ANTI-VASA ANTIBODIES, AND METHODS OF PRODUCTION AND USE THEREOF

Abstract

Anti-VASA antibodies (mAbs), particularly humanized mAbs that specifically bind to VASA with high affinity, are disclosed. The amino acid sequences of the CDRs of the light chains and the heavy chains, as well as consensus sequences for these CDRs, of these anti-VASA mAbs are provided. The disclosure also provides nucleic acid molecules encoding the anti-VASA mAbs, expression vectors, host cells, methods for making the anti-VASA mAbs, and methods for expressing the anti-VASA mAbs. Finally, methods of using the anti-VASA mAbs to isolate and/or purify cells expressing VASA are disclosed.

Description

[0001] This application is a continuation of U.S. application Ser. No. 15/203,040, filed Jul. 6, 2016, which is a continuation of U.S. application Ser. No. 14/856,380, filed Sep. 16, 2015 (now U.S. Pat. No. 9,403,913), which claims the benefit of priority of U.S. Provisional Application No. 62/089,054, filed Dec. 8, 2014, and U.S. Provisional Application No. 62/051,130, filed Sep. 16, 2014, the entire contents of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present disclosure relates generally to antibodies, their production and use. Specifically, the present disclosure pertains to antibodies which specifically bind to the human VASA protein, methods of producing such antibodies, and diagnostic, therapeutic and clinical methods of using such antibodies.

BACKGROUND

[0003] The VASA protein was identified in Drosophila as a component of the germplasm that encodes a DEAD-family ATP-dependent RNA helicase (Liang et al. (1994), Development, 120:1201-11; Lasko et al. (1988) Nature 335:611-17). The molecular function of VASA is directed to binding target mRNAs involved in germ cell establishment, oogenesis, and translation onset (Gavis et al. (1996), Development 110:521-28). VASA is required for pole cell formation and is exclusively restricted to the germ cell lineage throughout development.

[0004] Vasa homolog genes have been isolated in various animal species, and VASA can be used as a molecular marker for the germ cell lineage in most animal species (Noce et al. (2001), Cell Structure and Function 26:131-36). Castrillon et al. (2000), Proc. Natl. Acad. Sci. (USA) 97(17):958590-9590, for example, demonstrated that the human Vasa gene is expressed in ovary and testis but is undetectable in somatic tissues.

[0005] The existence of mammalian female germline stem cells, also known as oogonial stem cells or ovarian stem cells (OSCs) or egg precursor cells, in the somatic tissue of mammalian ovaries was first described in Johnson et al. (2004), Nature 428:145-50, and has now been confirmed by other research groups (e.g., Zou et al. (2009), Nature Cell Biology, published online DOI: 10.1038/ncb1869; Telfer & Albertini (2012), Nature Medicine 18(3):353-4). The potential use of OSCs to produce oocytes for use in artificial reproduction technologies (ART), including in vitro fertilization (IVF), or as sources of highly functional mitochondria for mitochondrial transfer to oocytes, as well as the use of OSCs to treat various symptoms of menopause, have been described in the scientific and patent literature (e.g., Tilly & Telfer (2009), Mol. Hum. Repro. 15(7):393-8; Zou et al. (2009), supra; Telfer & Albertini (2012), supra; White et al. (2012), Nature Medicine 18(3):413-21; WO 2005/121321; U.S. Pat. No. 7,955,846; U.S. Pat. No. 8,652,840; WO2012/142500; U.S. Pat. No. 8,642,329 and U.S. Pat. No. 8,647,869).

[0006] When OSCs were first characterized by Johnson et (2004), supra, it was demonstrated that the cells expressed the VASA protein, and antibodies against the VASA protein have been used to isolate OSCs from ovarian tissue homogenates (e.g., Zou et al. (2009), supra; White et al. (2012), supra). Moreover, White et al. (2012), supra, demonstrated that antibodies to an N-terminal domain of VASA could not be used to isolate viable VASA-expressing OSCs whereas antibodies to a C-terminal domain could effectively isolate the cells, suggesting that the C-terminal domain, but not the N-terminal domain, was extracellular and thus accessible to the antibodies.

[0007] The production of anti-VASA polyclonal antibodies was first described in Castrillon et al. (2000), supra, and WO01/36445. Polyclonal antibodies directed to the C-terminal portion of human VASA protein are commercially available from Abeam plc (Cambridge, UK; Product Code AB13840), and R&D Systems, Inc. (Minneapolis, Minn.; Catalog No. AF2030), and a monoclonal antibody directed against the N-terminal portion of human VASA is also commercially available from R&D Systems, Inc. (Minneapolis, Minn.; Catalog No. AF2030).

[0008] There remains, however, a need for high affinity antibodies directed to the C-terminal extracellular domain of VASA for identifying (e.g., by immunohistochemistry or labeled antibodies) and isolating (e.g., by magnetic or fluorescence activated cell sorting) cells, including but not limited to OSCs, expressing VASA.

SUMMARY

[0009] Anti-VASA antibodies (mAbs), particularly humanized mAbs that specifically bind to VASA with high affinity, are disclosed. The amino acid sequences of the CDRs of the light chains and the heavy chains, as well as consensus sequences for these CDRs, of these anti-VASA mAbs are provided. The disclosure also provides nucleic acid molecules encoding the anti-VASA mAbs, expression vectors, host cells, methods for making the anti-VASA mAbs, and methods for expressing the anti-VASA mAbs. Finally, methods of using the anti-VASA mAbs to isolate and/or purify cells expressing VASA are disclosed.

[0010] These and other aspects and embodiments of the disclosure are illustrated and described below. Other systems, processes, and features will become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, processes, and features be included within this description, be within the scope of the present invention, and be protected by the accompanying claims.

BRIEF DESCRIPTION OF THE FIGURES

[0011] FIG. 1 provides the amino acid sequence of the human VASA protein isoform 1 from GenBank Accession from NP_077726 (SEQ ID NO: 1).

[0012] FIG. 2 provides the amino acid sequence of the mouse VASA homolog protein isoform 1 from GenBank Accession from NP_01139357 (SEQ ID NO: 2).

[0013] FIG. 3 provides an amino acid alignment between the C-terminal portion of the human VASA protein (residues 690-724 of SEQ ID NO: I) and the mouse VASA homolog (residues 691-728 of SEQ ID NO: 2).

[0014] FIG. 4A shows the region of the C-terminal domains of the VASA/DDX4 polypeptide that is reactive with an antibody of the invention and the control antibody (AB13840, Abeam plc, Cambridge, UK) and FIG. 4B shows binding of the control antibody to the VASA protein and the V1 and V2 polypeptides.

[0015] FIG. 5A shows dose response binding curves of the affinity for VASA of 1E9 and 1A12; and FIG. 5B shows the results of ELISA assays with the VASA, V1 and V2 peptides that suggest that 1E9 binds the same epitope as the commercially available rabbit polyclonal antibody (AB13840, Abeam plc, Cambridge, UK). NC=negative control; VASA=SEQ ID NO: 1 residues 700-724; VASA-1=V1 or SEQ ID NO: 1 residues 712-721; VASA-2=V2 or SEQ ID NO: 1 residues 700-709.

[0016] FIG. 6A shows dose response binding curves of the affinity for VASA of the IgG and scFv-Fc forms of 1E9; and FIG. 6B shows the results of ELISA assays of the binding of the IgG and scFv-Fc forms of 1E9 with the VASA, V1 and V2 peptides. NC=negative control; VASA=SEQ ID NO: 1 residues 700-724; VASA-1=V1 or SEQ ID NO: 1 residues 712-721; VASA-2=V2 or SEQ ID NO: 1 residues 700-709.

[0017] FIG. 7A shows the results of binding experiments with three anti-VASA hybridoma antibodies (2M1/1K3, 2M1/1K23 and M1/1L5) and two negative controls (2M1/1F5 and 2M1/1H5) which are not VASA-specific; FIG. 7B shows close response curves of four VASA-specific hybridoma antibodies (2M1/1K3, 2M1/1K23 and 2M1/1L5) compared to 1E9-lambda; and FIG. 7C shows dose response curves of the VASA-specific hybridoma antibody 2M1/2K4 compared to 1E9-lambda.

[0018] FIG. 8 shows the result of subtyping analysis for anti-VASA antibodies from eight hybridomas (2M1/1L20, 2M1/1J20, 1M1/1C9, 2M1/1N3, 2M1/1K23, 1M1/1L5 and 2M1/2K4).

[0019] FIGS. 9A-9B show alignments of some of the VL sequences of the anti-VASA invention. The figure indicates the approximate locations of the three CDR regions (bold, underscore) and the SEQ ID NO corresponding to each sequence.

[0020] FIGS. 10A-10B show alignments of some of the VH sequences of the anti-VASA invention. The figure indicates the approximate locations of the three CDR regions (bold, underscore) and the SEQ ID NO corresponding to each sequence.

[0021] FIG. 11 shows alignments of the unique CDR sequences of the VL regions of FIG. 9.

[0022] FIG. 12 shows alignments of the unique CDR sequences of the VH regions of FIG. 10.

DETAILED DESCRIPTION

[0023] The present disclosure relates to isolated antibodies (Abs), particularly Abs that bind specifically to VASA with high affinity. In certain embodiments, the anti-VASA Abs are derived from particular heavy and light chain sequences and/or comprise particular structural features, such as CDR regions comprising particular amino acid sequences. This disclosure provides isolated anti-VASA Abs, methods of making such anti-VASA Abs, immunoconjugates and bispecific molecules comprising such anti-VASA Abs, and methods of expressing such anti-VASA Abs. This disclosure also relates to methods of using the anti-VASA Abs to isolate and/or purify cells expressing VASA, including mammalian female germline stem cells or oogonial stem cells (OSCs) or egg precursor cells and their progenitor cells.

[0024] In order that the present disclosure may be more readily understood, certain terms are defined. Additional definitions are set forth throughout the detailed description.

Definitions

[0025] The term "antibody" or abbreviation "Ab," as used herein, includes whole antibodies and any antigen binding fragment (i.e., "antigen-binding portion") or single chains thereof, with or without native glycosylation. A complete "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds or an antigen binding portion thereof. Each heavy chain includes a heavy chain variable region (V.sub.H) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, C.sub.H1, C.sub.H2, and C.sub.H3. Each light chain includes a light chain variable region (V.sub.L) and a light chain constant region with one domain, C.sub.L. The V.sub.H and V.sub.L regions can be further subdivided into complementarity determining regions (CDR) and framework regions (FR). The V.sub.H and V.sub.L regions each include three CDRs, designated CDR1, CDR2 and CDR3, that interact with an antigen (e.g., VASA).

[0026] The term "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., VASA). Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, F(ab').sub.2 fragment, Fab' fragment. Fd fragment, Fv fragment, scFv fragment, dAb fragment, and an isolated CDR.

[0027] The term "monoclonal antibody" or "monoclonal antibody preparation," as used herein, refers to a preparation of antibody molecules consisting essentially of antibodies having a single heavy chain amino acid sequence and a single light chain amino acid sequence (but which may have heterogeneous glycosylation).

[0028] The term "humanized antibody," as used herein, includes antibodies having constant region and variable region framework regions (FRs) but not CDRs derived from human germline immunoglobulin sequences.

