RU2789648C2 - Multivalent and multi-specific 41bb-binding fused proteins - Google Patents

Abstract

FIELD: biochemistry.

SUBSTANCE: invention relates to biochemistry, in general, to molecules, which specifically interact with 41BB – a representative of TNF receptor superfamily (hereinafter – TNFRSF), in particular to multivalent and/or multi-specific molecules, which bind at least 41BB. Fused proteins, according to the invention, are capable of enhanced clustering of TNFRSF representatives compared to bivalent antibodies, without crosslinking.

EFFECT: fused proteins, according to the invention, modulate immune cells, and they are suitable for use in the treatment of neoplasms, inflammatory pathological conditions.

16 cl, 25 dwg, 4 ex

Description

RELATED APPLICATIONS

[0001] This application claims priority over U.S. Provisional Application No. 62/277028, filed January 11, 2016, the entire contents of which are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY

[0002] The present invention relates generally to molecules that specifically interact with 41BB, a member of the TNF receptor superfamily (TNFRSF). More specifically, this invention relates to multivalent and/or multispecific molecules that bind at least 41BB.

BACKGROUND OF THE INVENTION

[0003] The tumor necrosis factor receptor superfamily consists of several structurally related cell surface receptors. Activation by multimeric ligands is a common feature of many of these receptors. Many members of TNFRSF are therapeutically effective in multiple pathologies if properly activated. Agonism of this family of receptors often requires higher order clustering, and conventional divalent antibodies are not ideal for this purpose. Therefore, there is a therapeutic need for more potent TNFRSF agonist molecules.

SUMMARY OF THE INVENTION

[0004] The present invention provides multivalent and multispecific TNF receptor superfamily (TNFRSF)-binding fusion polypeptides that bind at least 41BB (also known as a member of the tumor necrosis factor receptor superfamily 4 (TNFRSF9) and/or CD137)). The use of the term "41BB" is intended to cover any of its variants, for example, as a non-limiting example, 41-BB and/or 4-1BB, all variants are used interchangeably herein. These molecules that bind at least 41BB are referred to herein as "41BB-targeted molecules" or "41BB-targeted fusions" or "41BB-targeted proteins" or "41BB-targeted fusion polypeptides" or "41BB-targeted fusion proteins". ". In some embodiments of this invention, the 41BB-targeted molecule is a multivalent molecule, for example, a multivalent 41BB-targeted fusion protein. In some embodiments of this invention, the 41BB-targeted molecule is a multispecific molecule, for example, a multispecific 41BB-targeted fusion protein. In some embodiments of this invention, the 41BB-targeting molecule is a multivalent and multispecific molecule, for example, a multivalent and multispecific 41BB-targeted fusion protein. As used herein, the term "fusion protein" or "fusion polypeptide" or "41BB-targeted fusion protein" or "41BB-targeted fusion polypeptide", unless otherwise noted, refers to any embodiment of a protein fusion in this invention, including but not limited to without limitation, multivalent fusion proteins, multispecific fusion proteins, or multivalent and multispecific fusion proteins.

[0005] The invention also provides multivalent and multispecific fusion polypeptides that bind at least programmed death ligand 1 (PDL1), also known as PD-L1, CD274, B7 homologue 1 and/or B7-H1. The use of the term "PDL1" is intended to cover any of its variants, for example, as a non-limiting example, PD-L1 and/or PDL-1, all variants are used interchangeably herein. These molecules that bind at least PDL1 are referred to herein as "PDL1-targeted molecules" or "PDL1-targeted fusions" or "PDL1-targeted proteins" or "PDL1-targeted fusion polypeptides" or "PDL1-targeted fusion proteins". ". In some embodiments of this invention, the PDL1-targeted molecule is a multivalent molecule, for example, a multivalent PDL1-targeted fusion protein. In some embodiments of this invention, the PDL1-targeted molecule is a multispecific molecule, for example, a multispecific PDL1-targeted fusion protein. In some embodiments of this invention, the PDL1-targeted molecule is a multivalent and multispecific molecule, for example, a multivalent and multispecific PDL1-targeted fusion protein. As used herein, the term "fusion protein" or "fusion polypeptide" or "PDL1-targeted fusion protein" or "PDL1-targeted fusion polypeptide", unless otherwise noted, refers to any embodiment of a protein fusion in this invention, including but not limited to without limitation, multivalent fusion proteins, multispecific fusion proteins, or multivalent and multispecific fusion proteins.

[0006] The invention also provides multivalent and multispecific fusion polypeptides that bind at least PDL1 and 41BB. These molecules that bind at least PDL1 are referred to herein as "PDL1x41BB-targeted molecules" or "PDL1x41BB-targeted fusions" or "PDL1x41BB-targeted proteins" or "PDL1x41BB-targeted fusion polypeptides" or "PDL1x41BB-targeted fusion proteins". ". In some embodiments of the invention, the PDL1x41BB targeting molecule is a multivalent molecule, for example, a multivalent PDL1x41BB targeting fusion protein. In some embodiments of this invention, the PDL1x41BB targeting molecule is a multispecific molecule, for example, a PDL1x41BB multispecific targeting fusion protein. In some embodiments of this invention, the PDL1x41BB targeting molecule is a multivalent and multispecific molecule, for example, a multivalent and multispecific PDL1-targeted fusion protein. As used herein, the term "fusion protein" or "fusion polypeptide" or "PDL1x41BB-targeted fusion protein" or "PDL1x41BB-targeted fusion polypeptide", unless otherwise noted, refers to any embodiment of a protein fusion in this invention, including but not limited to without limitation, multivalent fusion proteins, multispecific fusion proteins, or multivalent and multispecific fusion proteins.

[0007] In some embodiments, the multivalent and/or multispecific fusion protein binds at least 41BB. Conventional antibodies targeting members of the TNF<g receptor superfamily (TNFRSF) have been shown to require exogenous cross-linking to achieve sufficient agonist activity, as evidenced by the need for Fc-gamma receptor (FcγRs) for anti-DR4, DR5, GITR and OX40 (Ichikawa et al 2001 al Nat. Med. 7, 954-960, Li et al 2008 Drug Dev. Res. 69, 69-82; Pukac et al 2005 Br. J. Cancer 92, 1430-1441; Yanda et al 2008 Ann Oncol 19, 1060-1067 Yang et al 2007 Cancer Lett 251: 146-157 Bulliard et al 2013 JEM 210(9): 1685 Bulliard et al 2014 Immunol and Cell Biol 92: 475- 480). In addition to cross-linking with FcγRs, other exogenous agents have been demonstrated, including the addition of oligomeric ligand units or binding antibodies (e.g., protein A and secondary antibodies) to enhance anti-TNFRSF antibody clustering and downstream signaling, for example, the addition of DR5 TRAIL ligand enhanced the ability anti-DR5 antibodies induce apoptosis (Graves et al 2014 Cancer Cell 26: 177-189). These data indicate the need for TNFRSF clustering outside the dimer.

[0008] The present invention provides multivalent TNFRSF binding fusion proteins that contain 2 or more TNFRSF binding domains (TBDs), with at least one TBD binding to 41BB. In some embodiments of this invention, the fusion proteins of this invention are suitable for use in the treatment of neoplasms.

[0009] In some embodiments of the present invention, the fusion protein contains two or more different TBDs, with each TBD binding 41BB. In some embodiments of this invention, the fusion protein contains multiple copies of TBD that binds 41BB, for example, in some embodiments of this invention, the fusion protein contains at least two copies of TBD that binds 41BB. In some embodiments of this invention, the fusion protein contains at least three copies of TBD that binds 41BB. In some embodiments, the fusion protein contains at least four copies of a TBD that binds 41BB. In some embodiments, the fusion protein contains at least five copies of a TBD that binds 41BB. In some embodiments, the fusion protein contains at least six copies of TBD that binds 41BB. In some embodiments of this invention, the fusion protein contains six or more copies of TBD that binds 41BB.

[0010] In other options for the implementation of this invention, merged proteins are connected by 41BB and the second representative of the TNFRSF family, for example GITR, OX40, CD27, TNFR2 and/or CD40. In these options for the implementation of this invention, merged proteins in this invention modulate immune cells, which leads to increased destruction of the tumor. In other options for the implementation of this invention, merged proteins in this invention are suitable for use in the treatment of inflammatory pathological conditions. In these options for the implementation of this invention, merged proteins in this invention are modulated by immune cells, which leads to a fading of the inflammatory process, for example, a specific agonistic effect on TNFR2 can enhance the proliferation of TREG, which leads to immune suppression.

[0011] The fusion proteins of this invention are capable of enhanced clustering of members of the TNFRSF family compared to bivalent antibodies without crosslinking. The enhanced clustering of members of the TNFRSF family mediated by the fusion proteins of the invention induces enhanced TNFRSF dependent signaling compared to non-crosslinked bivalent antibodies. In most embodiments of this invention, the fusion protein will include more than 2 TBDs, such as three, four, five or six.

[0012] In some embodiments of the present invention, the fusion proteins are multispecific, containing TBD and a binding domain directed to a second antigen. In these embodiments, implementation of the present invention, binding to the second antigen is able to provide additional crosslinking function, and activation of TNFRSF can be obtained with only one or two TBD. In these embodiments of the present invention, TNFRSF signaling is enhanced and focused by the presence of a second antigen. These multispecific TBDs containing fusion proteins are a useful means of achieving conditionally signaling a particular member of the TNFRSF family.

[0013] In these embodiments of this invention, binding to a member of the TNFRSF family via TBD causes minimal signaling if the second antigen is not co-involved in binding, for example, the multispecific fusion proteins of this invention are able to bind 41BB and PD-L1, while 41BB- dependent signaling is greatly enhanced when the fusion protein binds to a cell expressing PD-L1. In another example, the multispecific fusion proteins of the invention are able to bind 41BB and folic acid receptor alpha (FRα), with 41BB dependent signaling being significantly enhanced when the fusion protein binds to a cell expressing FRα.

[0014] The present invention provides isolated polypeptides that specifically bind 41BB. In some embodiments, the isolated polypeptide is derived from antibodies or antibody fragments, including scFvs, Fabs, single domain antibodies (sdAbs), V _NARs , or VHHs. In some embodiments of this invention, the isolated polypeptide is a human or humanized sdAb. Fragments of sdAb may be derived from VHH, V _NAR , engineered VH or VK domains. VHH can only be derived from camel heavy chain antibodies. V _NARs can only be derived from heavy chain cartilaginous fish antibodies. Various methods have been put into practice to produce monomeric sdAbs from conventional VH and VK heterodimeric domains, including interaction design and selection of specific germline families. In other embodiments, the isolated polypeptides are derived from non-antibody scaffold proteins, such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, anticalins/lipocalins, centirins, and finomers.

[0015] In some embodiments, the isolated polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 20, 23, 25, 29, 33, 39, 33-41, 43, 45-47, 49 , 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83. In some embodiments, the isolated polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83.

[0016] In some embodiments, the isolated polypeptide comprises an amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92% 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 20, 23, 25, 29, 33, 39, 33- 41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83. In some embodiments, the isolated polypeptide comprises an amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93% 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 33, 39, 33-41, 43, 45-47, 49, 51, 53 , 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83.

[0017] In some embodiments, the isolated polypeptide comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21, 26, 30, 50, 65, and 69; complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 27, 31, 42, 44, 48, 52, 61, 63, 71, 73, 75, 77 and 79 ; complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 24, 28, 32, 55 and 57.

[0018] The present invention provides multivalent fusion proteins that contain 2 or more binding domains (BDs), wherein at least one BD binds PDL1. In some embodiments of this invention, the fusion proteins of this invention are suitable for use in the treatment of neoplasms.

[0019] In some embodiments of the present invention, the fusion protein contains two or more different BDs, with each BD binding to PDL1. In some embodiments, the fusion protein contains multiple copies of a BD that binds PDL1, for example, in some embodiments of the invention, the fusion protein contains at least two copies of a BD that binds PDL1. In some embodiments of the present invention, the fusion protein contains at least three copies of a BD that binds PDL1. In some embodiments, the fusion protein contains at least four copies of a BD that binds PDL1. In some embodiments, the fusion protein contains at least five copies of a BD that binds PDL1. In some embodiments, the fusion protein contains at least six copies of a BD that binds PDL1. In some embodiments of this invention, the fusion protein contains six or more copies of a BD that binds PDL1.

