 400 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 400 Val Ser lie Ser His Tyr Asp Ser Ser Gly Arg Pro Gin Arg Val Phe 15 10 15 <210> 401 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 401 Val Ser lie Ser His Tyr Asp Ser Ser Gly Arg Pro Gin Arg Val Phe 15 10 15 Tyr Gly Met Asp Val 20 <210> 402 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 402 Gin Ala Arg Glu Asn Val Phe Tyr Asp Sen Sen Gly Pno Thn Ala Pno 15 10 15 <210> 403 <211> 19 <212> PRT <213> Antificial Sequence <220> <223> Synthetic peptide <400> 403 Gin Ala Ang Glu Asn Val Phe Tyn Asp Sen Sen Gly Pno Thn Ala Pno 15 10 15 Phe Asp His <210> 404 <211> 14 <212> PRT <213> Antificial Sequence <220> <223> Synthetic peptide <400> 404 Val Pno Ala Gly Asn Tyn Tyn Asp Thn Sen Gly Pno Asp Asn 15 10 <210> 405 <211> 16 <212> PRT <213> Antificial Sequence <220> <223> Synthetic peptide <400> 405 Val Pro Ala Gly Asn Tyr Tyr Asp Thr Ser Gly Pro Asp Asn Ala Asp 1 5 10 15 <210> 406 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 406 Trp Tyr Tyr Phe Asp Thr Ser Gly Tyr Tyr Pro Arg Asn Phe Tyr Tyr 1 5 10 15 Met Asp Val <210> 407 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 407 Trp Tyr Tyr Phe Asp Thr Ser Gly Tyr Tyr Pro Arg Asn Phe Tyr Tyr 1 5 10 15 Met Asp Val <210> 408 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 408 Gly Tyr Tyr Tyr Asp Ser Gly Gly Asn Tyr Asn Gly 1 5 10 <210> 409 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 409 Gly Tyr Tyr Tyr Asp Ser Gly Gly Asn Tyr Asn Gly Asp Tyr 1 5 10 <210> 410 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 410 Asp Leu Arg Ser Tyr Asp Pro Ser Gly Tyr Tyr Asn 1 5 10 <210> 411 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 411 Asp Leu Arg Ser Tyr Asp Pro Ser Gly Tyr Tyr Asn Asp Gly Phe Asp 1 5 10 15 Ile <210> 412 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 412 Gly Tyr Tyr Tyr Asp Arg Gly Gly Asn Cys Asn Gly 1 5 10 <210> 413 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 413 Gly Tyr Tyr Tyr Asp Arg Gly Gly Asn Cys Asn Gly Asp Tyr 1 5 10 <210> 414 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 414 Gly Tyr Tyr Tyr Asp Arg Gly Gly Asn Tyr Asn Gly 1 5 10 <210> 415 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 415 Gly Tyr Tyr Tyr Asp Arg Gly Gly Asn Tyr Asn Gly Asp Tyr 1 5 10 <210> 416 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 416 Thr His Tyr Asp Ser Ser Gly Leu 1 5 <210> 417 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 417 Thr His Tyr Asp Ser Ser Gly Leu Asp Ala Phe Asp Ile 1 5 10 <210> 418 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 418 Asp Asp Ser Ser Gly Ser 1 5 <210> 419 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 419 Asp Asp Ser Ser Gly Ser Tyr Tyr Phe Asp Tyr 1 5 10 <210> 420 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 420 Leu Ser Gly Gly Tyr Tyr Ser 1 5 <210> 421 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 421 Leu Ser Gly Gly Tyr Tyr Ser Asp Phe Asp Tyr 1 5 10 <210> 422 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 422 Gly Asp Tyr Ser Asp Ser Ser Asp Ser Tyr Ile 1 5 10 <210> 423 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 423 Gly Asp Tyr Sen Asp Ser Ser Asp Sen Tyn lie Asp Ala Phe Asp Val 15 10 15 <210> 424 <211> 12 <212> PRT <213> Antificial Sequence <220> <223> Synthetic