[0029] The term "recombinant antibody," as used herein, includes all antibodies prepared, expressed, created, or isolated by recombinant means. In certain embodiments, recombinant antibodies are isolated from a host cell transformed to express the antibody (e.g., from a transfectoma). In other embodiments, recombinant antibodies are isolated from a recombinant, combinatorial antibody library, such as a phage display library. Recombinant antibodies may also be prepared, expressed, created, or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.

[0030] The term "isotype," as used herein, refers to the heavy chain class (e.g., IgA, IgE, IgG, and IgM for human antibodies) or light chain class (e.g., kappa or lambda in humans) encoded by the constant region genes. The term "subtype" refers to subclasses within the subtype (e.g., IgA.sub.1, IgA.sub.2, IgG.sub.1, IgG.sub.2, IgG.sub.3, IgG.sub.4 in humans).

[0031] The phrase "an antibody specific for" a specified antigen is used interchangeably herein with the phrase "an antibody which specifically binds to" a specified antigen. As used herein, the term "K.sub.a" refers to the association rate and the term "K.sub.d" to the dissociation rate of a particular antibody-antigen complex. The term "K.sub.D" refers to the dissociation constant, which is obtained from the ratio of K.sub.d to K.sub.a and expressed as a molar concentration (M). According to some embodiments, an antibody that "specifically binds to human VASA" is intended to refer to an antibody that binds to human VASA with a K.sub.D of 5.times.10.sup.-8 M or less, more preferably 1.times.10.sup.-8 M or less.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Anti-VASA Antibodies

[0033] The invention provides a variety of new antibodies with high affinity against the human VASA protein, particularly the C-terminal region. The antibodies may comprise the complete VH and VL regions disclosed herein, or may comprise only the CDR sequences disclosed herein. In addition, based upon CDR sequences disclosed herein, sequence motifs for CDR sequences are provided, and the antibodies may comprise CDR sequences defined by the motifs.

[0034] The CDR sequences of the invention (including both the CDRs disclosed in FIGS. 11 and 12 and the CDRs defined by the sequence motifs disclosed herein) can be combined with other immunoglobulin sequences according to methods well known in the art to produce immunoglobulin molecules with antigen-binding specificity determined by the CDRs of the invention.

[0035] In some embodiments, the CDRs of the invention are combined with framework region (FR) and constant domain (CH or CL) sequences from other antibodies. For example, although some of the CDRs disclosed herein are derived from murine hybridomas and have murine FR and constant domain sequences, they can be recombined with human or other mammalian FR and constant domain sequences to produce humanized or other recombinant antibodies. The production of such recombinant antibodies is well known to those of skill in the art and requires only routine experimentation.

[0036] The type of constant regions included in such recombinant antibodies can be chosen according to their intended use. For example, if the antibodies are intended for therapeutic use to target VASA-expressing cells for destruction, heavy chain constant domains (i.e., Fc regions) of IgG subtypes can be used. If the antibodies are intended only as reagents for labeling cells (e.g., for fluorescence-activated cell sorting (FACS)), a complete antibody, antigen binding fragment (Fab), single-chain variable fragment (Fsc), single domain antibody (sdAb) or even non-antibody immunoglobulin molecule (e.g., an MHC receptor extracellular domain) can be used with the CDRs of the invention.

[0037] The CDRs of the invention can be selected independently such that the CDR1, CDR2 and CDR3 sequences of a given variable light (VL) chain or variable heavy (VH) chain can be chosen from different original VL and VH chains, from different VL and VH CDR motifs, or from a combination of the disclosed CDRs and motifs. However, sequences for light chain CDRs should be selected from the disclosed VL CDRs or VL CDR motifs, and sequences for heavy chain CDRs should be selected from the disclosed VH CDRs or VH CDR motifs. Similarly, the sequences for CDR1 regions should be selected from the disclosed CDR1 or CDR1 motif sequences, the sequences for CDR2 regions should be selected from the disclosed CDR2 or CDR2 motif sequences, and the sequences for CDR3 regions should be selected from the disclosed CDR3 or CDR3 motif sequences, for VL or VH chains as appropriate.

Methods of Using Anti-VASA Antibodies to Detect or Isolate Cells

[0038] The anti-VASA antibodies of the invention can be used in standard methods of immunoaffinity purification, immunohistochemistry and immunotherapy, but with specific application to cells and tissue expressing the VASA protein.

[0039] For example, the anti-VASA antibodies of the invention can be used to isolate cells expressing VASA from a mixed population of cells including only a fraction of cells that express VASA. For example, female germline stem cells or oogonial stem cells or their precursors have been discovered to be present in ovarian tissue at very low proportions. Ovarian tissue (e.g., ovarian surface epithelial and/or cortex) can be excised, dissociated into individual cells, and subjected to techniques such as FACs using fluorescently-labeled anti-VASA antibodies or immunoaffinity purification using immobilized anti-VASA antibodies. The isolated VASA-expressing cells have various utilities in assisted reproductive technologies, as described above.

[0040] Alternatively, immunohistochemistry may be performed using the anti-VASA antibodies of the invention to identify cells or tissues expressing VASA and/or to quantify VASA expression in such cells.

[0041] In addition, the anti-VASA antibodies of the invention can be used therapeutically to target VASA-expressing cells for destruction either by antibody-dependent cell-mediated cytotoxicity (ADCC) or immunotoxins comprising anti-VASA antibodies of the invention conjugated to radio- or chemo-toxic moieties. Antibody-drug conjugates of the anti-VASA antibodies of the invention could also be used to deliver therapeutic drugs to VASA-expressing cells.

Nucleic Acid Molecules Encoding Anti-VASA Antibodies

[0042] The invention also provides nucleic acid molecules encoding the anti-VASA antibodies of the invention. Such nucleic acids can be designed using standard tables for the universal genetic code to choose codons which will encode the desired amino acid sequence, or specialized codon tables can be used that reflect codon biases characteristic of different organisms. Thus, for example, to optimize expression of the anti-VASA antibodies of the invention in CHO cells, a nucleic acid encoding the desired antibody can be designed using a codon table optimized for CHO cells.

[0043] The nucleic acids encoding the anti-VASA antibodies of the invention can be included in a wide variety of vectors known in the art, including cloning vectors (e.g., bacterial or mammalian cloning vectors), transformation vectors (e.g., homologous recombination, viral integration or autonomously replicating vectors) and expression vectors (e.g., high copy number, inducible or constitutive mammalian expression vectors)

Cells Expressing Anti-VASA Antibodies

[0044] Also provided are host cells expressing heterologous sequences encoding the anti-VASA antibodies of the invention. Such host cells can be useful for commercial production of the anti-VASA antibodies of the invention, and can be produced by transforming appropriate host cells with expression vectors described above.

[0045] In some embodiments the invention provides mammalian cells, including CHO cells, expressing the anti-VASA antibodies of the invention. However, those of skill in the art can express the antibodies in a variety of host cells, including bacterial, yeast, insect and mammalian systems. See, e.g., Verma et al. (1998), J. Immunol. Methods 216(1-2):165-81, incorporated by reference in its entirety herein.

EXAMPLES

Immunogenic Peptides

[0046] The following peptides were used as immunogens to generate antibodies against the C-terminal domain of human VASA and to screen for antibodies with high affinity binding to VASA:

TABLE-US-00001 (SEQ ID NO: 1 residues 712-721) VASA-1 (V1) immunogen: SQAPNPVDDE (SEQ ID NO: 1 residues 700-709) VASA-2 (V2) immunogen: GKSTLNTAGF

[0047] As shown in FIG. 3, these immunogens comprise amino acid sequences from the C-terminal domain of VASA that are highly conserved between the human VASA protein and the mouse VASA homolog.

Hybridoma Generation

[0048] Hybridomas were formed in separate experiments with the VASA peptide immunogens V1 and V2 (above). Peptides were conjugated to carrier proteins by standard methods. Conjugated peptides were used to immunize mice, and to increase the immune response through boosting with the conjugated peptide. Following a period of increased antibody titer in the sera, animals were sacrificed and spleens removed. Splenic B cells were fused to mouse fusion partner cell lines (SP2-0) for isolation and cloning. Hybridomas were formed by outgrowth at limiting dilution, and clones were developed by cloning titration experiments. The presence of VASA-reactive antibodies was examined by ELBA assays. Hybridomas were derived by outgrowth and stabilization of cells plated at limiting dilution cell cloning.

[0049] The binding of the VASA-reactive antibodies in the region of the C-terminal domains of the VASA/DDX4 polypeptide was compared with the binding control antibodies (AB13840, Abcam plc, Cambridge, UK) to delineate the similarity of the binding epitopes. Exemplary results are shown in FIG. 4.

Analysis of Hybridomas

[0050] Hybridomas were injected intraperitoneally into mice and, after allowing for a period of growth, ascites fluid was collected and purified, all using standard procedures, and then analyzed by ELISA.

[0051] Binding of the ascites-derived antibodies to the VASA, VASA-1 and VASA-2 polypeptides was used to select antibodies for further analysis. For example, as shown in FIG. 7, the binding of four anti-VASA hybridoma antibodies (2M1/1K3, 2M1/1K23, 2M1/1L5 and 2M1/2K4) were compared to two negative controls (2M1/1F5 and 2M1/1H5) which are not VASA-specific and/or to the 1E9-lambda antibody (described below).

Recombinant Library Panning

[0052] As an alternative to hybridoma technology, the generation of antibodies against amino acid residues 700-724 of human VASA/DDX4 was conducted using phage display technology. The phage display library was formed from a pool of normal B cells from .about.40 blood donors. Phage were used to display the scFv chain of an antibody

[0053] The results of panning the human naive say library against the VASA/DDX4 700-724 peptide were as shown in Table 1 below:

TABLE-US-00002 TABLE 1 Titer of output Titer of rescued Peptide Round phage (cfu/ml) phage (cfu/ml) ELISA results VASA 1.sup.st 10.sup.7 10.sup.13 / 2.sup.nd 10.sup.7 10.sup.13 / 3.sup.rd 10.sup.7 10.sup.12 No positive clones 4.sup.th 10.sup.7 10.sup.13 Two positive clones 5.sup.th 10.sup.7 10.sup.13 Several positive clones 6.sup.th 10.sup.7 / /

[0054] ELISA results of single colonies identified after 3 and 4 rounds of selection are shown in Tables 2-4 below. Two clones were of note: "1A12" (plate 1, row A, column 12) and "1E9" (plate 1, row E, column 9).