[0020] The present invention provides isolated polypeptides that specifically bind 41BB. In some embodiments, the isolated polypeptide is derived from antibodies or antibody fragments, including scFvs, Fabs, single domain antibodies (sdAbs), V _NARs , or VHHs. In some embodiments of this invention, the isolated polypeptide is a human or humanized sdAb. Fragments of sdAb may be derived from VHH, V _NAR , engineered VH or VK domains. VHH can only be derived from camel heavy chain antibodies. V _NARs can only be derived from heavy chain cartilaginous fish antibodies. Various methods have been put into practice to produce monomeric sdAbs from conventional VH and VK heterodimeric domains, including interaction design and selection of specific germline families. In other embodiments, the isolated polypeptides are derived from non-antibody scaffold proteins, such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, anticalins/lipocalins, centirins, and finomers.

[0021] In some embodiments, the isolated polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116, and 119-124. In some embodiments, the isolated polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 119-124.

[0022] In some embodiments, the isolated polypeptide comprises an amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92% 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116 and 119-124. In some embodiments, the isolated polypeptide comprises an amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93% 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 119-124.

[0023] In some embodiments of the present invention, the isolated polypeptide comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 101, 105, and 109; complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 106, 110 and 117; complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 107, 111, 113, 115, and 118.

[0024] In some embodiments, this invention provides isolated polypeptides that specifically bind at least 41BB and PDL1. In some embodiments of this invention, each binding domain (BD) in the selected polypeptide is derived from antibodies or antibody fragments, including scFv, Fabs, single domain antibodies (sdAb), V _NAR or VHH. In some embodiments of this invention, each BD is a human or humanized sdAb. Fragments of sdAb may be derived from VHH, V _NAR , engineered VH or VK domains. VHH can only be derived from camel heavy chain antibodies. V _NARs can only be derived from heavy chain cartilaginous fish antibodies. Various methods have been put into practice to produce monomeric sdAbs from conventional VH and VK heterodimeric domains, including interaction design and selection of specific germline families. In other embodiments, the isolated polypeptides are derived from non-antibody scaffold proteins, such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, anticalins/lipocalins, centirins, and finomers.

[0025] In some embodiments, the isolated polypeptide comprises a first amino acid sequence that binds 4B11 selected from the group consisting of SEQ ID NOs: 16, 20, 23, 25, 29, 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83, as well as a second amino acid sequence that binds PDL1, selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116 and 119-124.

[0026] In some embodiments, the isolated polypeptide comprises a first amino acid sequence that binds 4B11 selected from the group consisting of SEQ ID NOs: 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83, as well as a second amino acid sequence that binds PDL1 selected from the group consisting of SEQ ID NO: 119-124.

[0027] In some embodiments, the isolated polypeptide comprises a first amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence that binds 4B11 selected from the group consisting of SEQ ID NO: 16, 20, 23, 25, 29, 33 , 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83, and also a second amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98% or 99% identical to the amino acid sequence that binds PDL1 selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116 and 119-124.

[0028] In some embodiments, the isolated polypeptide comprises a first amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence that binds 4B11 selected from the group consisting of SEQ ID NOs: 33, 39, 33-41, 43, 45 -47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78, and 80-83, and a second amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence that binds PDL1 selected from the group consisting of SEQ ID NO: 119-124.

[0029] In some embodiments, the isolated polypeptide comprises (i) a first amino acid sequence that binds 4B11 and contains a complementarity determining region 1 (CDR1) containing an amino acid sequence selected from the group consisting of SEQ ID NO: 17, 21, 26, 30, 50, 65 and 69; complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 27, 31, 42, 44, 48, 52, 61, 63, 71, 73, 75, 77 and 79 ; complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 24, 28, 32, 55 and 57; and (ii) a second amino acid sequence that binds PDL1 and contains a CDR1 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 101, 105 and 109; a CDR2 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 106, 110 and 117; and a CDR3 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 107, 111, 113, 115 and 118.

[0030] In some embodiments of this invention, the binding domains (BD) of this invention, for example, 41BB binding domains and/or PDL1 binding domains, are derived from antibodies or antibody fragments, including scFv, Fabs, single domain antibodies (sdAb) , V _NAR or VHH. In some embodiments of this invention, the BD is a human or humanized sdAb. Fragments of sdAb may be derived from VHH, V _NAR , engineered VH or VK domains. VHH can only be derived from camel heavy chain antibodies. V _NARs can only be derived from heavy chain cartilaginous fish antibodies. Various methods have been put into practice to produce monomeric sdAbs from conventional VH and VK heterodimeric domains, including interaction design and selection of specific germline families. In other embodiments of this invention, the BDs are derived from non-antibody scaffold proteins, such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, anticalins/lipocalins, centirins, and finomers.

[0031] Typically, the fusion proteins of this invention consist of at least two or more BDs operably linked via a linker polypeptide. The use of sdAb fragments as the specific BD in the fusion of the present invention has the advantage of avoiding the problem of heavy chain-light chain mismatch that is common with many bi/multispecific antibody approaches. In addition, the fusion proteins of the invention avoid the use of long linkers required by many bispecific antibodies.

[0032] In some embodiments of this invention, all BDs of a fusion protein are TBDs that recognize the same epitope in a given member of the TNFRSF family, for example, fusion proteins of this invention may include 2, 3, 4, 5, or 6 TBD with identical specificity for 41BB. In other embodiments of the present invention, the fusion protein comprises TBDs that recognize distinct epitopes in a given member of the TNFRSF family, e.g., the fusion proteins of the present invention may comprise 2, 3, 4, 5, or 6 TBDs with clearly distinct recognition specificity for different epitopes on 41BB . In these embodiments, the fusion proteins of the invention comprise a plurality of TBDs that target specific regions of a particular member of the TNFRSF family. In other embodiments of this invention, TBDs can recognize different epitopes in the same member of the TNFRSF family, or recognize epitopes on different members of the TNFRSF family, for example, the present invention provides multispecific fusion proteins comprising TBDs that bind GITR and 41BB or OX40 and 41BB , or CD27 and 41BB.

[0033] In some embodiments of this invention, the multispecific fusion protein is a bispecific molecule that targets 41BB and PDL1. In some embodiments, the bispecific fusion protein comprises a 41BB-targeted binding domain selected from the group consisting of SEQ ID NOs: 16, 20, 23, 25, 29, 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83, operably linked to a second binding domain (BD2) that binds PDL1. In some embodiments of this invention, BD2 contains an amino acid sequence that specifically binds PDL1. In some embodiments of this invention, BD2 contains a PDL1-targeted domain selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116, and 119-124. In some embodiments of this invention, BD2 contains a PDL1-targeted domain selected from the group consisting of SEQ ID NO: 119-124. In some embodiments of this invention, BD2 contains an amino acid sequence that specifically binds PDL1 and is selected from the group consisting of SEQ ID NOs: 126-408.

[0034] In some embodiments of this invention, the multispecific fusion protein is a bispecific molecule that targets 41BB and PDL1. In some embodiments, the bispecific fusion protein comprises a 41BB-targeted binding domain selected from the group consisting of SEQ ID NOs: 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83 operably linked to a second binding domain (BD2) that binds PDL1. In some embodiments of this invention, BD2 contains an amino acid sequence that specifically binds PDL1. In some embodiments of this invention, BD2 contains a PDL1-targeted domain selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116, and 119-124. In some embodiments of this invention, BD2 contains a PDL1-targeted domain selected from the group consisting of SEQ ID NO: 119-124. In some embodiments of this invention, BD2 contains an amino acid sequence that specifically binds PDL1 and is selected from the group consisting of SEQ ID NO: 126-408.

[0035] In some embodiments of this invention, the multispecific fusion protein is a bispecific molecule that targets 41BB and PDL1. In some embodiments, the bispecific fusion protein comprises a PDL1-targeted binding domain selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116, and 119-124 operably linked to a second TBD (TBD2) , which links 41BB. In some embodiments of this invention, TBD2 contains an amino acid sequence that specifically binds 41BB. In some embodiments of this invention, TBD2 contains a 41BB-targeted domain selected from the group consisting of SEQ ID NOs: 16, 20, 23, 25, 29, 33, 39, 33-41, 43, 45-47, 49, 51 , 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83. In some embodiments of this invention, TBD2 contains an amino acid sequence that specifically binds 41BB and is selected from the group consisting of SEQ ID NOs: 84-99.

[0036] In some embodiments of this invention, the multispecific fusion protein is a bispecific molecule that targets 41BB and PDL1. In some embodiments, the bispecific fusion protein comprises a PDL1-targeted binding domain selected from the group consisting of SEQ ID NOs: 119-124 operably linked to a second TBD (TBD2) that binds 41BB. In some embodiments of this invention, TBD2 contains an amino acid sequence that specifically binds 41BB. In some embodiments of this invention, TBD2 contains a 41BB-targeted domain selected from the group consisting of SEQ ID NOs: 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60 , 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83. In some embodiments of this invention, TBD2 contains an amino acid sequence that specifically binds 41BB and is selected from the group consisting of SEQ ID NOs: 84-99.

[0037] In some embodiments of this invention, the multispecific fusion protein is a bispecific molecule that targets 41BB and PDL1 and contains an amino acid sequence that is selected from the group consisting of SEQ ID NOs: 448-456.

[0038] In some embodiments, the multispecific fusion protein is a bispecific molecule that targets 41BB and PDL1 and contains an amino acid sequence that is at least 50%, 60%, 65%, 70%, 75%, 80% , 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 448-456 .

[0039] In some embodiments of this invention, all BDs of a fusion protein recognize the same epitope on PDL1, for example, fusion proteins of this invention may include 2, 3, 4, 5, or 6 BDs with identical PDL1 specificity. In other embodiments of this invention, the fusion protein includes BDs that recognize individual epitopes on PDL1, for example, fusion proteins of this invention may include 2, 3, 4, 5, or 6 BDs with distinct recognition specificity for different epitopes on PDL1. In these embodiments, the fusion proteins of the invention comprise a plurality of BDs that target specific regions of PDL1. In other embodiments of the invention, BDs can recognize different epitopes on PDL1.

[0040] In some embodiments of this invention, the fusion protein of this invention consists of a single polypeptide. In other embodiments of the invention, the fusion protein of the invention is comprised of more than one polypeptide, e.g., wherein the heterodimerization domain is included in the fusion protein, resulting in an asymmetric fusion protein construct, e.g., if the immunoglobulin Fc region is included in the fusion protein, the domain CH3 can be used as a homodimerization domain, or the CH3 dimer interaction region can be mutated to allow for heterodimerization.

[0041] In some embodiments of this invention, the fusion protein contains opposite ends of the BD, for example, the BD is located on both the amino-terminal (N-terminal) portion of the fusion protein and the carboxy-terminal (C-terminal) portion of the fusion protein. In some embodiments of this invention, all TBDs are at the same end of the fusion protein, for example, the BDs are either on the amino or carboxy terminal portions of the fusion protein.

[0042] In some embodiments of the invention, the linker polypeptide comprises an immunoglobulin Fc region. In certain embodiments, the immunoglobulin Fc region is an IgG isotype selected from the group consisting of IgG1 subclass, IgG2 subclass, IgG3 subclass, and IgG4 subclass.

[0043] In some embodiments of this invention, the FC area of immunoglobulin or its immunologically active fragment is an IgG isotype, for example, the FC area of the immunoglobulin of the merged protein belongs to the IgGG1 subclass having an amino acid sequence:

[0044] In some embodiments of the present invention, the Fc region of an immunoglobulin or an immunologically active fragment thereof contains a human IgG1 polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1.

[0045] In some embodiments, the human IgG1 Fc region is modified at the amino acid position Asn297 (shown in box in SEQ ID NOs: 1-4, Kabat numbering) to prevent glycosylation of a fusion protein, e.g., Asn297Ala (N297A) or Asn297Asp (N297D). In some embodiments, the Fc region of the fusion protein is modified at the amino acid position Leu235 (bold in SEQ ID NO: 1, Kabat numbering) to alter Fc receptor interactions, e.g., Leu235Glu (L235E) or Leu235Ala (L235A). In some embodiments, the Fc region of the fusion protein is modified at the amino acid position Leu234 (bold in SEQ ID NO: 1, Kabat numbering) to alter Fc receptor interactions, eg, Leu234Ala (L234A). In some embodiments of the present invention, the Fc region of the fusion protein is modified at the amino acid position Leu234 (in box, Kabat numbering) to alter Fc receptor interactions, eg, Leu235Glu (L235E). In some embodiments of the present invention, the Fc region of the fusion protein is altered at both amino acid positions 234 and 235, for example, Leu234Ala and Leu235Ala (L234A/L235A) or Leu234Val and Leu235Ala (L234V/L235A). In some embodiments, the Fc region of the fusion protein does not contain an amino acid at one or more of the following positions to reduce Fc receptor binding: Glu233 (E233, bold in SEQ ID NO: 1), Leu234 (L234), or Leu235 ( L235). In some embodiments of the present invention, the Fc region of the fusion protein is altered at the Gly235 position to reduce Fc receptor binding, for example, Gly235 is removed from the fusion protein. In some embodiments, the human IgG1 Fc region is modified at the Gly236 amino acid position (shown in box in SEQ ID NO: 1) to improve interaction with CD32A, eg, Gly236Ala (G236A). In some embodiments, the human IgG1 Fc region lacks Lys447 (EC index by Kabat et al 1991 Sequences of Proteins of Immunological Interest ).