peptide <400> 424 Gly Glu Thn Tyn Tyn Tyn Asp Sen Ang Gly Tyn Ala 15 10 <210> 425 <211> 15 <212> PRT <213> Antificial Sequence <220> <223> Synthetic peptide <400> 425 Gly Glu Thn Tyn Tyn Tyn Asp Sen Ang Gly Tyn Ala Phe Asp His 15 10 15 <210> 426 <211> 8 <212> PRT <213> Antificial Sequence <220> <223> Synthetic peptide <400> 426 Pno Thn Ang Asp Sen Sen Gly Tyn 1 5 <210> 427 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 427 Pro Thr Arg Asp Ser Ser Gly Tyr Tyr Val Gly Tyr 1 5 10 <210> 428 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 428 Gly Ser Phe Tyr Tyr Asp Ser Ser Gly Tyr Pro Pro 1 5 10 <210> 429 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 429 Gly Ser Phe Tyr Tyr Asp Ser Ser Gly Tyr Pro Pro Phe Asp Cys 1 5 10 15 <210> 430 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 430 Gly Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Leu 1 5 10 <210> 431 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 431 Gly Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Leu Leu Asp Tyr 1 5 10 15 <210> 432 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 432 Glu Glu Gly Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser Leu Gly Ala 1 5 10 15 <210> 433 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 433 Glu Glu Gly Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser Leu Gly Ala Ser 1 5 10 15 Asp Tyr <210> 434 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 434 Arg Pro Asp Ser Ser Gly Ser Arg Trp 1 5 <210> 435 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 435 Arg Pro Asp Ser Ser Gly Ser Arg Trp Tyr Phe Asp Tyr 1 5 10 <210> 436 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 436 Gly Tyr Tyr Asp Ile Ser Gly Tyr Tyr Phe 1 5 10 <210> 437 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 437 Gly Tyr Tyr Asp Ile Ser Gly Tyr Tyr Phe Asp Ala Phe Asn Ile 1 5 10 15 <210> 438 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 438 Asp Arg Gly Tyr Asp Ser Ser Gly Tyr Tyr Gly Asn 1 5 10 <210> 439 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 439 Asp Arg Gly Tyr Asp Ser Ser Gly Tyr Tyr Gly Asn Leu Asp Cys 1 5 10 15 <210> 440 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 440 Asp Arg Gly Tyr Asp Ser Ile Gly Tyr Tyr Gly Asn 1 5 10 <210> 441 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 441 Asp Arg Gly Tyr Asp Ser Ile Gly Tyr Tyr Gly Asn Leu Asp Cys 1 5 10 15 <210> 442 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 442 Ala Glu Asp Leu Thr Tyr Tyr Tyr Asp Arg Ser Gly Trp Gly Val His 1 5 10 15 Gly Leu Leu <210> 443 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 443 Ala Glu Asp Leu Thr Tyr Tyr Tyr Asp Arg Ser Gly Trp Gly Val His 1 5 10 15 Gly Leu Leu Tyr Tyr Phe Asp Tyr 20 <210> 444 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 444 Leu Tyr Pro His Tyr Asp Ser Ser Gly Tyr Tyr Tyr Val 1 5 10 <210> 445 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 445 Leu Tyr Pro His Tyr Asp Ser Ser Gly Tyr Tyr Tyr Val Leu Asp Tyr 1 5 10 15 <210> 446 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 446 Asp Arg Val Gly Tyr Tyr Asp Ser Ser Gly Tyr Pro Pro Gly Ser Pro 1 5 10 15 <210> 447 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 447 Asp Arg Val Gly Tyr Tyr Asp Ser Ser Gly Tyr Pro Pro Gly Ser Pro 1 5 10 15 Leu Asp Tyr