TABLE-US-00003 TABLE 3 plate 2-after 4 round of selection 1 2 3 4 5 6 7 8 9 10 11 12 VASA peptide A. 0.052 0.045 0.053 0.045 0.051 0.045 0.046 0.044 0.049 0.044 0.045 0.050 B. 0.049 0.051 0.051 0.045 0.042 0.054 0.046 0.045 0.055 0.045 0.048 0.053 C. 0.048 0.047 0.048 0.054 0.051 0.047 0.047 0.045 0.047 0.052 0.051 0.055 D. 0.062 0.050 0.048 0.047 0.059 0.056 0.059 0.063 0.048 0.057 0.052 0.061 E. 0.047 0.042 0.042 0.045 0.051 0.041 0.047 0.042 0.044 0.052 0.050 0.054 F. 0.047 0.049 0.040 0.042 0.046 0.043 0.046 0.042 0.052 0.045 0.051 0.054 G. 0.047 0.052 0.045 0.041 0.039 0.051 0.048 0.049 0.052 0.043 0.054 0.050 H. 0.055 0.048 0.054 0.042 0.043 0.048 0.048 0.049 0.051 0.051 0.048 0.054 non-relevant peptide A. 0.047 0.053 0.050 0.042 0.053 0.053 0.041 0.043 0.042 0.053 0.053 0.054 B. 0.052 0.053 0.054 0.054 0.053 0.043 0.043 0.045 0.053 0.045 0.055 0.054 C. 0.052 0.047 0.054 0.053 0.055 0.045 0.045 0.043 0.053 0.055 0.057 0.053 D. 0.047 0.049 0.054 0.056 0.047 0.049 0.054 0.051 0.056 0.062 0.065 0.062 E. 0.052 0.045 0.042 0.045 0.041 0.051 0.040 0.047 0.041 0.056 0.053 0.054 F. 0.052 0.053 0.041 0.045 0.052 0.053 0.054 0.052 0.533 0.049 0.045 0.053 G. 0.051 0.053 0.049 0.050 0.051 0.043 0.049 0.052 0.053 0.053 0.054 0.051 H. 0.055 0.052 0.054 0.053 0.045 0.051 0.051 0.051 0.052 0.062 0.054 0.053

TABLE-US-00004 TABLE 4 plate 3-after 4 rounds of selection 1 2 3 4 5 6 7 8 9 10 11 12 VASA peptide A. 0.074 0.052 0.058 0.076 0.052 0.063 0.052 0.055 0.040 0.052 0.054 0.072 B. 0.047 0.041 0.052 0.064 0.072 0.051 0.059 0.048 0.053 0.048 0.054 0.053 C. 0.051 0.042 0.042 0.044 0.053 0.056 0.052 0.048 0.044 0.048 0.060 0.056 D 0.057 0.049 0.045 0.051 0.053 0.046 0.067 0.047 0.046 0.046 0.059 0.058 E. 0.054 0.046 0.042 0.126 0.041 0.047 0.051 0.040 0.042 0.043 0.048 0.073 F. 0.077 0.045 0.040 0.047 0.042 0.040 0.042 0.039 0.041 0.053 0.051 0.051 G. 0.178 0.056 0.044 0.041 0.051 0.050 0.055 0.042 0.042 0.051 0.044 0.052 H. 0.054 0.042 0.045 0.041 0.049 0.039 0.045 0.089 0.050 0.051 0.061 0.055 non-relevant peptide A. 0.050 0.056 0.055 0.049 0.053 0.055 0.051 0.059 0.051 0.044 0.047 0.054 B. 0.058 0.075 0.061 0.064 0.073 0.061 0.053 0.054 0.059 0.056 0.059 0.063 C. 0.076 0.056 0.053 0.054 0.056 0.053 0.053 0.053 0.057 0.063 0.049 0.061 D. 0.069 0.052 0.052 0.058 0.056 0.048 0.059 0.059 0.056 0.052 0.051 0.056 E. 0.047 0.056 0.050 0.118 0.063 0.067 0.052 0.053 0.054 0.053 0.056 0.054 F. 0.053 0.054 0.054 0.052 0.054 0.054 0.053 0.053 0.043 0.056 0.046 0.056 G. 0.063 0.056 0.054 0.045 0.045 0.049 0.050 0.053 0.053 0.052 0.055 0.053 H. 0.058 0.055 0.054 0.047 0.053 0.048 0.050 0.051 0.054 0.053 0.053 0.058

[0055] ELISA results of single colonies identified after 5 rounds of selection are shown in Tables 5-7 below. Clones of note included 1A11, 1B4, 1B7, 1D4, 1D5, 1E2, 1E3, 1F7, 1G3, 1G12, 2B8, 2C7, 2E11, 2F1, 2G8, 2G-10, 2H9, 3B2, 3B5, 3B7, 3D11, 3E5, 3E12, 3F6 and 3H11.

[0056] Clones shown in bold were PCR amplified.

Conversion to scFv-Fc Fusion and Expression in Mammalian Cells

[0057] After 5 rounds of panning, DNA digestion patterns showed that many clones from the 5.sup.th round of panning were the same, indicating that additional rounds of selection and ELISA analysis were not needed.

[0058] Two unique clones (1A12, 1E9) were selected for conversion to scFv-Fc fusions for expression in mammalian cells and for ELISA and FACS analysis. FIG. 5A shows dose response binding curves that indicated that 1E9 had an EC50 of 0.02779 nM and 1A12 had an EC50 of 0.2156 nM. In addition, FIG. 5B shows the results of ELISA assays with the V1 and V2 VASA peptides which suggest that 1E9 binds the same epitope as the commercially available rabbit polyclonal antibody (AB13840, Abcam plc, Cambridge, UK).

[0059] Two different forms of the 1E9 antibody were compared: IgG and scFv-Fc. As shown in FIG. 6A, 1E9 IgG had an EC50 of 0.08919 nM and the 1E9 scFv-Fc had an EC50 of 0.3072 nM. In addition, as shown in FIG. 6B, both forms were specific towards the VASA-1 epitope.

Synthetic Antibody Gene Production

[0060] The following steps were employed to produce synthetic antibody genes:

[0061] (1) Subtype determination of hybridoma antibodies. The IgG subtypes of the hybridoma antibodies were determined using commercially available kits according to manufacturer's protocols (e.g., Mouse Monoclonal Antibody Isotyping Kit, Catalog No. MMT1, AbDSerotech, Kidlington, UK). FIG. 8 shows the result of subtyping analysis for anti-VASA antibodies from eight hybridomas (2M1/1L20, 2M1/1J20, 1M1/1C9, 2M1/1N3, 2M1/1K23, 1M1/1L5 and 2M1/2K4). All of the antibodies were IgG(, IgG2a or IgG2b.

[0062] (2) Degenerate primer synthesis. Based on the subtype information for the eight hybridoma antibodies tested, degenerate primers for mouse IgG VH and VL were designed using sequence information from a mouse IgG database (i.e., the International Immunogenetics Information System.RTM. or IMGT database; see Lefranc et al. (2003), Leukemia 17:260-266, and Alamyar et al. (2012), Methods Mol. Biol. 2012; 882:569-604). Ten degenerate forward primers were designed and synthesized for the VH chain and ten for the VL chain (9 for kappa and one for lambda chains). In addition, two degenerate reverse primers for the VH chain (one for the IgG1 and IgG2b subtypes, and one for the IgG2a subtype) and five for the VL chain (four for kappa and one for lambda chains) were designed and synthesized.

[0063] (3) RNA extraction, amplification, cloning and sequencing. RNA was extracted from hybridoma cells by standard techniques, first strand cDNA synthesis was performed by standard techniques using gene-specific and oligo(dT) primers, and the cDNA was amplified using gene-specific primers. The amplified DNA was then ligated into a commercially available bacterial cloning vector (pMD18-T, Sino Biological, Inc., Beijing, China). Standard methodologies were conducted to transform the ligation products into E. coli DH5a, and to sequence positive clones.

Antibody Sequence Analyses

[0064] Clones producing potentially useful anti-Vasa antibodies were DNA sequenced and the corresponding amino acid sequences were deduced. Sequences are disclosed for eight antibodies derived from the hybridomas described above (i.e., 1N23, 1K23, 2K4, 1C9, 1J20, 1L20, 1K3, 1L5), four additional antibodies derived from hybridomas produced under contract (i.e., CTA4/5, CTB4/11, CTC2/6, CTD2/6) and two antibodies derived from phage display (i.e., 1A12 and 1E9).

[0065] Variable Light Chain Sequences

[0066] VL of 1N23. Positive VL clones from the 1N23 hybridoma were sequenced and six were found to encode functional VL chains. These six clones were designated 1N23VL5-5, 1N23VL5-8_0816, 1N23VL1-8, 1N23VL1-2_0820, 1N23VL1-4_0820 and 1N23VL1-2.

[0067] VL of 1K23. Positive VL clones from the 1K23 hybridoma were sequenced and four were found to encode functional VL chains. These four clones were designated 1K23VL2-5, 1K23VL2-6, 1K23VL2-8_0822 and 1K23VL2-3_0829.

[0068] VL of 2K4. Positive VL clones from the 2K4 hybridoma were sequenced and eight were found to encode functional VL chains. These eight clones were designated 2K4VL1-3_0820, 2K4VL1-4, 2K4VL1-1, 2K4VL1-6_0820, 2K4VL2-5_0816, 2K4VL2-4, 2K4VL2-6_0816 and 2K4VL2-5.

[0069] VL of 1C9. Positive VL clones from the 1C9 hybridoma were sequenced and three were found to encode functional VL chains. These three clones were designated 1C9VL2-4, 1C9VL2-6 and IC9VL2-3_0816.

[0070] VL of 1J20. Positive VI clones from the 1J20 hybridoma were sequenced and three were found to encode functional VL chains. These three clones were designated 1J20VL5-2_0907, 1J20VL5-6_0907 and 1J20VL4-3_0901.

[0071] VL of 1L20. Positive VL clones from the 1L20 hybridoma were sequenced and one was found to encode a functional VL chain. That clone was designated 1L20VL5-0912_091.

[0072] VL of 1K3. Positive VL clones from the 1K3 hybridoma were sequenced and four were found to encode functional VL chains. These four clones were designated 1K3VL2-5, 1K3VL2-5, 1K3VL2-3 and 1K3VL2-4.

[0073] VL of 1L5. Positive VL clones from the 1L5 hybridoma were sequenced and two were found to encode functional VL chains. These two clones were designated 1L5VL2-4 and 1L5VL3-1.

[0074] Additional VLs. VL sequences were obtained for four additional hybridoma antibodies designated CTA4_VL, CTB4_VL, CTC6_CTD6_VL.

[0075] VL Sequence Alignments. Alignments of all of the VL sequences described above are shown in FIG. 9. The figure indicates the approximate locations of the three CDR regions (bold, underscore) and the SEQ ID NO corresponding to each sequence.

[0076] Unique VL CDR Sequences. Alignments of the unique CDR sequences of the VLs of FIG. 9 are shown in FIG. 11. Of the 34 VL sequences, there are only 5 unique CDR1 sequences, 6 unique CDR2 sequences and 8 unique CDR3 sequences, as shown in FIG. 11.

[0077] VL CDR Consensus Sequences. Based on the sequences disclosed in FIG. 11, as well as structure/function characteristics of the naturally occurring amino acids, consensus sequences for the VL CDRs can be determined.