[0046] In some embodiments, the Fc region of the fusion protein is altered at one or more of the following positions to reduce Fc receptor binding: Leu 234 (L234), Leu235 (L235), Asp265 (D265), Asp270 (D270), Ser298 (S298), Asn297 (N297), Asn325 (N325) or Ala327 (A327), e.g. Leu 234Ala (L234A), Leu235Ala (L235A), Asp265Asn (D265N), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala ( N297A), Asn325Glu (N325E), or rAla327Ser (A327S). In preferred embodiments of this invention, modifications within the Fc region reduce binding to Fc-receptor-gamma receptors while having minimal effect on neonatal Fc receptor (FcRn) binding.

[0047] In some embodiments, the Fc region of the fusion protein does not contain an amino acid at one or more of the following positions to reduce Fc receptor binding: Glu233 (E233), Leu234 (L234) or Leu235 (L235). In these embodiments, the Fc deletion of these three amino acids reduces complement fixation of the C1q protein. These modified Fc region polypeptides are referred to herein as "Fc deletion" polypeptides.

PAPGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK (SEQ ID NO: 2)

[0048] In some embodiments of the present invention, the Fc region of an immunoglobulin or an immunologically active fragment thereof contains a human IgG1 polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 2.

[0049] In some embodiments, the immunoglobulin Fc region or immunologically active fragment of the fusion protein is a human IgG2 subclass having the amino acid sequence:

[0050] In some embodiments, the fusion protein or immunologically active fragment thereof comprises a human IgG2 polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 3.

[0051] In some embodiments, the human IgG2 Fc region is modified at the amino acid position Asn297 (shown in box in SEQ ID NOs: 1, 3, 4, and 5) to prevent glycosylation of an antibody, e.g., Asn297Ala (N297A). In some embodiments, the human IgG2 Fc region lacks Lys447, corresponding to residue 217 of SEQ ID NO: 3 (EC index by Kabat et al 1991 Sequences of Proteins of Immunological Interest ).

[0052] In some embodiments of the invention, the immunoglobulin Fc region or immunologically active fragment of the fusion protein is a human IgG3 subclass having the amino acid sequence:

[0053] In some embodiments, the antibody or immunologically active fragment thereof comprises a human IgG3 polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 4.

[0054] In some embodiments of this invention, the FC IGG3 region is modified in the amino acid ASN297 (shown in the frame in the SEQ ID NO: 1-4, numbering in the cabata) in order to prevent antibody glycosylation, for example, ASN297ALA (N297A). In some options for the implementation of this invention, the FC IgG3 area is modified in the amino acid position 435, in order to extend the half -life period, for example, the Arg435his (R435H, shown in the frame in SEQ ID NO: 3). In some options for the implementation of this invention in the field of FC IGG3 of a person there is no LYS447, which corresponds to the balance of 218 from the SEQ ID No: 4 (the EU index according to Kabat et al 1991 Sequences of Immunological Interest ).

[0055] In some embodiments, the immunoglobulin Fc region or immunologically active fragment of the fusion protein is a human IgG4 subclass having the amino acid sequence:

[0056] In some embodiments, the antibody or immunologically active fragment thereof comprises a human IgG4 polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 5.

[0057] In other embodiments, the human IgG4 Fc region is modified at amino acid position 235 to alter Fc receptor interactions, eg, Leu235Glu (L235E). In some embodiments, the human IgG4 Fc region is modified at the amino acid position Asn297 (shown in box in SEQ ID NOs: 1-4, Kabat numbering) to prevent glycosylation of an antibody, e.g., Asn297Ala (N297A). In some embodiments, the human IgG4 Fc region lacks Lys447, corresponding to residue 218 of SEQ ID NO: 5 (EC index from Kabat et al 1991 Sequences of Proteins of Immunological Interest ).

[0058] In some embodiments of the invention, the immunoglobulin Fc region or immunologically active fragment of the fusion protein is of the human IgG4 isotype having the amino acid sequence:

[0059] In some embodiments, the antibody or immunologically active fragment thereof comprises a human IgG4 polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 6.

[0060] In some embodiments of the invention, the human IgG Fc region is modified to enhance FcRn binding. Examples of Fc mutations that enhance FcRn binding are Met252Tyr, Ser254Thr, Thr256Glu (M252Y, S254T, T256E, respectively) (Kabat numbering, Dall'Acqua et al 2006, J. Biol Chem Vol. 281(33) 23514-23524 ), Met428Leu and Asn434Ser (M428L, N434S) (Zalevsky et al 2010 Nature Biotech , Vol. 28(2) 157-159), or Met252Ile, Thr256Asp, Met428Leu (M252I, T256D, M428L, respectively), (EC index according to Kabat et al 1991 Sequences of Proteins of Immunological Interest ). Met252 corresponds to residue 23 in SEQ ID NOs: 1, 4 and 5, and also to residue 22 in SEQ ID NO: 3. Ser254 corresponds to residue 25 in SEQ ID NOs: 1, 4 and 5, and also to residue 24 in SEQ ID NO: 3. Thr256 corresponds to residue 27 of SEQ ID NOs: 1, 4 and 5, and also to residue 26 of SEQ ID NO: 3. Met428 corresponds to residue 199 of SEQ ID NOs: 1, 4 and 5, and also to residue 198 of SEQ ID NO: 3. Asn434 corresponds to residue 205 of SEQ ID NOs: 1, 4, and 5, as well as residue 204 of SEQ ID NO: 3. mutated or modified. In these embodiments, the mutant or modified Fc polypeptide comprises the following mutations: Met252Tyr and Met428Leu (M252Y, M428L) according to the Kabat numbering system.

[0061]In some embodiments of the invention, the human IgG Fc region is modified to alter antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC),For example, amino acid modifications described in Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Moore et al., 2010 mAbs, 2(2): 181-189; Lazar et al., 2006 PNAS, 103(11): 4005-4010, Shields et al., 2001 JBC, 276(9): 6591-6604; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48: 152-164; Alegre et al, 1992 J Immunol, 148: 3461-3468; see review in Kaneko and Niwa, 2011 Biodrugs, 25(1): 1-11. Examples of mutations that enhance ADCC include modification at position Ser239 and Ile332, eg Ser239Asp and Ile332Glu (S239D, I332E). Examples of mutations that enhance CDC include modifications at position Lys326, which corresponds to residue 97 of SEQ ID NO: 1, 4 and 5, as well as residue 96 of SEQ ID NO: 2, and Glu333, which corresponds to residue 104 of SEQ ID NO. : 1, 4 and 5, as well as residue 103 of SEQ ID NO: 3. In some embodiments of this invention, the Fc region is modified at one or both of these positions, for example, Lys326Ala and/or Glu333Ala (K326A and E333A).

[0062] In some embodiments of this invention, the FC IgG region is modified with the aim of inducing heterodimerization, for example, with modification of amino acids in the CH3 domain in the ThR366 domain, which, when replacing with a more voluminous amino acid, for example, TRP (T366W), is the possibility of predominant mating With the second Domain SN3, which has amino acid modifications to less voluminous amino acids in the positions of the ThR366, which corresponds to the remainder of 137 sequences SEQ ID: 1, 4 and 5, as well as the remainder of the SEQ ID NO: 3, LeU368 sequence, which corresponds to the residue of 139 sequences Seq ID NO: 1, 4 and 5, as well as the balance of 138 sequences SEQ ID NO: 2, and TYR407, which corresponds to the remainder of 178 sequences SEQ ID NO: 1, 4 and 5, as well as the balance of 177 sequences SEQ ID NO: 3, for example, for example , Ser, Ala, and Val, respectively (T366S/L368A/Y407V). Heterodimerization through CH3 modifications can be additionally stabilized by introducing disulfide, for example, by changing Ser354, which corresponds to the remainder of 125 sequences Seq ID NO: 1, 4 and 5, as well as the remainder of 124 sequences Seq ID NO: 3, to CYS (S354C) and TYR349, which corresponds to the balance of 120 sequences SEQ ID NO: 1, 4 and 5, as well as the remainder of 119 sequences Seq ID No: 3, to CYS (Y349C) on opposite CH3 domains (see Review in Carter, 2001 Journal of Immunological Methods, 248:7-15). In some of these options for the implementation of this invention, the FC area can be modified on the protein-a binding area on one heterodimer representative, in order to prevent protein-a binding and thereby ensuring more efficient purification of heterodimeric merged protein. The typical modification in this section of the binding is ILE253, which corresponds to the remainder of 24 sequences SEQ ID NO: 1, 4 and 5, as well as the balance of 23 sequences of Seq ID No: 3, for example, Ile253ARG (I253R), for example, modification I253R can be combined with modifications T366S/L368A/Y407V or with T366W modifications. T366S/L368A/Y407V-modified FC is capable of forming homoders, since there is no steric occlusion of the interaction of the dimension, which is characteristic in the case of T336W-modified FC. Therefore, in some options for the implementation of this invention, the I253R modification is combined with T366S/L368A/Y407V-modified FC in order to prevent the purification of any homodimal FC, which can form.

[0063] In some embodiments of the invention, the human IgG Fc region is modified to prevent dimerization. In these embodiments, the fusion proteins of the invention are monomeric, e.g., modification at Thr366 to a charged residue, e.g., Thr366Lys, Thr366Arg, Thr366Asp, or Thr366Glu (T366K, T366R, T366D, or T366E, respectively), prevents CH3-CH3 dimerization .

[0064] In some embodiments, the Fc region of the fusion protein is altered at one or more of the following positions to reduce Fc receptor binding: Leu 234 (L234), Leu235 (L235), Asp265 (D265), Asp270 (D270), Ser298 (S298), Asn297 (N297), Asn325 (N325) or Ala327 (A327), e.g. Leu 234Ala (L234A), Leu235Ala (L235A), Asp265Asn (D265N), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala ( N297A), Asn325Glu (N325E), or rAla327Ser (A327S). In preferred embodiments of the present invention, modifications within the Fc region reduce binding to Fc-receptor-gamma receptors while having minimal effect on neonatal Fc receptor (FcRn) binding.

[0065] In some embodiments of the present invention, the fusion protein comprises a polypeptide derived from the hinge region of an immunoglobulin. The hinge region can be selected from any of the human IgG subclasses, for example, the fusion protein can contain a modified IgG1 hinge having the sequence EPKSSDKTHTCPPC (SEQ ID NO: 7), while Cys220, which forms a disulfide with a light chain C-terminal cysteine, is mutated to serine, for example, Cys220Ser (C220S). In other embodiments, the fusion protein comprises a truncated hinge having the sequence DKTHTCPPC (SEQ ID NO: 8).

[0066] In some embodiments of the present invention, the fusion protein has a modified IgG4 hinge that is modified to prevent or reduce strand exchange, for example, Ser228Pro (S228P) having the ESKYGPPCPPC sequence (SEQ ID NO: 9). In some embodiments of this invention, the fusion protein contains one or more linker polypeptides. In other embodiments of this invention, the fusion protein contains linker and hinge polypeptides.

[0067] In some embodiments, the fusion proteins herein lack or contain a reduced amount of fucose attached to the N-linked glycan chain at position N297. There are many ways to prevent fucosylation, including, but not limited to, production in a FUT8 deficient cell line; the use of additional inhibitors of attachment to the medium for culturing mammalian cells, for example, castanospermine, 2-deoxyfucose, 2-flurofucose; the use of production cell lines with naturally reduced function of fucosylation pathways, as well as the metabolic design of the production cell line.

[0068] In some embodiments of the present invention, a single domain antibody, VHH, or a humanized single domain antibody or a human single domain antibody is designed to eliminate recognition by pre-existing antibodies found in humans. In some options for the implementation of this invention, single -dimensional antibodies in this invention are modified by mutation of the Leu11 position, for example, Leu11glu (L11E) or Leu11lys (L11k). In other options for the implementation of this invention, single -dimensional antibodies in this invention are modified by changes in the carboxycoconsery region, for example, the terminal sequence consists of GQGTLVTVKPGG (SEQ ID NO: 14) or GQGTLVTVEPGG (Seq ID NO: 15) or their modifications. In some options for the implementation of this invention, single -dimensional antibodies in this invention are modified through a mutation of position 11 and through changes in the carboxicon region.