[0078] One consensus sequence is VL CDR1 Motif 1:

TABLE-US-00005 (SEQ ID NO: 132) X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7 X.sub.8 X.sub.9 X.sub.10 X.sub.11

where X.sub.1 is Q, N, K, R, S or T; X.sub.2 is S, T, C, N or Q; X.sub.3 is I, L, V, M or A; X.sub.4 is V, L, I, M, A or absent; X.sub.5 is H, K, R or absent; X.sub.6 is S, T, C or absent; X.sub.7 is N, Q or absent; X.sub.8 is G, A or absent; X.sub.9 is N or Q; X.sub.10 is T, S, C, N or Q; and X.sub.11 is Y, F or W. In some embodiments, X.sub.1 is limited to Q, K or S; and/or X.sub.2 is limited to S or N; and/or X.sub.3 is limited to I or L; and/or X.sub.4 is limited to V, L or absent; and/or X.sub.5 is limited to H or absent; and/or X.sub.6 is limited to S or absent; and/or X.sub.7 is limited to N or absent; and/or X.sub.8 is limited to G or absent; and/or X.sub.9 is limited to N; and/or X.sub.10 is limited to T, S or N; and/or X.sub.11 is limited to Y or F. In some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to Q N I; in some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to Q S L; and in some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to K S L. In addition, in some embodiments, when X.sub.1 X.sub.2 X.sub.3 is Q S L or Q N I, then X.sub.4 is V; whereas in other embodiments, when X.sub.1 X.sub.2 X.sub.3 is K S L, then X.sub.4 is L. In some embodiments, when X.sub.9 X.sub.10 is N T, then X.sub.11 is Y.

[0079] Noting in particular that the VL CDR1 sequences of SEQ ID NOs: 86-88 are quite distinct from the others in FIG. 11, an alternative consensus sequence is VL CDR1 Motif 2:

TABLE-US-00006 (SEQ ID NO: 133) X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7 X.sub.8 X.sub.9 X.sub.10 X.sub.11

where X.sub.1 is Q, N, K or R; X.sub.2 is S, T, C, N or Q; X.sub.3 I, L, V, M or A; X.sub.4 is V, L, I, M or A; X.sub.5 is H, K or R; X.sub.6 is S, T or C; X.sub.7 is N or Q; X.sub.8 is G or A; X.sub.9 is N or Q; X.sub.10 is T, S or C; and X.sub.11 is Y, F or W. In some embodiments, X.sub.1 is limited to Q or K; and/or X.sub.2 is limited to S or N; and/or X.sub.3 is limited to I or L; and/or X.sub.4 is limited to V or L; and/or X.sub.5 is limited to H; and/or X.sub.6 is limited to S; and/or X.sub.7 is limited to N; and/or X.sub.8 is limited to G; and/or X.sub.9 is limited to N; and/or X.sub.10 is limited to T; and/or X.sub.11 is limited to Y. In some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to Q N I; in some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to Q S L; and in some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to K S L. In addition, in some embodiments, When X.sub.1 X.sub.2 X.sub.3 is Q S L or Q N I, then X.sub.4 is V; whereas in other embodiments, when X.sub.1 X.sub.1 X.sub.2 X.sub.3 is K S L, then X.sub.4 is L. In some embodiments, when X.sub.9 X.sub.10 is N T, then X.sub.11 is Y.

[0080] For the VL CDR2, one consensus sequence is VL CDR2 Motif 1:

TABLE-US-00007 (SEQ ID NO: 134) Y.sub.1 Y.sub.2 Y.sub.3

where Y.sub.1 is K, R or H; Y.sub.2 is V, I, L, M, A, T, S or C; and Y.sub.3 is S, T, C, N or Q. In some embodiments, Y.sub.2 is limited to V, I, M or I; and/or Y.sub.3 is limited to S or N.

[0081] Noting in particular that the VL CDR2 sequences of SEQ ID NO: 94 is quite distinct from the others in FIG. 11, an alternative consensus sequence is VL CDR2 Motif 2:

TABLE-US-00008 (SEQ ID NO: 135) Y.sub.1 Y.sub.2 Y.sub.3

where Y.sub.1 is D or E; Y.sub.2 is N or Q; and Y.sub.3 is N or Q. In some embodiments, Y.sub.1 is limited to D; and/or Y.sub.2 is limited to N; and/or Y.sub.3 is limited to N.

[0082] Similarly, noting that the VL CDR2 sequences of SEQ ID NO: 95 is quite distinct from the others in FIG. 11, an alternative consensus sequence is VL CDR2 Motif 3:

TABLE-US-00009 (SEQ ID NO: 136) Y.sub.1 Y.sub.2 Y.sub.3

where Y.sub.1 is Q or N; Y.sub.2 is D or E; and Y.sub.3 is K, R or H. In some embodiments, Y.sub.1 is limited to Q; and/or Y.sub.2 is limited to D; and/or Y.sub.3 is limited to K.

[0083] For the VL CDR3, one consensus sequence is VL CDR3 Motif 1:

TABLE-US-00010 (SEQ ID NO: 137) Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 Z.sub.5 Z.sub.6 Z.sub.7 Z.sub.8 Z.sub.9 Z.sub.10

where Z.sub.1 is S, T, C, F, Y, M, L, V, I or A; Z.sub.2 is Q, N, S, T or C; Z.sub.3 is S, T, C, G, A, H, K, R, Q, N, F or F; Z.sub.4 is A, G, S, T, C, L, I, V, M, D or E; Z.sub.5 is K, R, E, D, S, T or C; Z.sub.6 is V, L, I, M, A, Y, F, W, S, T or C; Z.sub.7 is P, S, T, C or absent; Z.sub.8 is S, T, C or absent; Z.sub.9 is W, P, L, I, V, M, A, F, or Y; and Z.sub.10 is T, S, C, V, L, I, M, A. In some embodiments, Z.sub.1 is limited to S, F, M or L; and/or Z.sub.2 is limited to Q or S; and/or Z.sub.3 is limited to S, G, H, Q or Y; and/or Z.sub.4 is limited to A, S, T, L, or D; and/or Z.sub.5 is limited to H, E, D or S; and/or Z.sub.6 is limited to V, Y, F, or S; and/or Z.sub.7 is limited to P, S or absent; and/or Z.sub.8 is limited to S or absent; and/or Z.sub.9 is limited to W, P, L or F; and/or Z.sub.10 is limited to T or V.

[0084] Noting in particular that the VL CDR3 sequences of SEQ ID NOs: 96-98 have a positive charge at position Z.sub.5 whereas the others in FIG. 11 do not, an alternative consensus sequence is VL CDR3 Motif 2:

TABLE-US-00011 (SEQ ID NO: 138) Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 Z.sub.5 Z.sub.6 Z.sub.7 Z.sub.8 Z.sub.9 Z.sub.10

where Z.sub.1 is S, T, C, F or Y; Z.sub.2 is Q or N, Z.sub.3 is S, T, C, G or A; Z.sub.4 is A, G, S, T or C, Z.sub.5 H, K or R; Z.sub.6 is V, L, I, M or A; Z.sub.7 is P or absent; Z.sub.8 is absent; Z.sub.9 is W, P, L, I, V, M, A, F or Y; and Z.sub.10 S, or C. In some embodiments, Z.sub.1 is limited to S or F; and/or Z.sub.2 is limited to Q; and/or Z.sub.3 is limited to S or G; and/or Z.sub.4 is limited to A, S or T; and/or Z.sub.5 is limited to H; and/or Z.sub.6, is limited to V; and/or Z.sub.7 is limited to P or absent; and/or Z.sub.8 is limited to absent; and/or Z.sub.9 is limited to W, P, L or F; and/or Z.sub.10 is limited to T.

[0085] Noting in particular that the VL CDR3 sequences of SEQ ID NOs: 99-102 have a negative charge at position Z.sub.5 whereas the others in FIG. 11 do not, an alternative consensus sequence is VL CDR3 Motif 3:

TABLE-US-00012 (SEQ ID NO: 139) Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 Z.sub.5 Z.sub.6 Z.sub.7 Z.sub.8 Z.sub.9 Z.sub.10

where Z.sub.1 is M, C, L, V, A; Z.sub.2 is Q or N; Z.sub.3 is H, K, R, Q, N, A, Y or F; Z.sub.4 is L, I, V, M, A, D or E; Z.sub.5 is E or D; Z.sub.6 is Y or F; Z.sub.7 is P; Z.sub.8 is absent; Z.sub.9 is W, P, L, V, M, A, F or Y; and Z.sub.10 is T, S, or C. In some embodiments, Z.sub.1 is limited to M or L; and/or Z.sub.2 is limited to Q; and/or Z.sub.3 is limited to H, Q, G or Y; and/or Z.sub.4 is limited to L or D; and/or Z.sub.5 is limited to E or D; and/or Z.sub.6 is limited to Y or F; and/or Z.sub.7 is limited to P; and/or Z.sub.8 is limited to absent; and/or Z.sub.9 is limited to W, P, L or F; and/or Z.sub.10 is limited to T.

[0086] Noting in particular that the VL CDR3 sequence of SEQ ID NO: 103 is quite distinct from the others in FIG. 11, an alternative consensus sequence is VL CDR3 Motif 4:

TABLE-US-00013 (SEQ ID NO: 140) Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 Z.sub.5 Z.sub.6 Z.sub.7 Z.sub.8 Z.sub.9 Z.sub.10

where Z.sub.1 is S, T or C; Z.sub.2 is S, T or C; Z.sub.3 is Y or F; Z.sub.4 is T, S, or C; Z.sub.5 is S, T or C; Z.sub.6 is S, T or C; Z.sub.7 is S, T or C; Z.sub.8 is S, T or C; Z.sub.9 is W, P, F or Y; and Z.sub.10 is V, L, I, M, A, T, S or C. In some embodiments, Z.sub.1 is limited to S or T; and/or Z.sub.2 is limited to S or T; and/or Z.sub.3 is limited to Y; and/or Z.sub.4 is limited to T or S; and/or Z.sub.5 is limited to S or T; and/or Z.sub.6 is limited to S or T; and/or Z.sub.7 is limited to S or T; and/or Z.sub.8 is limited to S or T; and/or Z.sub.9 is limited to W, P or F; and/or Z.sub.10 is limited to V, L, I, T or S. In some embodiments, Z.sub.1 is limited to S; and/or Z.sub.2 is limited to S; and/or Z.sub.3 is limited to Y; and/or Z.sub.4 is limited to T; and/or Z.sub.5 is limited to S; and/or Z.sub.6 is limited to S; and/or Z.sub.7 is limited to S; and/or Z.sub.8 is limited to S; and/or Z.sub.9 is limited to W; and/or Z.sub.10 is limited to V.

[0087] Finally, noting in particular that the VL CDR3 sequence of SEQ ID NO: 104 is quite distinct from the others in FIG. 11, an alternative consensus sequence is VL CDR3 Motif 5:

TABLE-US-00014 (SEQ ID NO: 141) Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 Z.sub.5 Z.sub.6 Z.sub.7 Z.sub.8 Z.sub.9 Z.sub.10

where Z.sub.1 is Q or N; Z.sub.2 is A or G; Z.sub.3 is W, Y or F; Z.sub.4 is D or E; Z.sub.5 is S, T or C; Z.sub.6 is R, K or H; Z.sub.7 is T, S or C; Z.sub.8 is V, I, L, M or A; Z.sub.9 is V, I, L, M or A; and Z.sub.10 is I, L, V, M or A. In some embodiments, Z.sub.1 is limited to Q; and/or Z.sub.2 is limited to A; and/or Z.sub.3 is limited to W; and/or Z.sub.4 is limited to D; Z.sub.5 is limited to S; and/or Z.sub.6 is limited to R; and/or Z.sub.7 is limited to T; and/or Z.sub.8 is limited to V; and/or Z.sub.9 is limited to V; and/or Z.sub.10 is limited to I.