[0069] In some embodiments of this invention, the BD fusion proteins of this invention are operably linked via amino acid linkers. In some embodiments of this invention, these linkers consist predominantly of the amino acids glycine and serine, referred to herein as GS-linkers. The fusion protein GS linkers of this invention may be of various lengths, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 amino acids in length.

[0070] In some embodiments, the implementation of the present invention, the GS-linker contains an amino acid sequence selected from the group consisting of GGSGGS, that is, (GGS) ₂ (SEQ ID NO: 10); GGSGGSGGS, i.e., (GGS) ₃ (SEQ ID NO: 11); GGSGGSGGSGGS, i.e., (GGS) ₄ (SEQ ID NO: 12); as well as GGSGGSGSGSGSGS, t. E., (GGS) ₅ (SEQ ID NO: 13).

[0071] In some embodiments of this invention, the multivalent binding fusion protein is tetravalent. In some embodiments, the tetravalent fusion protein has the following structure: BD-linker-BD-linker-hinge-Fc. In some embodiments, the tetravalent fusion protein has the following structure: BD-linker-hinge-Fc-linker-BD.

[0072] In some embodiments of this invention, the BD of the tetravalent fusion protein is a single domain antibody or VHH. In some embodiments, each BD of the tetravalent fusion protein is a single domain antibody or VHH. In some embodiments, the tetravalent fusion protein has the following structure: VHH-linker-VHH-linker-hinge-Fc, wherein the VHH is a humanized or fully human VHH sequence. In some embodiments, the tetravalent fusion protein has the following structure: VHH-linker-hinge-Fc-linker-VHH, wherein the VHH is a humanized or fully human VHH sequence.

[0073] In some embodiments of the invention, the multivalent TNFRSF binding fusion protein is tetravalent. In some embodiments, the tetravalent TNFRSF binding fusion protein has the following structure: TBD-linker-TBD-linker-hinge-Fc. In some embodiments, the tetravalent TNFRSF binding fusion protein has the following structure: TBD-linker-hinge-Fc-linker-TBD.

[0074] In some embodiments, the TBD of the tetravalent TNFRSF binding fusion protein is a single domain antibody or VHH. In some embodiments of the invention, each TBD of the multivalent TNFRSF binding fusion protein is a single domain antibody or VHH. In some embodiments, the tetravalent TNFRSF binding fusion protein has the following structure: VHH-linker-VHH-linker-hinge-Fc, wherein VHH is a humanized or fully human VHH sequence. In some embodiments, the tetravalent TNFRSF binding fusion protein has the following structure: VHH-linker-hinge-Fc-linker-VHH, wherein the VHH is a humanized or fully human VHH sequence.

[0075] In some embodiments, the implementation of the present invention, the GS-linker contains an amino acid sequence selected from the group consisting of GGSGGS, that is, (GGS) ₂ (SEQ ID NO: 10); GGSGGSGGS, i.e., (GGS) ₃ (SEQ ID NO: 11); GGSGGSGGSGGS, i.e., (GGS) ₄ (SEQ ID NO: 12); and also GGSGGSGGSGGSGGS, i.e., (GGS) ₅ (SEQ ID NO: 13).

[0076] In some embodiments of this invention, the multivalent fusion protein is hexavalent. In some embodiments of this invention, the hexavalent fusion protein has the following structure: BD-linker-TBD-linker-BD-linker-hinge-Fc. In some embodiments, the hexavalent fusion protein has the following structure: BD-linker-BD-linker-hinge-Fc-linker-BD, or BD-linker-hinge-Fc-linker-BD-linker-BD.

[0077] In some embodiments, the BD of the hexavalent fusion protein is a single domain antibody or VHH. In some embodiments of the invention, each BD of the hexavalent fusion protein is a single domain antibody or VHH. In some embodiments of this invention, the hexavalent fusion protein has the following structure: VHH-linker-VHH-linker-VHH-linker-hinge-Fc, wherein the VHH is a humanized or fully human VHH sequence. In some embodiments, the hexavalent fusion protein has the following structure: VHH-linker-VHH-linker-hinge-Fc-linker-VHH, or VHH-linker-hinge-Fc-linker-VHH-linker-VHH, wherein the VHH is a humanized or fully human VHH sequence.

[0078] In some embodiments of the invention, the multivalent TNFRSF binding fusion protein is hexavalent. In some embodiments of this invention, the hexavalent TNFRSF-binding fusion protein has the following structure: TBD-linker-TBD-linker-TBD-linker-hinge-Fc. In some embodiments of the present invention, the hexavalent TNFRSF binding fusion protein has the following structure: TBD-linker-TBD-linker-hinge-Fc-linker-TBD or TBD-linker-hinge-Fc-linker-TBD-linker-TBD.

[0079] In some embodiments, the TBD of the hexavalent TNFRSF binding fusion protein is a single domain antibody or VHH. In some embodiments of the invention, each TBD of the hexavalent TNFRSF binding fusion protein is a single domain antibody or VHH. In some embodiments of the present invention, the hexavalent TNFRSF binding fusion protein has the following structure: VHH-linker-VHH-linker-VHH-linker-hinge-Fc, wherein the VHH is a humanized or fully human VHH sequence. In some embodiments of the present invention, the hexavalent TNFRSF binding fusion protein has the following structure: VHH-linker-VHH-linker-hinge-Fc-linker-VHH, or VHH-linker-hinge-Fc-linker-VHH-linker-VHH, when this VHH is a humanized or fully human VHH sequence.

[0080] In some embodiments of the invention, the multivalent fusion protein lacks an Fc region. In some of these embodiments, the fusion protein is tetravalent and has the following structure: BD-linker-BD-linker-BD-linker-BD-linker. In some of these embodiments of the present invention, the fusion protein is pentavalent and has the following structure: BD-linker-BD-linker-BD-linker-BD-linker-BD. In some of these embodiments, the fusion protein is hexavalent and has the following structure: BD-linker-BD-linker-BD-linker-BD-linker-BD-linker-BD.

[0081] In some embodiments of the present invention, the multivalent TNFRSF binding fusion protein lacks an Fc region. In some of these embodiments of the present invention, the TNFRSF-binding fusion protein is tetravalent and has the following structure: TBD-linker-TBD-linker-TBD-linker-TBD-linker. In some of these embodiments, the TNFRSF binding fusion protein is pentavalent and has the following structure: TBD-linker-TBD-linker-TBD-linker-TBD-linker-TBD. In some of these embodiments, the TNFRSF binding fusion protein is hexavalent and has the following structure: TBD-linker-TBD-linker-TBD-linker-TBD-linker-TBD-linker-TBD.

[0082] In some embodiments of this invention, the BD of the multivalent fusion protein is a single domain antibody or VHH. In some embodiments of the present invention, the multivalent fusion protein lacks an Fc region. In some of these embodiments of the present invention, the fusion protein is tetravalent and has the following structure: VHH-linker-VHH-linker-VHH-linker-VHH-linker. In some of these embodiments, the fusion protein is pentavalent and has the following structure: VHH-linker-VHH-linker-VHH-linker-VHH-linker-VHH. In some of these embodiments, the fusion protein is hexavalent and has the following structure: VHH-linker-VHH-linker-VHH-linker-VHH-linker-VHH-linker-VHH. In any of these embodiments of the invention, the VHH is a humanized or fully human VHH sequence.

[0083] In some embodiments of this invention, the TBD of the multivalent TNFRSF-binding protein is a single-day antibody or VHH. In some options for the implementation of this invention, the multivalent TNFRSF-reinforcing, the merged protein does not have an FC area. In some of these options for the implementation of this invention, TNFRSF-binding protein is tetravalent and has the following structure: VHH-linker-vhh-vhh-linker-vhh-linker. In some of these options for the implementation of this invention, TNFRSF-binding protein is pentavalent and has the following structure: VHH-linker-VHH-VHH-VHHH-VHH. In some of these options for the implementation of this invention, TNFRSF-binding protein is hexavalent and has the following structure: VHH-linker-VHH-VHH-VHH-VHH-VHH-VHH. In any of these options for the implementation of this invention, VHH is a humanized or completely human sequence VHH.

[0084] In some embodiments of the present invention, the GS linker contains an amino acid sequence selected from the group consisting of GGSGGS, ie, (GGS) ₂ (SEQ ID NO: 10); GGSGGSGGS, i.e., (GGS) ₃ (SEQ ID NO: 11); GGSGGSGGSGGS, i.e., (GGS) ₄ (SEQ ID NO: 12); as well as GGSGGSGSGSGSGS, t. E., (GGS) ₅ (SEQ ID NO: 13).

[0085] In some embodiments of the present invention, the fusion proteins are multispecific, containing TBD and a binding domain directed to a second antigen. In these embodiments, implementation of the present invention, the second antigennegative domain can be located in many positions within the molecule relative to TBD. In some embodiments, implementation of this invention, the second antigen-binding domain is located in the N-terminal position relative to the TBD. In some embodiments of this invention, the second antigen-binding domain is located at the C-terminal position relative to the TBD. In some embodiments of this invention, the second antigen-binding domain is located on a separate polypeptide that binds to the first TBD-containing polypeptide.

[0086] In some embodiments of this invention, the fusion proteins are multispecific, containing an anti-41BB binding domain and a binding domain directed to a second antigen. In these embodiments, implementation of the present invention, the second antigennegative domain can be located in many positions within the molecule relative to the anti-41BB-binding domain. In some embodiments of the invention, the second antigen-binding domain is N-terminal to the anti-41BB binding domain. In some embodiments, implementation of this invention, the second antigennegative domain is located in the C-terminal position relative to the anti-41BB-binding domain. In some embodiments of this invention, the second antigen binding domain is located on a separate polypeptide that binds to the first polypeptide containing the anti-41BB binding domain.

[0087] In some embodiments of the present invention, the fusion proteins are multispecific, containing an anti-PDL1 binding domain and a binding domain directed to a second antigen. In these embodiments, implementation of the present invention, the second antigennegative domain can be located in many positions within the molecule relative to the anti-PDL1-binding domain. In some embodiments, implementation of the present invention, the second antigennegative domain is located in the N-terminal position relative to the anti-PDL1-binding domain. In some embodiments of this invention, the second antigen-binding domain is located at the C-terminal position relative to the anti-PDL1-binding domain. In some embodiments of this invention, the second antigen-binding domain is located on a separate polypeptide that binds to the first polypeptide containing the anti-PDL1-binding domain.

[0088] In some embodiments of this invention, the TBD in the multispecific TNFRSF binding fusion protein is a single domain antibody or VHH. In some embodiments of this invention, the TBD in the multispecific TNFRSF binding fusion protein consists of the variable heavy chain (VH) and variable light chain (VL) region of an antibody. In some embodiments of this invention, the VH and VL in TBD are formatted as a single chain variable fragment (scFv) attached via a linker region. In some embodiments of the present invention, the VH and VL in the TBD are formatted as a FAB fragment that binds via a heavy chain 1 constant domain (CH1) and a light chain constant domain (CL). In some embodiments of this invention, non-antibody heterodimerization domains are used to ensure proper VH and VL binding in TBD. In some embodiments of this invention, the TBD in the multispecific TNFRSF binding fusion protein is derived from non-antibody scaffold proteins such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, anticalin/lipocalins, centirins, and finomers.

[0089] In some embodiments, the TBD in the multispecific TNFRSF binding fusion protein is a single domain antibody or VHH that binds 41BB. In some embodiments, the anti-41BB binding domain in the multispecific TNFRSF binding fusion protein consists of the variable heavy chain (VH) and variable light chain (VL) region of an antibody. In some embodiments of this invention, the VH and VL in the anti-41BB binding domain are formatted as a single chain variable fragment (scFv) attached via a linker region. In some embodiments of the present invention, the VH and VL in the anti-41BB binding domain are formatted as a Fab fragment that binds via a heavy chain 1 constant domain (CH1) and a light chain constant domain (CL). In some embodiments of the invention, non-antibody heterodimerization domains are used to ensure proper VH and VL binding in the anti-41BB binding domain. In some embodiments, the anti-41BB binding domain in the multispecific TNFRSF binding fusion protein is derived from non-antibody scaffold proteins, such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, ancalin/lipocalins, centirins, and finomers.