[0088] Variable Heavy Chain Sequences

[0089] VH of 1N23. Positive VH clones from the 1N23 hybridoma were sequenced and all four were found to encode functional VH chains. These four clones were designated 1N23VH3-5, 1N23VH3-7, 1N23VH2-1 and 1N23VH1-5.

[0090] VH of 1K23. Positive VH clones from the 1K23 hybridoma were sequenced and six were found to encode functional VH chains. These six clones were designated 1K23VH2-1_0910, 1K23VH1-4_0907, 1K23VH1-10_0907, 1K23VH8-4_0907, 1K23VH8-5_0907 and 1K23VH8-9_0907.

[0091] VH of 2K4. Positive VH clones from the 2K4 hybridoma were sequenced and four were found to encode functional VH chains. These four clones were designated 2K4VH3-8, 2K4VH2-8, 2K4VH1-1 and 2K4VH1-4.

[0092] VH of 1C9. Positive VH clones from the 1C9 hybridoma were sequenced and eight were found to encode functional VL chains. These eight clones included four unique sequences which are designated 1C9VH2-404-8_1024, 1C9VH2-405-12_1024, 1C9VH2-411-1_1024 and 1C9VH2-406-4_1024.

[0093] VH of 1J20. Positive VH clones from the 1J20 hybridoma were sequenced and two were found to encode functional VH chains. These two clones were designated 1J20VH1-7_0910 and 1J20VH1-1-6_0829.

[0094] VH of 1L20. Positive VH clones from the 1L20 hybridoma were sequenced and three were found to encode functional VH chains. These three clones were designated 1L20VH2-3_0903, 1L20VH2-1_0907 and 1L20VH.sub.2-3_0910.

[0095] VH of 1K3. Positive VH clones from the 1K3 hybridoma were sequenced and five were found to encode functional VH chains. These five clones were designated 1K3VH6-7, 1K3VH6-8_0816, 1K3VH3-4, 1K3VH3-4 and 1K3VH3-3_0816.

[0096] VH of 1L5. Positive VH clones from the 1L5 hybridoma were sequenced and nine were found to encode functional VH chains, These nine clones were designated 1L5VH003-5-8_0907, 1L5VH003-6-3_0907, 1L5VH001-7-6_0907, 1L5VH001-6-5_0907, 1L5VH001-6-11_0907, 1L5VH003-6-2_0910, 1L5VH.sub.001-6-12_0907, 1L5VH003-3-4_0907 and 1L5VH003-3-8_0907.

[0097] Additional VHs. VH sequences were obtained for four additional hybridoma antibodies designated CTA5_VH, CTB11_VH, CTC2_VH, CTD2_VH.

[0098] VH Sequence Alignments. Alignments of all of the VH sequences described above are shown in FIG. 10. The figure indicates the approximate locations of the three CDR regions (bold, underscore) and the SEQ ID NO corresponding to each sequence.

[0099] Unique VH CDR Sequences. Alignments of the unique CDR sequences of the VHs of FIG. 10 are shown in FIG. 12. Of the 43 VH sequences, there are only 8 unique CDR1 sequences, 9 unique CDR2 sequences and 10 unique CDR3 sequences, as shown in FIG. 12.

[0100] VH CDR Consensus Sequences. Based on the sequences disclosed in FIG. 12, as well as structure/function characteristics of the naturally occurring amino acids, consensus sequences for the VH CDRs can be determined.

[0101] For the VH CDR1, one consensus sequence is VH CDR1 Motif 1:

TABLE-US-00015 (SEQ ID NO: 142) X1 X2 X3 X4 X5 X6 X7 X8

where X.sub.1 is G or A; X.sub.2 is Y, F, W, D or E; X.sub.3 is T, S, C or M; X.sub.4 is F, Y, W, V, L, I, M or A; X.sub.5 is T, S, C, N, or Q; X.sub.6 is S, T, C, A or G; X.sub.7 is Y, F, W, N, Q, G or A; and X.sub.8 is W, A, G, Y or F. In some embodiments, X.sub.1 is limited to G; and/or X.sub.2 is limited to Y, F or D; and/or X.sub.3 is limited to T or S; and/or X.sub.4 is limited to F or V; and/or X.sub.5 is limited to T, S or N; and/or X.sub.6 is limited to S, T or A; and/or X.sub.7 is limited to Y, F, N or G; and/or X.sub.8 is limited to W, A or Y. In some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to G Y T; and in some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to G F T. In addition, in some embodiments, the subsequence X.sub.1 X.sub.7 X.sub.8 is limited to S Y W.

[0102] Noting in particular that the VH CDR1 sequence of SEQ NOs: 109-110 and 112 are quite distinct from the others in FIG. 12, an alternative consensus sequence is VH CDR1 Motif 2:

TABLE-US-00016 (SEQ ID NO: 143) X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7 X.sub.8

where X.sub.1 is G or A; X.sub.2 is Y, F or W; X.sub.3 is T, S, C or M; X.sub.4 is F, Y or W; X.sub.5 T, S or C; X.sub.6 is S, T or C; X.sub.7 is Y, F or W; and X.sub.8 is W. In some embodiments, X.sub.1 is limited to G; and/or X.sub.2 is limited to Y or F; and/or X.sub.3 is limited to T or S; and/or X.sub.4 is limited to F; and/or X.sub.5 is limited to T or S; and/or X.sub.6 is limited to S or T; and/or X is limited to Y or F; and/or X.sub.8 is limited to W. In some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to G Y T; and in some embodiments, the subsequence X.sub.1 X.sub.2 X.sub.3 is limited to G F T. In addition, in some embodiments, the subsequence X.sub.1 X.sub.7 X.sub.8 is limited to S Y W.

[0103] For the VH CDR2, one consensus sequence is VH CDR2 Motif 1:

TABLE-US-00017 (SEQ ID NO: 144) Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10

where Y.sub.1 is I, L, V, M or A; Y.sub.2 is Y, F, H, R, K, S or T; Y.sub.3 is P, S, T, Y, F, R, K or H; Y.sub.4 is G, A, S, T, K, R, H, D or E; Y.sub.5 is T, S or absent; Y.sub.6 is R, K, H or absent; Y.sub.7 is N, Q, D, E, G, A or absent; Y.sub.8 is G, A, S, T, or F; Y.sub.9 is D, E, G, N or Q; and Y.sub.10 is T, S, I, L, V, M, A, K, R or H. In some embodiments, Y.sub.1 is limited to I; and/or Y.sub.2 is limited to Y, H, R, K or S; and/or Y.sub.3 is limited to P, S, Y or R; and/or Y.sub.4 is limited to G, S, K or D; and/or Y.sub.5 is limited to T or absent; and/or Y.sub.6 is limited to R or absent; and/or Y.sub.7 is limited to N, D, G or absent; and/or Y.sub.8 is limited to G, A, S or Y; and/or Y.sub.9 is limited to D, E, A or N; and/or Y.sub.10 is limited to T, I or K.

[0104] Noting in particular that the VH CDR2 sequence of SEQ 1113 NO: 120-121 are quite distinct from the others in FIG. 12, an alternative consensus sequence is VH CDR2 Motif 2:

TABLE-US-00018 (SEQ ID NO: 145) Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10

where Y.sub.1 is I, L, V, M or A; Y.sub.2 is Y, F, H, R, K, S or T; Y.sub.3 is P, S, T, Y or F; Y.sub.4 is G, A, S, T, K, R or H; Y.sub.5 is T, S or absent; Y.sub.6 is R, K, H or absent; Y.sub.7 is N, Q, D, E or absent; Y.sub.8 is G, A, S, T, Y or F; Y.sub.9 is D, E, G, N or Q; and Y.sub.10 is T, S, L, V, M or A. In some embodiments, Y.sub.1 is limited to I; and/or Y.sub.2 is limited to Y, H, R or S; and/or Y.sub.3 is limited to P, S or Y; and/or Y.sub.4 is limited to G, S or K; and/or Y.sub.5 is limited to T or absent; and/or Y.sub.6 is limited to R or absent; and/or Y.sub.7 is limited to N, D or absent; and/or Y.sub.8 is limited to G, A, S or Y; and/or Y.sub.9 is limited to D, E, A or N; and/or Y.sub.10 is limited to T or I.

[0105] For the VH CDR3, one consensus sequence is VH CDR3 Motif 1:

TABLE-US-00019 (SEQ ID NO: 146) Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 Z.sub.5 Z.sub.6 Z.sub.7 Z.sub.8 Z.sub.9 Z.sub.10 Z.sub.11 Z.sub.12 Z.sub.13 Z.sub.14 Z.sub.15

where Z.sub.1 is A, G, V, L, I or M; Z.sub.2 is R, K, H, C or M; Z.sub.3 is G, A, R, K, H, S, T, Y, F, W, D, E or absent; Z.sub.4 is Y, F, W, N, Q, G, A, R, K, H or absent; Z.sub.5 is S, T, N, Q, E, D or absent; Z.sub.6 is D, E or absent; Z.sub.7 is L, I, V, M, A, S, T or absent; Z.sub.8 is L, I, V, M, A or absent; Z.sub.9 is G, A, R, K, H or absent; Z.sub.10 is I, L, V, M, A, N, Q, R, K, H or absent; Z.sub.11 is A, M, F, Y, W, S, T, G or absent; Z.sub.12 is W, Y, F, A, G or absent; Z.sub.13 is F, Y, W, G, A, M or C; Z.sub.14 is A, G, M, D, E, W, Y or F; and Z.sub.15 is Y, F, W, G, A or V. In some embodiments, Z.sub.1 is limited to A or V; and/or Z.sub.2 is limited to R, K or C; and/or Z.sub.3 is limited to G, R, S, Y, D or absent; and/or Z.sub.4 is limited to Y, N, G, R or absent; and/or Z.sub.5 is limited to S, N, E or absent; and/or Z.sub.6 is limited to D or absent; and/or Z.sub.7 is limited to L, S or absent; and/or Z.sub.8 is limited to L or absent; and/or Z.sub.9 is limited to G, R or absent; and/or Z.sub.10 is limited to I, N, R, L or absent; and/or Z.sub.11 is limited to A, F, S, G or absent; and/or Z.sub.12 is limited to W, Y, A or absent; and/or Z.sub.13 is limited to F, Y, G or M; and/or Z.sub.14 is limited to A, D, W or Y; and/or Z.sub.15 is limited to Y, F, W or G.

[0106] Although the disclosed subject matter has been described and illustrated in the foregoing exemplary embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the disclosed subject matter may be made without departing from the spirit and scope of the disclosed subject matter, which is limited only by the claims which follow.