[0090] In some embodiments of this invention, the binding domain in the multispecific fusion protein is a single domain antibody or VHH that binds PDL1. In some embodiments, the anti-PDL1 binding domain in the multispecific TNFRSF binding fusion protein consists of the variable heavy chain (VH) and variable light chain (VL) region of an antibody. In some embodiments of this invention, the VH and VL in the anti-PDL1 binding domain are formatted as a single chain variable fragment (scFv) attached via a linker region. In some embodiments of the present invention, the VH and VL in the anti-PDL1 binding domain are formatted as a Fab fragment that binds via a heavy chain 1 constant domain (CH1) and a light chain constant domain (CL). In some embodiments of the present invention, non-antibody heterodimerization domains are used to ensure proper VH and VL binding in the anti-PDL1 binding domain. In some embodiments of the present invention, the anti-PDL1 binding domain in the multispecific fusion protein is derived from non-antibody scaffold proteins such as, but not limited to, engineered ankyrin repeat proteins (darpins), avimers, anticalins/lipocalins, centirins, and finomers.

[0091] In some embodiments, the anti-41BB binding domain of the multispecific TNFRSF binding fusion protein is a bispecific antibody or an antigen binding fragment thereof.

[0092] In some embodiments of the invention, the anti-PDL1 binding domain of the multispecific fusion protein is a bispecific antibody or an antigen-binding fragment thereof.

[0093] In any of these embodiments, the bispecific antibody or antigen fragment thereof may be in any suitable bispecific format known in the art, including, by way of non-limiting example, antibody fragment formats such as, for example, X-linked Fabs, cross-linked Fab fragments; tascFv/BiTE, tandem-scFv/T-cell-attracting bispecific activator; Db, diabody; taDb, tandem diabodies; Fc fusion formats such as, for example, Db-Fc, "diabody-Fc"fusion; taDb-Fc, "diabody-Fc" tandem fusion; taDb-CH3, "diabody-CH3" tandem fusion; (scFv) 4-Fc, scFv-Fc tetra fusion; DVD-Ig, double variable domain immunoglobulin; IgG formats such as, for example, ridge-in-gap and SEED, an engineered chain exchange domain; CrossMab, key-to-hole in combination with domain heavy and light chain exchange; bsAb, a quadroma-derived bispecific antibody; sdAb, single domain antibody; and kappa-lambda bodies such as those described in PCT Publication No. WO 2012/023053.

[0094] In any of the above embodiments of this invention, at least one TBD contains an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 20, 23, 25, 29, 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83.

[0095] In any of the above embodiments of this invention, at least one TBD contains an amino acid sequence selected from the group consisting of SEQ ID NO: 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83.

[0096] In any of the above embodiments of the invention, at least one TBD comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21, 26, 30, 50, 65 and 69; complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 27, 31, 42, 44, 48, 52, 61, 63, 71, 73, 75, 77 and 79 ; complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 24, 28, 32, 55 and 57.

[0097] In any of the above embodiments of this invention, at least one BD contains an amino acid sequence selected from the group consisting of SEQ ID NOS: 100, 104, 108, 112, 114, 116, and 119-124.

[0098] In any of the above embodiments of this invention, at least one BD contains an amino acid sequence selected from the group consisting of SEQ ID NO: 119-124.

[0099] In any of the above embodiments of the present invention, at least one BD contains a CDR1 containing an amino acid sequence selected from the group consisting of SEQ ID NO: 101, 105 and 109; a CDR2 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 106, 110 and 117; and a CDR3 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 107, 111, 113, 115 and 118.

[00100] In any of the above embodiments of this invention, at least one TBD contains an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 20, 23, 25, 29, 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83, and at least one BD contains the amino acid sequence, selected from the group consisting of SEQ ID NOs: 100, 104, 108, 112, 114, 116 and 119-124.

[00101] In any of the above embodiments of this invention, at least one TBD contains an amino acid sequence selected from the group consisting of SEQ ID NO: 33, 39, 33-41, 43, 45-47, 49, 51, 53, 54, 56, 58-60, 62, 65, 66, 68, 70, 72, 74, 76, 78 and 80-83, and at least one BD contains an amino acid sequence selected from the group consisting of SEQ ID NO: 119-124.

[00102] In any of the above embodiments of the invention, at least one TBD comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21, 26, 30, 50, 65 and 69; complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 27, 31, 42, 44, 48, 52, 61, 63, 71, 73, 75, 77 and 79 ; complementarity determining region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 24, 28, 32, 55 and 57, and at least one BD contains a CDR1 containing an amino acid sequence, selected from the group consisting of SEQ ID NOs: 101, 105 and 109; a CDR2 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 106, 110 and 117; and a CDR3 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 107, 111, 113, 115 and 118.

BRIEF DESCRIPTION OF GRAPHICS

[00103] Figure 1 is a diagram of exemplary multivalent and multispecific fusion proteins of the invention.

[00104] Figures 2A and 2B are a pair of graphs showing the ability of 41BB single domain antibodies (sdAbs) to bind recombinant human 41BB (Figure 2A) or cynomolgus monkey 41BB (Figure 2B). Binding was assessed by ELISA, while the recombinant 41BB-mFc protein was immobilized on a 96-well Medisorp plate.

[00105] Figure 3 is a graph showing the ability of 41BB single domain antibodies (sdAbs) to bind 41BB on the cell surface. Binding was assessed by flow cytometry using CHO cells expressing 41BB, with data presented as median fluorescence intensity.

[00106] Figure 4 is a graph showing the ability of 41BB single domain antibodies, RH3 and 4H04, to bind cynomolgus monkey 41BB. Binding was assessed by ELISA, while the recombinant 41BB-mFc protein was immobilized on a 96-well Medisorp plate.

[00107] Figure 5 is a graph showing the ability of 41BB single domain antibodies (VHH) to block the interaction between 41BB and 41BBL. All analyzed single-domain antibodies, with the exception of RH3, block the interaction between 41BB and 41BBL. Blocking was assessed by flow cytometry using recombinant 41BB fusion protein and CHO cells expressing 41BB, with data presented as median fluorescence intensity.

[00108] Figure 6 is a graph demonstrating the failure of conventional divalent anti-41BB antibody PF-05082566 to induce 41BB signaling, except when additional clustering is performed with exogenous anti-human IgG crosslinker. 41BB signaling was monitored using the NFkB reporter cell line 293 expressing 41BB.

[00109] Figures 7A and 7B are a pair of graphs showing the ability of a typical PDL1 single domain antibody (28A10) to bind PDL1 on the cell surface and block interaction with PD1. Binding (Figure 7A) was assessed by flow cytometry on CHO cells expressing PDL1. Blocking (Figure 7B) was assessed by flow cytometry using recombinant PD1 fusion protein and CHO cells expressing PDL1, with data presented as median fluorescence intensity.

[00110] Figures 8A, 8B and 8C are a series of illustrations and a graph depicting PDL1-dependent 41BB agonism mediated by the bispecific fusion proteins of this invention targeting PDL1-41BB. Figures 8A and 8B are conceptual diagrams in which the bispecific fusion proteins have minimal 41BB agonistic properties (Figure 8A), except when they are associated with a PD-L1 expressing cell (Figure 8B). Figure 8C is a graph demonstrating the ability of a PDL1 positive cell (herein PDL1 transfected CHO cells) to mediate 41BB signaling and the inability of a PDL1 negative cell (herein nontransfected CHO cells) to mediate 41BB signaling. 41BB signaling was monitored using the NFkB reporter cell line 293 expressing 41BB.

[00111] Figures 9A, 9B, 9C, 9D and 9E are a series of graphs showing the binding of humanized RH3 variants to human 41BB (Figure 9A and Figure 9C) or cynomolgus monkey (Figure 9B and Figure 9D). Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB. Figure 9E is a graph demonstrating that the humanized hzRH3v5-1 and hzRH3v9 variants do not block 41BBL binding to 41BB on the cell surface. In these studies, a recombinant 41BBL-mFc fusion protein containing a mouse Fc region was used, and 41BBL binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00112] Figure 10 is a graph showing the specific binding of hzRH3v5-1 (40 nM) to 41BB compared to other members of the TNFRSF family: OX40 and GITR. Binding was assessed by flow cytometry using CHO cells expressing this member of the TNFRSF family.

[00113] Figures 11A, 11B, 11C and 11D are a series of graphs showing the binding of humanized 4E01 variants to human 41BB (Figure 11A and Figure 11C) or cynomolgus monkey (Figure 11B). Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB. Figure 11D is a graph demonstrating that hz4E01v16, hz4E01v18, hz4E01v21, hz4E01v22 and hz4E01v23 humanized variants block 41BBL binding to 41BB on the cell surface. In these studies, a recombinant 41BBL-mFc fusion protein containing a mouse Fc region was used, and 41BBL binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00114] Figure 12 is a graph showing the binding of humanized single domain antibodies targeting PDL1. Binding was assessed by flow cytometry on CHO cells expressing PDL1.

[00115] Figure 13 is a schematic representation of two exemplary formats of the bispecific PDL1x41BB, INBRX-105-1. INBRX-105-1-A (left) has PDL1 and 41BB binding domains located at opposite end positions from the central Fc region, while INBRX-105-1-B (right) has PDL1 and 41BB binding domains, Located in tandem, on the N-adle regarding the FC area.

[00116] Figures 14A, 14B and 14C are a series of graphs demonstrating equivalent binding to human (Figure 14A) or cynomolgus monkey (Figure 14B) 41BB by two different formats of the bispecific fusion protein targeting PDL1 and 41BB and designated herein as INBRX-105-1-A and INBRX-105-1-B. Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB. Figure 14C is a graph demonstrating that the hzRh3v5-1 containing bispecific fusion protein does not block 41BBL binding to 41BB on the cell surface. In these studies, a recombinant 41BBL fusion protein and mouse Fc region was used, and 41BBL binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00117] Figures 15A, 15B, 15C and 15D are a series of graphs showing equivalent binding (Figure 15A and Figure 15C) and blocking of PD1 (Figure 15B and Figure 15D) by two different formats of the bispecific fusion protein targeting PDL1 and 41BB, and referred to in this document as INBRX-105-1-A and INBRX-105-1-B. Binding was assessed by flow cytometry on human 293freestyle cells (Figure 15A) or cynomolgus monkey (Figure 15C) expressing PDL1. Blocking was assessed by flow cytometry on human 293freestyle cells (Figure 15B) or cynomolgus monkey (Figure 15D) expressing PDL1 with either recombinant human PD1-mFc fusion protein (Figure 15B) or cynomolgus monkey (Figure 15D). PD1 binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00118] Figure 16 is a graph demonstrating the ability of humanized versions of the PDL1x41BB bispecific fusion protein (INBRX-105-1) to induce PDL1-dependent 41BB agonism. The 41BB-expressing NFkB reporter cell line HEK293 was used to assess 41BB signaling, and the PDL1-expressing CHO cell line was used as the PDL1 source.

[00119] Figures 17A and 17B are a pair of graphs showing 41BB-specific binding by the 41BB-binding portion of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention. Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB (Figure 17A) or the closest homologue, TNFRSF21/DR6 (Figure 17B). An anti-DR6 antibody (Invitrogen) was used as a positive control for DR6 expression.

[00120] Figures 18A, 18B and 18C are a series of graphs showing PDL1-specific binding by the PDL1-binding portion of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention. Binding was assessed by flow cytometry on 293freestyle cells expressing PDL1 (Figure 18A) or its closest homologue PDL2 (Figure 18B) or VISTA/PDL3 (Figure 18C) Anti-PDL2 and anti-VISTA antibodies were used as positive controls for PDL2 and PDL3 expression respectively.

[00121] Figures 19A and 19B are a pair of graphs demonstrating the ability of the PDL1x41BB bispecific fusion protein to simultaneously bind PDL1 and 41BB. 41BB binding was detected using a specific anti-mouse IgG-Fc secondary antibody. Figure 19A shows a graph demonstrating the binding of the INBRX-105-1 with K562 cells expressing PDL1. The 19v figure shows a graph that demonstrates the binding of the 41BB recombinant with INBRX-105-1 on the cells expressing PDL1.

[00122] Figure 20 is a graph demonstrating the ability of the PDL1x41BB bispecific fusion protein to simultaneously bind recombinant PDL1 and recombinant 41BB in an ELISA assay. Bound recombinant 41BB was detected using streptavidin-HRP.

[00123] Figures 21A, 21B and 21C are a series of graphs showing the effect of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the present invention on T cell activation and proliferation. INFγ production in the cell supernatant was monitored by ELISA and normalized to a standard curve. T cell proliferation was monitored by flow cytometry using CTV labeling of T cells. T cell activation was assessed by the presence of the activation marker CD25 monitored by flow cytometry. Antibodies were used at a concentration of 10 nM.

[00124] Figures 22A and 22B are a pair of graphs showing PDL1-dependent 41BB agonism mediated by the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention. The proliferation of CD8 ⁺ T cells (Figure 22A) was monitored using CTV-labeling, and the production of INFγ (Figure 22B) in the cell supernatant was monitored by ELISA analysis and normalized to a standard curve.

[00125] Figure 23 is a graph demonstrating the ability of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention to enhance the Th1 lineage transcription factor, T-bet, expressed in T cell populations. T-bet expression was assessed on populations of CD4 ⁺ and CD8 ⁺ T cells by flow cytometry by intracellular staining after fixation and permeabilization.

[00126] Figures 24A and 24B are a pair of graphs comparing the ability of the bispecific PDL1x41BB fusion protein (INBRX-105-1) of the present invention and the combination of the monospecific antibodies Atezolizumab (anti-PDL1) and Utomilumab (anti-41BB) to induce INFγ production (Figure 24A) or TNFα (Figure 24B) from CD4 ⁺ or CD8 ⁺ T cells. Cytokine expression was assessed on populations of CD4 ⁺ and CD8 ⁺ T cells using flow cytometry by intracellular staining after fixation and permeabilization.

[00127] Figures 25A and 25B are a pair of graphs demonstrating the agonistic ability of the tetravalent 41BB binding fusion protein and the PDL1x41BB bispecific fusion proteins of this invention in the presence of an additional PDL1 positive (Figure 25A) or negative (Figure 25B) cell line. In this study, a 41BB NFkB-expressing HEK293 reporter cell was used and co-incubated with either a PDL1-negative K562 cell line (Figure 25B) or a stably transfected PDL1-expressing K562 cell line (Figure 25A).

DETAILED DESCRIPTION OF THE INVENTION

[00128] All patents and publications mentioned in this specification are incorporated herein by reference to the same extent as if each independent patent and publication were specifically and separately indicated as incorporated herein by reference.

Definitions

[00129] Unless otherwise indicated, scientific and technical terms used in connection with this invention should have meanings that are commonly understood by those skilled in the art. In addition, unless otherwise required by context, singular terms include plural forms, and plural terms include singular forms. In general, the terminology used in connection with cell and tissue culture methods, molecular biology, immunology, protein and oligo- or polynucleotide chemistry, and hybridization described herein is well known and widely used in the art. To obtain recombinant DNA, the synthesis of oligonucleotides and tissue culture, as well as transformation, standard methods are used ( for example, electroporation, lipofection). Enzymatic reactions and purification methods are carried out according to the manufacturer's specification or as is commonly done in the art or as described herein. The following procedures and techniques are generally carried out using conventional methods well known in the art and described in various general and more specialized sources, which are cited and discussed in the text of this description . See, for example, Sambrook et al . Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989)). The terminology used in connection with the laboratory techniques and methods of analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry described herein is well known and widely used in the art. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical formulation, formulation and administration, and for the treatment of patients.

[00130] In accordance with the use in this description, the following terms, unless otherwise indicated, should be understood as having the following meanings:

[00131] In this context, the terms "bi-targeted fusion protein" and "antibody" may be synonymous. As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, that is, molecules that contain an antigen-binding site that specifically binds (immunely reacts) to an antigen. By "specifically binds" or "immunely reacts with" or "anti" is meant that an antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides or binds with much lower affinity (K _d > 10 ^-6 ). Antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, dAb (domain antibody), single chain, Fab, Fab _' and F(ab') ₂ fragments, Fv, scFvs, Fab expression library, and single domain antibody (sdAb) fragments, for example, V _H H, V _NAR constructed by V _H or V _K .

[00132] It is known that the basic structural unit of an antibody is a tetramer. Each tetramer consists of two identical pairs of polypeptide chains, each pair has one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino terminal portion of each chain contains a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The C-terminal portion of each strand defines a constant region primarily responsible for effector function. Typically, human-derived antibody molecules belong to any of the IgG, IgM, IgA, IgE, and IgD classes, which differ from one another in the nature of the heavy chain present in the molecule. In addition, some classes have subclasses (also known as isotypes), such as IgG ₁ , IgG ₂ and others. In addition, in humans, the light chain can be a kappa chain or a lambda chain.

[00133] In this context, the term "monoclonal antibody" (MAb) or "composition of monoclonal antibodies" refers to a population of antibody molecules that contain only one molecular species of the antibody molecule, consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of a monoclonal antibody are identical across all molecules in the population. MAbs contain an antigen-binding site capable of immune reaction with a specific antigen epitope, characterized by a unique binding affinity for it.

[00134] The term "antigen binding site" or "binding portion" refers to the part of the immunoglobulin molecule that is involved in antigen binding. The antigen-binding site is formed by the amino acid residues of the N-terminal variable ("V") regions of the heavy ("H") and light ("L") chains. Three highly deviant regions within the V regions of the heavy and light chains, called "hypervariable regions", are located between more conserved flanking regions, known as "framework regions" or "FRs". Thus, the term "FR" refers to amino acid sequences that are naturally found between and adjacent to hypervariable regions in immunoglobulins. In an antibody molecule, three light chain hypervariable regions and three heavy chain hypervariable regions are located relative to each other in three-dimensional space, forming an antigen-binding surface. The antigen-binding surface complements the three-dimensional surface of the bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as "complementarity-determining regions" or "CDRs". The amino acid assignments in each domain correspond to the Kabat sequence definitions from Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196: 901-917 (1987), Chothia et al . Nature 342: 878-883 (1989).

[00135] Portions of the single domain antibody (sdAb) fragments of the fusion proteins of this invention are referred to herein interchangeably and are referred to herein as "targeted polypeptides".

[00136] As used herein, the term "epitope" includes any protein determinant capable of specifically binding to/via an immunoglobulin or fragment thereof or a T cell receptor. The term "epitope" includes any determinant of a protein capable of specifically binding to/being bound to an immunoglobulin or T cell receptor. Epitope determinants typically consist of reactive surface groupings of molecules such as amino acids or sugar side chains and typically have specific three-dimensional structural characteristics as well as specific charge characteristics. An antibody is said to specifically bind to an antigen when the dissociation constant is ≤ 1 mM, eg ≤ 1 μM; eg ≤ 100 nM, eg ≤ 10 nM and eg ≤ 1 nM.

[00137] As used herein, the terms "immunological binding" and "immunological binding properties" refer to certain types of non-covalent interactions that occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (K _d ) of the interaction, with a lower K _d value representing a higher affinity. The immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method involves measuring the rates of antigen-binding site/antigen complex formation and dissociation, these rates being dependent on complex partner concentrations, interaction affinities, and geometrical parameters that equally affect the rate in both directions. Thus, both the "association rate constant" (k _on ) and the "dissociation rate constant" (k _off ) can be determined by calculating concentrations and actual association and dissociation rates. ( See Nature 361: 186-87 (1993)). The ratio k _off /k _on allows you to exclude all parameters that are not related to affinity, and is equal to the dissociation constant K _d . ( See, in general terms , Davies et al. (1990) Annual Rev Biochem 59: 439-473). An antibody of this invention is said to specifically bind to an antigen when the equilibrium binding constant (K _d ) is from ≤1 μM, such as ≤100 nM, such as ≤10 nM, and, for example, ≤100 pM to about 1 pM, what is measured by assays such as radioligand binding assays, surface plasmon resonance (SPR), flow cytometry binding assays, or similar assays known to those skilled in the art.

[00138] As used herein, the term "isolated polynucleotide" means a polynucleotide of genomic, cDNA, or synthetic origin, or a combination thereof, which, by its nature as an "isolated polynucleotide" (1), is not associated with all or part of the polynucleotide in which the "isolated polynucleotide" occurs in nature, (2) is operably linked to a polynucleotide that is not linked to a naturally occurring polynucleotide, or (3) does not occur naturally as part of a larger sequence.

[00139] The term "isolated protein" as used herein means a cDNA protein, recombinant RNA, or a protein of synthetic origin, or some combination thereof, which, by their nature or source of excretion, is an "isolated protein" that (1) is not associated with naturally occurring proteins, (2) does not contain other proteins from the same source, such as does not contain marine proteins, (3) is expressed by a cell from another species, or (4) does not occur naturally.

[00140] In this context, the term "polypeptide" is used as a general term to refer to a native protein, fragments or analogs of a polypeptide sequence. Therefore, native protein fragments and analogs are species of the polypeptide genus.

[00141] In this context, the term "naturally occurring" applied to an object refers to the fact that the object can be found in nature, for example, a polypeptide or polynucleotide sequence present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory or otherwise, is "naturally occurring".

[00142] In this context, the term “functionally connected” refers to the provisions of the components defined in such a relationship, which ensures the opportunity for them to function as intended. The regulatory sequence, which is functionally connected with the encoding sequence, is ligated with it in such a way that the expression of the coding sequence is achieved under conditions compatible with regulatory sequences.

[00143] As used herein, the term "regulatory sequence" refers to polynucleotide sequences that are necessary for the expression and processing of the coding sequences to which they are ligated. The nature of such regulatory sequences differs depending on the host organism in prokaryotes, such control sequences typically include a promoter, a ribosome binding site and a transcription termination sequence in eukaryotes, typically such regulatory sequences include promoters and a transcription termination sequence. The term "regulatory sequences" is intended to include, at a minimum, all components whose presence is required for expression and processing, and may also include additional components whose presence is appropriate, such as leader sequences and fusion partner sequences. As used herein, the term "polynucleotide" refers to polymeric nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides, or a modified form of any type of nucleotide. This term includes single- and double-stranded forms of DNA.

[00144] As used herein, the term "oligonucleotide" includes naturally occurring and modified nucleotides linked together via naturally occurring and non-naturally occurring oligonucleotide linkages. Oligonucleotides are a subset of polynucleotides, typically 200 bases or less in length. In other embodiments of this invention, the length of the oligonucleotides is from 10 to 60 bases, for example, 12, 13, 14, 15, 16, 17, 18, 19, or from 20 to 40 bases in length. Typically, oligonucleotides are single stranded, eg for probes, although oligonucleotides can be double stranded, eg for use in gene mutant construction. The oligonucleotides of this invention may be either sense or antisense oligonucleotides.

[00145] As used herein, the term "naturally occurring nucleotides" includes deoxyribonucleotides and ribonucleotides. As used herein, the term "modified nucleotides" includes nucleotides with modified or substituted sugar groups and the like. As used herein, the term "oligonucleotide linkages" includes oligonucleotide linkages such as phosphorothioate, phosphorodithioate, phosphoroselerloate, phosphorodiselenoate, phosphoranylothioate, phosphoraniladate, phosphoronemidate, and the like . See, for example, LaPlanche et al . Nucl. Acids Res. 14:9081 (1986); Stec et al . J. Am. Chem. soc. 106:6077 (1984), Stein et al . Nucl. Acids Res. 16:3209 (1988), Zon et al . Anti Cancer Drug Design 6:539 (1991); Zon et al . Oligonucleotides and Anaalogues: A Practical Approach, PP. 87-108 (F. Eckstein, Ed., Oxford University Press, Oxford England (1991)); Stec et al . in US patent No. 5151510; Uhlmann and Pekan Chemical Reviews 90: 543 (1990). The oligonucleotide may include a label for detection if desired.

[00146] As used herein, the term "selectively hybridize" means to detect and specifically bind. The polynucleotides, oligonucleotides, and fragments thereof of the present invention hybridize selectively to nucleic acid strands under hybridization and wash conditions that minimize detectable binding to non-specific nucleic acids. High stringency conditions can be used to achieve selective hybridization conditions known in the art and discussed herein. Typically, the nucleic acid sequence homology between the polynucleotides, oligonucleotides, and fragments of this invention and the nucleic acid sequence of interest will be at least 80% and more typically increasing to at least 85%, 90%, 95%, 99% and 100%. Two amino acid sequences are homologous if there is partial or complete identity between their sequences, for example, 85% homology means that 85% of the amino acids are identical when aligning the two sequences for maximum match. Preferably, when determining maximum matching gap lengths (in either of the two respective sequences), 5 or less is allowed, more preferably 2 or less. Alternatively, two protein sequences (or polypeptide sequences derived therefrom and consisting of at least 30 amino acids in length) are homologous, as that term is used herein, if they have an alignment score greater than 5 (in units of standard deviation ) obtained using the ALIGN program with a mutation data matrix and a gap penalty of 6 or higher . See Dayhoff, MO, in Atlas of Protein Sequence and Structure, pp. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Supplement 2 thereto, pp. 1-10. Two sequences or parts thereof are more preferably homologous if their amino acids are 50% or more identical when optimally aligned using the ALIGN program. The term "matches" is used herein to mean that a polynucleotide sequence is homologous ( i.e. , identical, not strictly evolutionarily related) to all or part of a reference polynucleotide sequence, or that a polypeptide sequence is identical to a reference polypeptide sequence. In the opposite sense, the term "complementary" in this document is used to mean that the complementary sequence is homologous to all or part of the reference polynucleotide sequence. For purposes of illustration, the nucleotide sequence "TATAC" corresponds to the reference sequence "TATAC" and is complementary to the reference sequence "GTATA".