Sequence CWU 1

1

1481724PRTHomo sapiens 1Met Gly Asp Glu Asp Trp Glu Ala Glu Ile Asn Pro His Met Ser Ser 1 5 10 15 Tyr Val Pro Ile Phe Glu Lys Asp Arg Tyr Ser Gly Glu Asn Gly Asp 20 25 30 Asn Phe Asn Arg Thr Pro Ala Ser Ser Ser Glu Met Asp Asp Gly Pro 35 40 45 Ser Arg Arg Asp His Phe Met Lys Ser Gly Phe Ala Ser Gly Arg Asn 50 55 60 Phe Gly Asn Arg Asp Ala Gly Glu Cys Asn Lys Arg Asp Asn Thr Ser 65 70 75 80 Thr Met Gly Gly Phe Gly Val Gly Lys Ser Phe Gly Asn Arg Gly Phe 85 90 95 Ser Asn Ser Arg Phe Glu Asp Gly Asp Ser Ser Gly Phe Trp Arg Glu 100 105 110 Ser Ser Asn Asp Cys Glu Asp Asn Pro Thr Arg Asn Arg Gly Phe Ser 115 120 125 Lys Arg Gly Gly Tyr Arg Asp Gly Asn Asn Ser Glu Ala Ser Gly Pro 130 135 140 Tyr Arg Arg Gly Gly Arg Gly Ser Phe Arg Gly Cys Arg Gly Gly Phe 145 150 155 160 Gly Leu Gly Ser Pro Asn Asn Asp Leu Asp Pro Asp Glu Cys Met Gln 165 170 175 Arg Thr Gly Gly Leu Phe Gly Ser Arg Arg Pro Val Leu Ser Gly Thr 180 185 190 Gly Asn Gly Asp Thr Ser Gln Ser Arg Ser Gly Ser Gly Ser Glu Arg 195 200 205 Gly Gly Tyr Lys Gly Leu Asn Glu Glu Val Ile Thr Gly Ser Gly Lys 210 215 220 Asn Ser Trp Lys Ser Glu Ala Glu Gly Gly Glu Ser Ser Asp Thr Gln 225 230 235 240 Gly Pro Lys Val Thr Tyr Ile Pro Pro Pro Pro Pro Glu Asp Glu Asp 245 250 255 Ser Ile Phe Ala His Tyr Gln Thr Gly Ile Asn Phe Asp Lys Tyr Asp 260 265 270 Thr Ile Leu Val Glu Val Ser Gly His Asp Ala Pro Pro Ala Ile Leu 275 280 285 Thr Phe Glu Glu Ala Asn Leu Cys Gln Thr Leu Asn Asn Asn Ile Ala 290 295 300 Lys Ala Gly Tyr Thr Lys Leu Thr Pro Val Gln Lys Tyr Ser Ile Pro 305 310 315 320 Ile Ile Leu Ala Gly Arg Asp Leu Met Ala Cys Ala Gln Thr Gly Ser 325 330 335 Gly Lys Thr Ala Ala Phe Leu Leu Pro Ile Leu Ala His Met Met His 340 345 350 Asp Gly Ile Thr Ala Ser Arg Phe Lys Glu Leu Gln Glu Pro Glu Cys 355 360 365 Ile Ile Val Ala Pro Thr Arg Glu Leu Val Asn Gln Ile Tyr Leu Glu 370 375 380 Ala Arg Lys Phe Ser Phe Gly Thr Cys Val Arg Ala Val Val Ile Tyr 385 390 395 400 Gly Gly Thr Gln Leu Gly His Ser Ile Arg Gln Ile Val Gln Gly Cys 405 410 415 Asn Ile Leu Cys Ala Thr Pro Gly Arg Leu Met Asp Ile Ile Gly Lys 420 425 430 Glu Lys Ile Gly Leu Lys Gln Ile Lys Tyr Leu Val Leu Asp Glu Ala 435 440 445 Asp Arg Met Leu Asp Met Gly Phe Gly Pro Glu Met Lys Lys Leu Ile 450 455 460 Ser Cys Pro Gly Met Pro Ser Lys Glu Gln Arg Gln Thr Leu Met Phe 465 470 475 480 Ser Ala Thr Phe Pro Glu Glu Ile Gln Arg Leu Ala Ala Glu Phe Leu 485 490 495 Lys Ser Asn Tyr Leu Phe Val Ala Val Gly Gln Val Gly Gly Ala Cys 500 505 510 Arg Asp Val Gln Gln Thr Val Leu Gln Val Gly Gln Phe Ser Lys Arg 515 520 525 Glu Lys Leu Val Glu Ile Leu Arg Asn Ile Gly Asp Glu Arg Thr Met 530 535 540 Val Phe Val Glu Thr Lys Lys Lys Ala Asp Phe Ile Ala Thr Phe Leu 545 550 555 560 Cys Gln Glu Lys Ile Ser Thr Thr Ser Ile His Gly Asp Arg Glu Gln 565 570 575 Arg Glu Arg Glu Gln Ala Leu Gly Asp Phe Arg Phe Gly Lys Cys Pro 580 585 590 Val Leu Val Ala Thr Ser Val Ala Ala Arg Gly Leu Asp Ile Glu Asn 595 600 605 Val Gln His Val Ile Asn Phe Asp Leu Pro Ser Thr Ile Asp Glu Tyr 610 615 620 Val His Arg Ile Gly Arg Thr Gly Arg Cys Gly Asn Thr Gly Arg Ala 625 630 635 640 Ile Ser Phe Phe Asp Leu Glu Ser Asp Asn His Leu Ala Gln Pro Leu 645 650 655 Val Lys Val Leu Thr Asp Ala Gln Gln Asp Val Pro Ala Trp Leu Glu 660 665 670 Glu Ile Ala Phe Ser Thr Tyr Ile Pro Gly Phe Ser Gly Ser Thr Arg 675 680 685 Gly Asn Val Phe Ala Ser Val Asp Thr Arg Lys Gly Lys Ser Thr Leu 690 695 700 Asn Thr Ala Gly Phe Ser Ser Ser Gln Ala Pro Asn Pro Val Asp Asp 705 710 715 720 Glu Ser Trp Asp 2728PRTMus musculus 2Met Gly Asp Glu Asp Trp Glu Ala Glu Ile Leu Lys Pro His Val Ser 1 5 10 15 Ser Tyr Val Pro Val Phe Glu Lys Asp Lys Tyr Ser Ser Gly Ala Asn 20 25 30 Gly Asp Thr Phe Asn Arg Thr Ser Ala Ser Ser Glu Met Glu Asp Gly 35 40 45 Pro Ser Gly Arg Asp Asp Phe Met Arg Ser Gly Phe Pro Ser Gly Arg 50 55 60 Ser Leu Gly Ser Arg Asp Ile Gly Glu Ser Ser Lys Lys Glu Asn Thr 65 70 75 80 Ser Thr Thr Gly Gly Phe Gly Arg Gly Lys Gly Phe Gly Asn Arg Gly 85 90 95 Phe Leu Asn Asn Lys Phe Glu Glu Gly Asp Ser Ser Gly Phe Trp Lys 100 105 110 Glu Ser Asn Asn Asp Cys Glu Asp Asn Gln Thr Arg Ser Arg Gly Phe 115 120 125 Ser Lys Arg Gly Gly Cys Gln Asp Gly Asn Asp Ser Glu Ala Ser Gly 130 135 140 Pro Phe Arg Arg Gly Gly Arg Gly Ser Phe Arg Gly Cys Arg Gly Gly 145 150 155 160 Phe Gly Leu Gly Arg Pro Asn Ser Glu Ser Asp Gln Asp Gln Gly Thr 165 170 175 Gln Arg Gly Gly Gly Leu Phe Gly Ser Arg Lys Pro Ala Ala Ser Asp 180 185 190 Ser Gly Asn Gly Asp Thr Tyr Gln Ser Arg Ser Gly Ser Gly Arg Gly 195 200 205 Gly Tyr Lys Gly Leu Asn Glu Glu Val Val Thr Gly Ser Gly Lys Asn 210 215 220 Ser Trp Lys Ser Glu Thr Glu Gly Gly Glu Ser Ser Asp Ser Gln Gly 225 230 235 240 Pro Lys Val Thr Tyr Ile Pro Pro Pro Pro Pro Glu Asp Glu Asp Ser 245 250 255 Ile Phe Ala His Tyr Gln Thr Gly Ile Asn Phe Asp Lys Tyr Asp Thr 260 265 270 Ile Leu Val Glu Val Ser Gly His Asp Ala Pro Pro Ala Ile Leu Thr 275 280 285 Phe Glu Glu Ala Asn Leu Cys Gln Thr Leu Asn Asn Asn Ile Ala Lys 290 295 300 Ala Gly Tyr Thr Lys Leu Thr Pro Val Gln Lys Tyr Ser Ile Pro Ile 305 310 315 320 Val Leu Ala Gly Arg Asp Leu Met Ala Cys Ala Gln Thr Gly Ser Gly 325 330 335 Lys Thr Ala Ala Phe Leu Leu Pro Ile Leu Ala His Met Met Arg Asp 340 345 350 Gly Ile Thr Ala Ser Arg Phe Lys Glu Leu Gln Glu Pro Glu Cys Ile 355 360 365 Ile Val Ala Pro Thr Arg Glu Leu Ile Asn Gln Ile Tyr Leu Glu Ala 370 375 380 Arg Lys Phe Ser Phe Gly Thr Cys Val Arg Ala Val Val Ile Tyr Gly 385 390 395 400 Gly Thr Gln Phe Gly His Ser Val Arg Gln Ile Val Gln Gly Cys Asn 405 410 415 Ile Leu Cys Ala Thr Pro Gly Arg Leu Met Asp Ile Ile Gly Lys Glu 420 425 430 Lys Ile Gly Leu Lys Gln Val Lys Tyr Leu Val Leu Asp Glu Ala Asp 435 440 445 Arg Met Leu Asp Met Gly Phe Gly Pro Glu Met Lys Lys Leu Ile Ser 450 455 460 Cys Pro Gly Met Pro Ser Lys Glu Gln Arg Gln Thr Leu Leu Phe Ser 465 470 475 480 Ala Thr Phe Pro Glu Glu Ile Gln Arg Leu Ala Gly Asp Phe Leu Lys 485 490 495 Ser Ser Tyr Leu Phe Val Ala Val Gly Gln Val Gly Gly Ala Cys Arg 500 505 510 Asp Val Gln Gln Thr Ile Leu Gln Val Gly Gln Tyr Ser Lys Arg Glu 515 520 525 Lys Leu Val Glu Ile Leu Arg Asn Ile Gly Asp Glu Arg Thr Met Val 530 535 540 Phe Val Glu Thr Lys Lys Lys Ala Asp Phe Ile Ala Thr Phe Leu Cys 545 550 555 560 Gln Glu Lys Ile Ser Thr Thr Ser Ile His Gly Asp Arg Glu Gln Arg 565 570 575 Glu Arg Glu Gln Ala Leu Gly Asp Phe Arg Cys Gly Lys Cys Pro Val 580 585 590 Leu Val Ala Thr Ser Val Ala Ala Arg Gly Leu Asp Ile Glu Asn Val 595 600 605 Gln His Val Ile Asn Phe Asp Leu Pro Ser Thr Ile Asp Glu Tyr Val 610 615 620 His Arg Ile Gly Arg Thr Gly Arg Cys Gly Asn Thr Gly Arg Ala Ile 625 630 635 640 Ser Phe Phe Asp Thr Asp Ser Asp Asn His Leu Ala Gln Pro Leu Val 645 650 655 Lys Val Leu Ser Asp Ala Gln Gln Asp Val Pro Ala Trp Leu Glu Glu 660 665 670 Ile Ala Phe Ser Thr Tyr Val Pro Pro Ser Phe Ser Ser Ser Thr Arg 675 680 685 Gly Gly Ala Val Phe Ala Ser Val Asp Thr Arg Lys Asn Tyr Gln Gly 690 695 700 Lys His Thr Leu Asn Thr Ala Gly Ile Ser Ser Ser Gln Ala Pro Asn 705 710 715 720 Pro Val Asp Asp Glu Ser Trp Asp 725 3112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 3Phe Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 4112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 4Ser Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 5112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 5Leu Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Asp Trp 100 105 110 6112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 6Ser Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Asp Trp 100 105 110 7112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 7Tyr Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 8112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 8Gln Val Leu Met Thr Gln Ala Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 9112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 9Arg Phe Gln Val Ser Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe

Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 10112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 10Val Phe Val Met Thr Gln Ala Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 11112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 11Leu Ile Val Met Thr Gln Ala Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Thr Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 12112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 12Ser Ile Val Met Thr Gln Ala Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Ala His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Lys Thr Gly Ser 100 105 110 13112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 13Ser Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Ser Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 14111PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 14Leu Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 15111PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 15Leu Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 16111PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 16Leu Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 17112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 17Leu Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Thr Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Ser Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 110 18112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 18Tyr Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Thr Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Ser Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 110 19112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 19Ser Gly Leu Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Thr Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Ser Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 20112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 20Pro Gly Leu Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 110 21112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 21Ser Leu Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 110 22112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 22Ser Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Gly Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 110 23112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 23Asp Ile Val Met Thr Gln Ser Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 24112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 24Asp Ile Val Met Thr Gln Ser Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 25112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 25Asp Ile Val Leu Thr Gln Ser Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Val Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 26112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 26Asp Gly Val Met Thr Gln Ser Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 27112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 27Leu Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 28112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 28Leu Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10

15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Arg 100 105 110 29112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 29Ser Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 30112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 30Val Phe Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 31112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 31Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Ala Ala Glu Asp Val Gly Val Tyr Tyr Cys Leu Gln Gln 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 32112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 32Leu Ile Val Ile Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Leu Gln Gln 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 33112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 33Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Ser Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Thr Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Arg Leu Ile Tyr His Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Gly Leu Lys 100 105 110 34112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 34Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Ser Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Thr Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Arg Leu Ile Tyr His Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95 Leu Glu Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 35107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 35Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Val Phe Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Ser Phe 20 25 30 Leu Thr Trp Phe His Gln Lys Pro Gly Lys Ser Pro Thr Thr Leu Ile 35 40 45 Tyr Arg Thr Asn Arg Leu Leu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Phe 65 70 75 80 Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Asp Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Val Glu Leu Lys 100 105 36107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 36Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Val Phe Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Ser Phe 20 25 30 Leu Thr Trp Phe His Gln Lys Pro Gly Lys Ser Pro Thr Thr Leu Ile 35 40 45 Tyr Arg Thr Asn Arg Leu Leu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Leu 65 70 75 80 Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Asp Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Val Glu Leu Lys 100 105 37110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 37Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser 85 90 95 Ser Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110 38107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 38Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Val Thr Cys Ser Gly Asp Lys Leu Gly Asn Lys Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Gln Asp Lys Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Arg Thr Val Val 85 90 95 Ile Gly Arg Gly Thr Lys Leu Thr Val Leu Gly 100 105 39117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 39Leu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 40117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 40Leu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 41117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 41Leu Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 42117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 42Leu Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 43117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 43Ser Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 44117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 44Ser Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 45117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 45Arg Ser Gln Leu Lys Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 46117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 46Ser Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50

55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 47117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 47Ser Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 48116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 48Gln Val Gln Leu Gln Pro Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30 Trp Met Gln Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Glu Thr Arg His Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Gly Tyr Pro Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala 115 49116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 49Gln Val Gln Leu Gln Pro Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30 Trp Met Gln Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asp Gly Glu Thr Arg His Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Gly Tyr Pro Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala 115 50116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 50Gln Val Gln Leu Gln Pro Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Pro Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30 Trp Met Gln Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asp Gly Glu Thr Arg His Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Gly Tyr Pro Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala 115 51116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 51Gln Val Gln Leu Gln Pro Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30 Trp Met Gln Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asp Gly Glu Thr Arg His Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Ser Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Gly Tyr Pro Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala 115 52118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 52Gln Val Gln Leu Lys Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Asn 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Asp Gly Asn Phe Trp Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 53118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 53Gln Val Gln Leu Lys Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Asn 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Asp Gly Asn Phe Trp Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 54118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 54Gln Val Gln Leu Lys Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Asn 65 70 75 80 Met Gln Leu Ser Gly Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Asp Gly Asn Phe Trp Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 55118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 55Asp Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Asn 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Asp Gly Asn Phe Trp Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 56118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 56Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Arg Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Asn 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Asp Gly Asn Phe Trp Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 57118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 57Glu Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 58118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 58Glu Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 59118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 59Glu Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 60118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 60Glu Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 61118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 61Glu Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 62118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 62Glu Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 63118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 63Arg Val Gln Leu Gln Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 64118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 64Gln Val Gln Leu Lys Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr

Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 65118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 65Gln Val Gln Leu Lys Gln Ser Gly Ala Ala Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Leu Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 66113PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 66Gln Val Gln Leu Gln Gln Pro Gly Ser Glu Phe Val Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Leu Ser Arg Lys Ser Ser Gly Tyr Thr Phe Thr Thr Phe 20 25 30 Trp Ile Asn Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asn Ile Tyr Pro Gly Asp Ala Ala Thr Arg Phe Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Ser Val Asp Thr Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met His Leu Phe Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Val Arg Ser Gly Asp Phe Trp Gly Gln Gly Thr Thr Leu Thr Val Ser 100 105 110 Ser 67113PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 67Gln Val Gln Leu Gln Gln Pro Gly Ser Glu Phe Val Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Leu Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Thr Phe 20 25 30 Trp Ile Asn Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asn Ile Tyr Pro Gly Asp Ala Ala Thr Arg Phe Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Ser Val Asp Thr Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met His Leu Phe Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Val Arg Ser Gly Asp Phe Trp Gly Gln Gly Thr Thr Leu Thr Val Ser 100 105 110 Ser 68115PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 68Glu Val Arg Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Glu Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ala Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Thr Arg Asn Tyr Ala Ile Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Phe Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Asp Gly Trp Trp Trp Gly Gln Gly Thr Ser Val Thr 100 105 110 Val Ser Ser 115 69115PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 69Glu Val Arg Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Glu Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ala Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Thr Arg Asn Tyr Ala Ile Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Phe Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Asp Gly Trp Trp Trp Gly Gln Gly Thr Ser Val Thr 100 105 110 Val Ser Ser 115 70120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 70Leu Val Gln Leu Lys Gln Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 71120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 71Leu Val Gln Leu Lys Gln Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 72120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 72Leu Val Gln Leu Lys Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 73120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 73Ser Val Gln Leu Lys Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 74120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 74Asp Val Lys Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 75120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 75Asp Val Lys Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 76120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 76Leu Val Lys Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 77120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 77Glu Val Lys Leu Val Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 78120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 78Glu Val Lys Leu Val Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 79120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 79Glu Val Lys Leu Val Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Val Thr Ser Gly 20 25 30 Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met 35 40 45 Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 80116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 80Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Arg Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asn Ser Tyr Tyr Gly Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 81116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 81Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Arg Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly

Asn Ser Phe Arg Asp Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 82117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 82Gln Val Asn Leu Arg Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Arg Glu Asp Gly Met Asp Val Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ala 115 8311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 83Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr 1 5 10 8411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 84Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr 1 5 10 8511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 85Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr 1 5 10 866PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 86Gln Asn Ile Asn Ser Phe 1 5 877PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 87Ser Asn Ile Gly Asn Asn Tyr 1 5 886PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 88Lys Leu Gly Asn Lys Tyr 1 5 893PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 89Lys Val Ser 1 903PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 90Lys Ile Ser 1 913PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 91Arg Met Ser 1 923PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 92His Met Ser 1 933PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 93Arg Thr Asn 1 943PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 94Asp Asn Asn 1 953PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 95Gln Asp Lys 1 969PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 96Ser Gln Ser Ala His Val Pro Trp Thr 1 5 979PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 97Ser Gln Ser Thr His Val Pro Pro Thr 1 5 988PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 98Phe Gln Gly Ser His Val Leu Thr 1 5 999PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 99Met Gln His Leu Glu Tyr Pro Leu Thr 1 5 1009PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 100Leu Gln Gln Leu Glu Tyr Pro Phe Thr 1 5 1019PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 101Met Gln Gly Leu Glu Tyr Pro Leu Thr 1 5 1029PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 102Leu Gln Tyr Asp Asp Phe Pro Leu Thr 1 5 10310PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 103Ser Ser Tyr Thr Ser Ser Ser Ser Trp Val 1 5 10 10410PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 104Gln Ala Trp Asp Ser Arg Thr Val Val Ile 1 5 10 1058PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 105Gly Tyr Thr Phe Thr Ser Tyr Trp 1 5 1068PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 106Gly Phe Thr Phe Thr Asn Tyr Trp 1 5 1078PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 107Gly Tyr Ser Phe Thr Ser Tyr Trp 1 5 1088PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 108Gly Tyr Thr Phe Thr Thr Phe Trp 1 5 1098PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 109Gly Phe Thr Phe Asn Ala Asn Ala 1 5 1108PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 110Gly Asp Ser Val Thr Ser Gly Tyr 1 5 1118PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 111Gly Phe Thr Phe Ser Ser Tyr Trp 1 5 1128PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 112Gly Phe Thr Phe Ser Asn Tyr Gly 1 5 1138PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 113Ile Tyr Pro Gly Asn Gly Asp Thr 1 5 1148PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 114Ile Tyr Pro Gly Asn Gly Glu Thr 1 5 1158PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 115Ile Tyr Pro Gly Asp Gly Glu Thr 1 5 1168PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 116Ile His Pro Ser Asp Ser Glu Thr 1 5 1178PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 117Ile Tyr Pro Gly Asp Ala Ala Thr 1 5 11810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 118Ile Arg Ser Lys Thr Arg Asn Tyr Ala Ile 1 5 10 1197PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 119Ile Ser Tyr Ser Gly Asn Thr 1 5 1208PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 120Ile Lys Arg Asp Gly Ser Glu Lys 1 5 1218PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 121Ile Ser Tyr Asp Gly Ile Asn Lys 1 5 12210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 122Ala Arg Gly Gly Ile Ala Trp Phe Ala Tyr 1 5 10 1239PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 123Ala Ser Gly Tyr Pro Tyr Phe Ala Tyr 1 5 12411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 124Ala Lys Gly Asp Gly Asn Phe Trp Phe Ala Tyr 1 5 10 12511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 125Ala Cys Arg Tyr Asp Arg Ser Tyr Phe Asp Tyr 1 5 10 1266PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 126Val Arg Ser Gly Asp Phe 1 5 1276PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 127Val Arg Asp Gly Trp Trp 1 5 12814PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 128Ala Arg Tyr Asn Ser Leu Leu Arg Leu Gly Ala Met Asp Tyr 1 5 10 1299PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 129Ala Arg Gly Gly Asn Ser Tyr Tyr Gly 1 5 1309PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 130Ala Arg Gly Gly Asn Ser Phe Arg Asp 1 5 13110PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 131Ala Lys Asp Arg Glu Asp Gly Met Asp Val 1 5 10 13211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Gln, Asn, Lys, Arg, Ser or ThrMOD_RES(2)..(2)Ser, Thr, Cys, Asn or GlnMOD_RES(3)..(3)Ile, Leu, Val, Met or AlaMOD_RES(4)..(4)Val, Leu, Ile, Met, Ala or absentMOD_RES(5)..(5)His, Lys, Arg or absentMOD_RES(6)..(6)Ser, Thr, Cys or absentMOD_RES(7)..(7)Asn, Gln or absentMOD_RES(8)..(8)Gly, Ala or absentMOD_RES(9)..(9)Asn or GlnMOD_RES(10)..(10)Thr, Ser, Cys, Asn or GlnMOD_RES(11)..(11)Tyr, Phe or Trpsee specification as filed for detailed description of substitutions and preferred embodiments 132Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 13311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Gln, Asn, Lys or ArgMOD_RES(2)..(2)Ser, Thr, Cys, Asn or GlnMOD_RES(3)..(3)Ile, Leu, Val, Met or AlaMOD_RES(4)..(4)Val, Leu, Ile, Met or AlaMOD_RES(5)..(5)His, Lys or ArgMOD_RES(6)..(6)Ser, Thr or CysMOD_RES(7)..(7)Asn or GlnMOD_RES(8)..(8)Gly or AlaMOD_RES(9)..(9)Asn or GlnMOD_RES(10)..(10)Thr, Ser or CysMOD_RES(11)..(11)Tyr, Phe or Trpsee specification as filed for detailed description of substitutions and preferred embodiments 133Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 1343PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Lys, Arg or HisMOD_RES(2)..(2)Val, Ile, Leu, Met, Ala, Thr, Ser or CysMOD_RES(3)..(3)Ser, Thr, Cys, Asn or Glnsee specification as filed for detailed description of substitutions and preferred embodiments 134Xaa Xaa Xaa 1 1353PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Asp or GluMOD_RES(2)..(2)Asn or GlnMOD_RES(3)..(3)Asn or Gln 135Xaa Xaa Xaa 1 1363PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Gln or AsnMOD_RES(2)..(2)Asp or GluMOD_RES(3)..(3)Lys, Arg or Hissee specification as filed for detailed description of substitutions and preferred embodiments 136Xaa Xaa Xaa 1 13710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ser, Thr, Cys, Phe, Tyr, Met, Leu, Val, Ile or AlaMOD_RES(2)..(2)Gln, Asn, Ser, Thr or CysMOD_RES(3)..(3)Ser, Thr, Cys, Gly, Ala, His, Lys, Arg, Gln, Asn, Tyr, Phe or TrpMOD_RES(4)..(4)Ala, Gly, Ser, Thr, Cys, Leu, Ile, Val, Met, Asp or GluMOD_RES(5)..(5)His, Lys, Arg, Glu, Asp, Ser, Thr or CysMOD_RES(6)..(6)Val, Leu, Ile, Met, Ala, Tyr, Phe, Trp, Ser, Thr or CysMOD_RES(7)..(7)Pro, Ser, Thr, Cys or absentMOD_RES(8)..(8)Ser, Thr, Cys or absentMOD_RES(9)..(9)Trp, Pro, Leu, Ile, Val, Met, Ala, Phe or TyrMOD_RES(10)..(10)Thr, Ser, Cys, Val, Leu, Ile, Met or Alasee specification as filed for detailed description of substitutions and preferred embodiments 137Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 1389PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ser, Thr, Cys, Phe or TyrMOD_RES(2)..(2)Gln or AsnMOD_RES(3)..(3)Ser, Thr, Cys, Gly or AlaMOD_RES(4)..(4)Ala, Gly, Ser, Thr or CysMOD_RES(5)..(5)His, Lys or ArgMOD_RES(6)..(6)Val, Leu, Ile, Met or AlaMOD_RES(7)..(7)Pro or absentMOD_RES(8)..(8)Trp, Pro, Leu, Ile, Val, Met, Ala, Phe or TyrMOD_RES(9)..(9)Thr, Ser or Cyssee specification as filed for detailed description of substitutions and preferred embodiments 138Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 1399PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Met, Cys, Leu, Ile, Val or AlaMOD_RES(2)..(2)Gln or AsnMOD_RES(3)..(3)His, Lys, Arg, Gln, Asn, Gly, Ala, Tyr or PheMOD_RES(4)..(4)Leu, Ile, Val, Met, Ala, Asp or GluMOD_RES(5)..(5)Glu or AspMOD_RES(6)..(6)Tyr or PheMOD_RES(8)..(8)Trp, Pro, Leu, Ile, Val, Met, Ala, Phe or TyrMOD_RES(9)..(9)Thr, Ser or Cyssee specification as filed for detailed description of substitutions and preferred embodiments 139Xaa Xaa Xaa Xaa Xaa Xaa Pro Xaa Xaa 1 5 14010PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ser, Thr or CysMOD_RES(2)..(2)Ser, Thr or CysMOD_RES(3)..(3)Tyr or PheMOD_RES(4)..(4)Thr, Ser or CysMOD_RES(5)..(5)Ser, Thr or CysMOD_RES(6)..(6)Ser, Thr or CysMOD_RES(7)..(7)Ser, Thr or CysMOD_RES(8)..(8)Ser, Thr or CysMOD_RES(9)..(9)Trp, Pro, Phe or TyrMOD_RES(10)..(10)Val, Leu, Ile, Met, Ala, Thr, Ser or Cyssee specification as filed for detailed description of substitutions and preferred embodiments 140Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 14110PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Gln or AsnMOD_RES(2)..(2)Ala or GlyMOD_RES(3)..(3)Trp, Tyr or PheMOD_RES(4)..(4)Asp or GluMOD_RES(5)..(5)Ser, Thr or CysMOD_RES(6)..(6)Arg, Lys or HisMOD_RES(7)..(7)Thr, Ser or CysMOD_RES(8)..(8)Val, Ile, Leu, Met or AlaMOD_RES(9)..(9)Val, Ile, Leu, Met or AlaMOD_RES(10)..(10)Ile, Leu, Val, Met or Alasee specification as filed for detailed description of substitutions and preferred embodiments 141Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 1428PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Gly or AlaMOD_RES(2)..(2)Tyr, Phe, Trp, Asp or GluMOD_RES(3)..(3)Thr, Ser, Cys or MetMOD_RES(4)..(4)Phe, Tyr, Trp, Val, Leu, Ile, Met or AlaMOD_RES(5)..(5)Thr, Ser, Cys, Asn or GlnMOD_RES(6)..(6)Ser, Thr, Cys, Ala or GlyMOD_RES(7)..(7)Tyr, Phe, Trp, Asn, Gln, Gly or AlaMOD_RES(8)..(8)Trp, Ala, Gly, Tyr or Phesee specification as filed for detailed description of substitutions and preferred embodiments 142Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 1438PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Gly or AlaMOD_RES(2)..(2)Tyr, Phe or TrpMOD_RES(3)..(3)Thr, Ser, Cys or MetMOD_RES(4)..(4)Phe, Tyr or TrpMOD_RES(5)..(5)Thr, Ser or CysMOD_RES(6)..(6)Ser, Thr or CysMOD_RES(7)..(7)Tyr, Phe or Trpsee specification as filed for detailed description of substitutions and preferred embodiments 143Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp 1 5 14410PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ile, Leu, Val, Met or AlaMOD_RES(2)..(2)Tyr, Phe, His, Arg, Lys, Ser or ThrMOD_RES(3)..(3)Pro, Ser, Thr, Tyr, Phe, Arg, Lys or HisMOD_RES(4)..(4)Gly, Ala, Ser, Thr, Lys, Arg, His, Asp or GluMOD_RES(5)..(5)Thr, Ser or absentMOD_RES(6)..(6)Arg, Lys, His or absentMOD_RES(7)..(7)Asn, Gln, Asp, Glu, Gly, Ala or absentMOD_RES(8)..(8)Gly, Ala, Ser, Thr, Tyr or PheMOD_RES(9)..(9)Asp, Glu, Ala, Gly, Asn or GlnMOD_RES(10)..(10)Thr, Ser, Ile, Leu, Val, Met, Ala, Lys, Arg or Hissee specification as filed for detailed description of substitutions and preferred embodiments 144Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 14510PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ile, Leu, Val, Met or AlaMOD_RES(2)..(2)Tyr, Phe, His, Arg, Lys, Ser or ThrMOD_RES(3)..(3)Pro, Ser, Thr, Tyr or PheMOD_RES(4)..(4)Gly, Ala, Ser, Thr, Lys, Arg or HisMOD_RES(5)..(5)Thr, Ser or absentMOD_RES(6)..(6)Arg, Lys, His or absentMOD_RES(7)..(7)Asn, Gln, Asp, Glu or absentMOD_RES(8)..(8)Gly, Ala, Ser, Thr, Tyr or PheMOD_RES(9)..(9)Asp, Glu, Ala, Gly, Asn or GlnMOD_RES(10)..(10)Thr, Ser, Ile, Leu, Val, Met or Alasee specification as filed for detailed description of substitutions and preferred embodiments 145Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 14615PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ala, Gly, Val, Leu, Ile or MetMOD_RES(2)..(2)Arg, Lys, His, Cys or MetMOD_RES(3)..(3)Gly, Ala, Arg, Lys, His, Ser, Thr, Tyr, Phe, Trp, Asp, Glu or absentMOD_RES(4)..(4)Tyr, Phe, Trp, Asn, Gln, Gly, Ala, Arg, Lys, His or absentMOD_RES(5)..(5)Ser, Thr, Asn, Gln, Glu, Asp or absentMOD_RES(6)..(6)Asp, Glu or absentMOD_RES(7)..(7)Leu, Ile, Val, Met, Ala, Ser, Thr or absentMOD_RES(8)..(8)Leu, Ile, Val, Met, Ala or absentMOD_RES(9)..(9)Gly, Ala, Arg, Lys, His or absentMOD_RES(10)..(10)Ile, Leu, Val, Met, Ala, Asn, Gln, Arg, Lys, His or absentMOD_RES(11)..(11)Ala, Met, Phe, Tyr, Trp, Ser, Thr, Gly or absentMOD_RES(12)..(12)Trp, Tyr, Phe, Ala, Gly or absentMOD_RES(13)..(13)Phe, Tyr, Trp, Gly, Ala, Met or CysMOD_RES(14)..(14)Ala, Gly, Met, Asp, Glu, Trp, Tyr or

PheMOD_RES(15)..(15)Tyr, Phe, Trp, Gly, Ala or Valsee specification as filed for detailed description of substitutions and preferred embodiments 146Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 1477PRTUnknownDescription of Unknown Human or Mouse VASA peptide peptide 147Pro Asn Pro Val Asp Asp Glu 1 5 1484PRTUnknownDescription of Unknown 'DEAD' family motif peptide 148Asp Glu Ala Asp 1

Claims

1. A cell transformed with a nucleic acid molecule encoding an immunoglobulin heavy chain that specifically binds to a human VASA protein, wherein the variable region of said immunoglobulin heavy chain comprises: (i) a CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 105-112; (ii) a CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 113-121; and (iii) a CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122-131.

2. The cell of claim 1, wherein said nucleic acid molecule is selected from the group consisting of a cloning vector, an expression vector, a heterologous recombination vector, and a viral integration vector.

3. The cell of claim 1, wherein said cell is a mammalian cell.

4. The cell of claim 3, wherein said cell is a rodent cell.

5. The cell of claim 3, wherein said cell is a Chinese Hamster Ovary (CHO) cell.

6. The cell of claim 3, wherein said cell is a human cell.