[00147] The following terms are used to describe sequence relationships between two or more polynucleotide or amino acid sequences: "reference sequence", "comparison window", "sequence identity", "percent sequence identity", and "substantial identity". A "reference sequence" is a specific sequence used as a basis for comparing sequences, a reference sequence may be a subset of a larger sequence, such as a segment of a full-length cDNA or a gene sequence listed in a sequence listing, or may contain the entire cDNA or gene sequence. Typically, the reference sequence is at least 18 nucleotides or 6 amino acids long, often at least 24 nucleotides or 8 amino acids long, and often at least 48 nucleotides or 16 amino acids long. Because two polynucleotides or amino acid sequences may each (1) contain a sequence ( i.e., part of a complete polynucleotide or amino acid sequence) that is similar between the two molecules, and (2) may additionally contain a sequence that diverges between the two polynucleotides or amino acid sequences, sequence comparisons between two (or more) molecules are typically performed by comparing the sequences of the two molecules in a "comparison window" to identify and compare local areas of sequence similarity. As used herein, the term "comparison window" refers to a conceptual segment of at least 18 contiguous nucleotide positions or 6 amino acid sequences, wherein a polynucleotide sequence or amino acid sequence can be compared to a reference sequence of at least 18 contiguous nucleotide or 6 amino acid sequences, and In this case, the portion of the polynucleotide sequence in the comparison window may contain additions, deletions, substitutions, etc. ( i.e., gaps) of 20 percent or less compared to the reference sequence (which contains no additions or deletions) to optimally align the two sequences. Optimal sequence alignment to align the comparison window can be achieved using the local homology algorithm according to Smith and Waterman Adv. Appl. Math. 2: 482 (1981), an algorithm for aligning regions of homology according to Needleman and Wunsch J. Mol. Biol. 48: 443 (1970), using the similarity search method of Pearson and Lipman, Proc. Natl. Acad. sci. (USA) 85: 2444 (1988), computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in Wisconsin Genetics Software Package Release 7.0, (Genetics Computer Group, 575 Science Dr., Madison, Wis.) , Geneworks, or MacVector software packages) or by checking and by using the best alignment ( i.e. , resulting in the highest percentage of homology in the comparison window) generated by the various methods chosen.

[00148] The term "identity of the sequence" means that two polynucleotide or amino acid sequences are identical ( that is, on the basis of the principle of "nucleotide-s-nucleotide" or "residue-sosstatka") in the comparison window. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences in the comparison window, determining the number of provisions in which the identical base of nucleic acid ( for example, a, t, c, g, u or i) or amino acid residue are found in both sequences , with the receipt of the number of matching provisions, after which the number of matching provisions is divided into the total number of provisions in the comparison window ( that is, the size of the window), and multiply the result by 100, thus obtaining the percentage of sequence identity. In this context, the terms “essential identity” mean the characterization of polynucleotide or amino acid sequence, in which polynucleotide or amino acid contains a sequence that has at least 85 percent of the sequence identity, from at least 90 to 95 percent of the identity of sequences, more preferably at least at least at least at least 99 percent of the sequence identity compared to the reference sequence in the comparison window with at least 18 nucleotide (6 amino acids) provisions, often in the comparison window at least 24-48 nucleotide (8-16 amino acids) provisions, while the percentage of sequence identity Calculated by comparing a reference sequence with a sequence that may include deletions or additions, which make up 20 percent or less reference sequence in the comparison window. The reference sequence can be a subset of a greater sequence.

[00149] In this context, twenty traditional amino acids and their abbreviations are used in the traditional way. See Immunology - A Synthesis (2nd Edition, ES Golub and DR Gren, Eds., Sinauer Associates, Sunderland7 Mass. (1991)). Stereoisomers ( e.g., D-amino acids) of twenty conventional amino acids, non-naturally occurring amino acids such as α-α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other non-traditional amino acids may also be useful components for the polypeptides of this invention. . Examples of non-traditional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-N, N, N-trimethyllysine, ε-N-acetylysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, σ -N-methylarginine and other similar amino acids and imino acids ( eg 4-hydroxyproline). In the designation of a polypeptide as used herein, left-handed is the amino-terminal direction and right-handed is the carboxy-terminal direction, in accordance with standard application and convention.

[00150] Similarly, unless otherwise indicated, the left-handed end of a single stranded polynucleotide sequence is the 5'end; while the left direction of the double-stranded polynucleotide sequences is called the 5' direction. The 5' to 3' direction in which nascent RNA transcripts are added is called the direction of transcription; regions of sequence on a DNA strand having the same sequence as the RNA transcript and which are located 5' to 5' of the RNA transcript are referred to as "upstream sequences"; regions of sequence on a DNA strand having the same sequence as the RNA transcript and which are located 3' to 3' of the RNA transcript are referred to as "downstream sequences".

[00151] When applying to polypeptides, the term “essential identity” means that two sequences of peptides with optimal leveling, for example, using the GAP or Bestfit program using a fine for a default deed, have at least 80% of the sequence identity, for example, according to at least 90% of the sequence identity, for example, at least 95% of the sequence identity and, for example, at least 99% of the sequence identity.

[00152] In some embodiments of this invention, the positions of non-identical residues differ by conservative amino acid substitutions.

[00153] Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains, for example, the group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; the group of amino acids having aliphatic hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine and tryptophan; a group of amino acids having basic side chains is lysine, arginine and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. Suitable groups of conservative amino acid substitutions are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate and asparagine-glutamine.

[00154] As discussed herein, minor changes in the amino acid sequences of antibodies or immunoglobulin molecules are considered to be covered by this invention, provided that the changes in the amino acid sequence provide at least 75%, for example, at least 80%, 90%, 95% and, for example, 99%. In particular, conservative amino acid replacements are supposed. Conservative substitutions are those that occur within a family of amino acids that are linked in their side chains. Genetically encoded amino acids are usually divided into families: (1) acidic amino acids are aspartate, glutamate; (2) The main amino acids are Lizin, Arginine, Phydin; (3) non-polar amino acids are alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) non-charged polar amino acids are glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. Hydrophilic amino acids include arginine, asparagine, aspartate, glutamine, glutamate, histidine, lysine, serine, and threonine. Hydrophobic amino acids include alanine, cysteine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, tyrosine, and valine. Other families of amino acids include (i) serine and threonine, which are aliphatic hydroxy groups; (II) asparagine and glutamine, which are a family containing amid; (iii) alanine, valine, leucine and isoleucine, which are an aliphatic family; and (iv) phenylalanine, tryptophan, and tyrosine, which are an aromatic family, for example, an isolated leucine to isoleucine or valine substitution, an aspartate to glutamate substitution, a threonine to serine substitution, or a similar amino acid substitution to a structurally related amino acid would not be characterized. a significant effect on the binding or properties of the resulting molecule, especially if the substitution does not include an amino acid within the framework region. Whether a change in amino acid results in the formation of a functional peptide can be easily determined by analyzing the specific activity of the derived polypeptide. Analyzes are described in detail in this document. Fragments or analogues of antibodies or immunoglobulin molecules can easily be prepared by those of ordinary skill in the art. Suitable amino- and carboxy-terminal fragments or analogs are found near the boundaries of the functional domains. Structural and functional domains can be identified by comparing nucleotide and/or amino acid sequence data with public or proprietary sequence databases. In some embodiments of the present invention, computerized comparison methods are used to identify sequence motifs or domains of putative protein conformation that occur in other proteins of known structure and/or function. Methods are known for identifying protein sequences that fold into a known three-dimensional structure. Bowie et al . Science 253: 164 (1991). Thus, the above examples demonstrate that experts in this area can recognize sequences of motives and structural conformations that can be used to determine structural and functional domains in accordance with this invention.

[00155] Suitable amino acid substitutions are those that: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) change the binding affinity to form protein complexes, (4) change the binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogues. Analogues may include various muteins of a sequence other than naturally occurring peptide sequences, e.g., one or more amino acid substitutions (e.g., conservative amino acid substitutions) can be made in a naturally occurring sequence (e.g., in a portion of the polypeptide outside the domain(s) A conservative amino acid substitution should not substantially alter the structural characteristics of the parent sequence ( e.g., a substituting amino acid should not seek to break the helix that is defined in the parent sequence, or break other types of secondary structure that characterize the parent sequence). of the art of polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., WH Freeman and Company, New York (1984)); Introduction to Protein Structure (C. B randen and J. Tooze, eds., Garland Publishing, New York, NY (1991)); and Thornton et al. Nature 354:105 (1991).

[00156] In this context, the term "polypeptide fragment" refers to polypeptide, which has aminocondal and/or carboxy-neutrally deed, but in which the remaining amino acid sequence is identical to the corresponding positions in the natural sequence, which is derived, for example, from a full-sized sequence of KDNK . As a rule, fragments have at least 5, 6, 8 or 10 amino acids in length, for example, at least 14 amino acids in length, for example, at least 20 amino acids in length, usually at least 50 amino acids in length and, for example,, for example , at least 70 amino acids in length. In this context, the term “analogue” refers to polypeptides, which consist of at least 25 amino acids, which has a significant identity with part of the excreted amino acid sequence and characterized by specific binding with CD47 in suitable ties for binding. As a rule, polypeptide analogues include conservative amino acid replacement (or adding or deletion) in relation to the sequence found in nature. As a rule, analogues have at least 20 amino acids in length, for example, at least 50 amino acids in length or more, and can often reach the length characteristic of the polypeptide found in nature.

[00157] Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties similar to those of a matrix peptide. These types of non-peptide compound are referred to as "peptide mimetics" or "peptidomimetics". Fauchere, J. Adv. DrugRes. 15:29 (1986), Veber and Freidinger TINS p. 392 (1985); and Evans et al . J. Med. Chem. 30:1229 (1987). Such compounds are often designed using computerized molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides can be used to obtain an equivalent therapeutic or prophylactic effect. Typically, peptidomimetics are structurally similar to a reference polypeptide ( i.e., a polypeptide that has a biochemical property or pharmacological activity), such as a human antibody, but have one or more peptide bonds, optionally replaced by a bond selected from the group consisting of: -- CH ₂ NH--, --CH ₂ S-, --CH ₂ -CH ₂ --, --CH=CH--(cis and trans), --COCH ₂ --, CH(OH)CH ₂ --, and -CH ₂ SO--, according to methods well known in the art. Systematic substitution of one or more amino acids of the consensus sequence with a D-amino acid of the same type ( eg, D-lysine instead of L-lysine) can be used to produce more stable peptides. In addition, limited peptides containing a consensus sequence or a substantially identical consensus sequence can be obtained using methods known in the art (Rizo and Gierasch Ann. Rev. Biochem. 61: 387 (1992)); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges that cyclize the peptide.

[00158] As used herein, the term "agent" is used to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, and/or an extract derived from biological materials.

[00159] In this context, the term "labeled" or "labeled" refers to the inclusion of a detectable marker, for example, by introducing a radioactively labeled amino acid or attaching biotinyl fragments to the polypeptide, which can be detected using labeled avidin ( for example, streptavidin containing a fluorescent marker or enzymatic activity, which can be detected by optical or calorimetric methods). In certain situations, the label or marker may also be therapeutic. Many methods for labeling polypeptides and glycoproteins are known in the art and can be used. Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides ( e.g. ³ H, ¹⁴ C, ¹⁵ N, ³⁵ S, ⁹⁰ Y, ⁹⁹ Tc, ¹¹¹ In, ¹²⁵ I, ¹³¹ I), fluorescent labels ( e.g., FITC, rhodamine, lanthanide-based phosphor), enzymatic labels ( e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent, biotinyl groups, predefined polypeptide epitopes recognized by the secondary reporter ( e.g., paired leucine zipper sequences, binding sites for secondary antibodies, metal-binding domains, epitope tags). In some embodiments of the present invention, the tags are attached using spacer "legs" of various lengths to reduce potential dimensional obstruction. As used herein, the term "pharmaceutical agent or drug" refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.

[00160] As used herein, the term "antineoplastic agent" is used to refer to agents that have the functional property of inhibiting the development or progression of a neoplasm in humans, especially malignant (cancerous) lesions such as carcinoma, sarcoma, lymphoma, or leukemia. Inhibition of metastasis is often one of the properties of anticancer agents.

[00161] As used herein, the terms "treat", "treating", and "treatment" and the like refer to reducing the severity and/or alleviating a disorder and/or symptoms associated therewith. By "alleviate" and/or "alleviate" is meant the reduction, suppression, attenuation, attenuation, inhibition and/or stabilization of the development or progression of a disease, such as, for example, cancer. It is understood, although not excluded, that the treatment of a disorder or condition does not require that the disease, condition or symptoms associated therewith be completely eliminated.

[00162] Other chemical terms are used herein in accordance with normal use in the art, as described in The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)) .

[00163] As used herein, the term "substantially pure" means that the entity species is the predominant species present ( i.e., on a molar basis, it is more abundant than any other single species in the composition), and the substantially purified fraction is the composition in which the entity species contains at least about 50 percent (on a molar basis) of all macromolecular compounds present.

[00164] Typically, a substantially pure composition will contain greater than 80% of all macromolecular components present in the composition, such as greater than 85%, 90%, 95%, and 99%. In some embodiments of the present invention, the object species is purified to the required homogeneity (contaminant species cannot be detected in the composition using conventional detection methods), while the composition consists mainly of one macromolecular species.

[00165] In this specification, the terms "comprises", "comprising", "accommodating", "having" and the like may have the meanings assigned to them in the US Patent Law and may mean "includes", "including" and the like ; the terms "consisting essentially of" or "consisting essentially of" also have the meanings set forth in the US Patent Law and these terms are open-ended, allowing more to be covered than what is set forth provided that the essential or novel features of what is what is stated is not changed by the presence of more than what is stated, but excludes prior art embodiments.

[00166] By "effective amount" is meant the amount necessary to improve the symptoms of the disease compared to an untreated patient. The effective amount of the active compound(s) used to carry out the present invention for the purpose of therapeutic treatment of a disease varies depending on the route of administration, age, body weight and general health of the subject. Ultimately, the attending physician or veterinarian will determine the proper amount and schedule of administration. Such an amount is referred to herein as an "effective" amount.

[00167] By "subject" is meant a mammal, including, but not limited to, a human or non-human mammal such as a bull, horse, dog, rodent, sheep, primate, camel, or cat.

[00168] As used herein, the term "administration" refers to any method of transferring, delivering, administering, or transporting a therapeutic agent to a subject in need of treatment with such agent. Such methods include, but are not limited to, oral, topical, intravenous, intraperitoneal, intramuscular, intradermal, intranasal, and subcutaneous administration.

[00169] The term "fragment" refers to a portion of a polypeptide or nucleic acid molecule. This portion contains, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 nucleotides or amino acids.

[00170] The ranges provided herein should be understood to mean all values within the range, for example, the range from 1 to 50 should be understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50.

[00171] In the present description, terms in the singular include the corresponding terms in the plural, unless specifically indicated or the context clearly implies otherwise. In the present description, the term "or" should be understood as open, unless specifically indicated or the context clearly follows otherwise.

[00172] In the present description, the term "about" should be understood as the range of normal maximum permissible deviation in the art, for example, within 2 standard deviations of the mean, unless specifically indicated or the context clearly indicates otherwise. "About" can be understood as a value within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0 .05%, or 0.01% of the set value. All numerical values presented in this document are modified by the term "about" unless the context clearly dictates otherwise.

Targeting 41BB (CD137, TNFRSF9)

[00173] 41BB is a member of the TNF receptor superfamily that is predominantly expressed on activated T cells and NK cells and functions as a stimulatory molecule. 41BB agonist action enhances T cell proliferation and survival, cytolytic activity, and secretion of cytokines (eg, IL-2, TNFα, and INFγ). In mice, 41BB activation has been shown to increase antitumor immunity. (Croft, 2009, Nat Rev Immunol 9: 271-285; Lynch, 2008, Immunol Rev. 22: 277-286). Importantly, tumor-infiltrating cytotoxic T cells (CTLs) have been shown to express 41BB, and it is these 41BB-positive CTLs that have the highest antitumor cytotoxic activity (Ye et al Clin Cancer Res; 20(1) : 44-55). The 41BB ligand, 41BBL, is inherently homotrimeric, suggesting that signaling is mediated by higher order 41BB clustering. This activation mechanism is shared by many members of the TNFRSF. Interest in the use of 41BB signaling for antitumor immunotherapy has led to the development of therapeutic 41BB antibodies. However, the ability of bivalent antibodies 41BB to induce signaling is weak in the absence of exogenous clustering factor. This can be achieved to some extent through interaction with Fcγ receptors (FcγRs), however it can also lead to depletion of the 41BB expressing cell through effector mechanisms (eg ADCC and ADCP). In addition, competition with high serum IgG concentration impairs effective FcγR interactions. Therefore, existing bivalent antibodies targeting 41BB are either ineffective agonists or are responsible for the depletion of various cells that require 41BB signaling. The therapeutic 41BB antibody, PF-05082566, has previously been shown to be capable of mediated 41BB signaling only when crosslinked to an anti-human secondary antibody (Fisher et al Cancer Immunol Immunother (2012) 61: 1721-1733). Therefore, there is a need for an optimized 41BB agonist capable of mediating signaling in the absence of an exogenous crosslinker or Fcγ R interaction. The fusion proteins of the invention are capable of mediating potent 41BB signaling 1) without any additional interactions when formatted as a multivalent fusion protein or 2) provided that it interacts with at least the second antigen when formatted as a multispecific fusion protein. The fusion proteins of the present invention are capable of autonomous (multivalent fusion proteins) or under certain conditions (multispecific fusion proteins) co-stimulatory activity on T cells and NK cells.

[00174] Exemplary amino acid sequences of 41BB binding single domain antibodies are shown below:

[00175] In some embodiments of the present invention, the 41BB binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which comprises a combination of a heavy chain variable region (VH) sequence and a light chain variable region (VL) sequence selected from the group, consisting of:

VH sequences:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGGIIPGFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARKNEEDGGFDHWGQGTLVTVSS (SEQ ID NO: 84)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMHWVRQAPGKGLEWVSVISGSGSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYAQFEGDFWGQGTLVTVSS (SEQ ID NO: 85)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSS (SEQ ID NO: 86)

EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSS (SEQ ID NO: 87)

VL sequences:

DIELTQPPSVSVAPGQTARISCSGDNLGDYYASWYQQKPGQAPVLVIYDDSNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTWDGTLHFVFGGGTKLTVL (SEQ ID NO: 88)

DIELTQPPSVSVAPGQTARISCSGDNIGSKYVSWYQQKPGQAPVLVIYSDSERPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSWDGSISRVFGGGTKLTVL (SEQ ID NO: 89)

DIELTQPPSVSVAPGQTARISCSGDNIGDQYAHWYQQKPGQAPVVVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCATYTGFGSLAVFGGGTKLTVL (SEQ ID NO: 90)

SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVLVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYTGFGSLAVFGGGTKLTVL (SEQ ID NO: 91)

SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVVVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYTGFGSLAVFGGGTKLTVL (SEQ ID NO: 92)

DIELTQPPSVSVAPGQTARISCSGDNIGDQYAHWYQQKPGQAPVVVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSTYTFVGFTTVFGGGTKLTVL (SEQ ID NO: 93)

SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVLVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCSTYTFVGFTTVFGGGTKLTVL (SEQ ID NO: 94)

SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVVVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCSTYTFVGFTTVFGGGTKLTVL (SEQ ID NO: 95)

[00176] In some embodiments of the present invention, the 41BB binding domain comprises or is derived from an antibody sequence, or an antigen-binding fragment thereof, that includes a combination of a heavy chain (HC) sequence and a light chain (LC) sequence selected from the group consisting of:

HC sequences:

QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 96)

QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 97)

LC sequences:

EIVLTQSPATLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYQEKHKVYACENSFTHQGL9

[00177] In some embodiments, the 41BB binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof selected from the antibody sequences described in U.S. Patent Application Publication No. 20160244528, the contents of which are incorporated herein by reference in its entirety. volume.

[00178] In some embodiments, the 41BB binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof selected from the antibody sequences described in US Pat. No. 8,337,850, the contents of which are incorporated herein by reference in their entirety.

[00179] In some embodiments of the invention, the 41BB binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof selected from the antibody sequences described in PCT Publication No. WO 2005/035584, the contents of which are incorporated herein by reference in its entirety. volume.

[00180] In some options for the implementation of this invention, the 41BB-binding domain contains or is a derivative of the antibodies sequence or its antigen-binding fragment selected from antibodies described in the EP No. EP 1670828 B1, the content of which is included in this document through the reference in full .

[00181] In some embodiments of the invention, the 41BB binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof selected from the antibody sequences described in PCT Publication No. WO 2006/088447, the contents of which are incorporated herein by reference in its entirety. volume.

[00182] In some embodiments, the 41BB binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof selected from the antibody sequences described in U.S. Patent Application Publication No. 20080166336, the contents of which are incorporated herein by reference in its entirety. volume.

[00183] In some embodiments, the 41BB binding domain comprises or is derived from an anti-cancer fusion protein or antigen-binding fragment thereof sequence selected from the sequences described in PCT Publication No. WO 2016/177802, the contents of which are incorporated herein by reference in in full. In some embodiments of this invention, the 41BB binding domain contains or is derived from an amino acid sequence containing:

(SEQ ID NO: 99)

[00184] In some embodiments, the 41BB binding domain comprises or is derived from a 41BB targeting polypeptide sequence, or an antigen-binding fragment thereof, selected from the sequences described in PCT Publication No. WO 2016/177762, the content of which is incorporated herein by reference in its entirety. In some embodiments of this invention, the 41BB binding domain contains or is derived from an amino acid sequence containing:

Targeting PDL1-

[00185] In some embodiments of this invention, the fusion proteins are multispecific, containing at least a first binding domain, for example, TBD, and a second binding domain directed to programmed death ligand 1 (PD-L1). In these embodiments of the invention, PD-L1 binding is able to provide an additional crosslinking function and TNFRSF activation is achieved with only one or two TBDs. In these embodiments of the present invention, TNFRSF signaling is enhanced and focused by the presence of a PD-L1 expressing cell.

[00186] PDL1 is a 40 kDa type I transmembrane protein that forms a complex with its programmed cell death receptor (PD1) protein 1, also known as CD279. Interaction of PDL1 with its PD1 receptor on T cells generates a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. Aberrant expression and/or activity of PDL1 and PDL1-related signaling has been implicated in the pathogenesis of many diseases and disorders such as cancer, inflammation, and autoimmune conditions.

[00187] In some embodiments of the invention, the PD-L1 binding portion is a single domain antibody. In some embodiments of this invention, the PDL1-binding portion of the fusion protein blocks or reduces the interaction of PDL1 and PD-1. Exemplary PDL1-targeted single domain sequences are shown below:

[00188] In other embodiments of this invention, the PD-L1 binding portion is derived from the extracellular domain of PD-1 containing at least an IgV domain, as shown below:

PTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVT (SEQ ID NO: 125)

[00189] In some embodiments of the invention, the PDL1 binding domain comprises or is derived from a known sequence of an anti-PDL1 antibody or antigen-binding fragment thereof. In some embodiments of this invention, the PDL1 binding domain contains or is derived from the antibody sequence described in PCT Publication No. WO 2016/149201, the contents of which are incorporated herein by reference in their entirety.

[00190] In some embodiments of the present invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which comprises a combination of a heavy chain variable region (VH) sequence and a light chain variable region (VL) sequence selected from the group, consisting of:

VH sequences:

QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGFSWVRQAPGQGLEWMGWITAYNGNTNYAQKLQGRVTMTTDTSTSTVYMELRSLRSDDTAVYYCARDYFYGMDVWGQGTTVTVSS (SEQ ID NO: 126)

QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 127)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDVHWVRQAPGQRLEWMGWLHADTGITKFSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARERIQLWFDYWGQGT (SEQ ID NO: 128)

QVQLVQSGAEVKKPGSSVKVSCKVSGGIFSTYAINWVRQAPGQGLEWMGGIIPIFGTANHAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDQGIAAALFDYWGQGTLVTVSS (SEQ ID NO: 129)

EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYVVHWVRQAPGKGLEWVSGNSGNIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAVPFDYWGQGTLVTVSS (SEQ ID NO: 130)

QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSSYAISWVRQAPGQGLEWMGGIIPIFGRAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 131)

QVQLVQSGAEVKKPGSSVKVSCKTSGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTTTAYMELSSLRSEDTAVYYCARKYDYVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 132)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGLEWMGGIIPIFGSANYAQKFQDRVTITADESTSAAYMELSSLRSEDTAVYYCARDSSGWSRYYMDVWGQGTTVTVSS (SEQ ID NO: 133)

QVQLVQSGAEVKEPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGGIIPLFGIAHYAQKFQGRVTITADESTNTAYMDLSSLRSEDTAVYYCARKYSYVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 134)

EVQLVESGGGLVQPGRSLRLSCAASGITFDDYGMHWVRQAPGKGLEWVSGISWNRGRIEYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGRFRYFDWFLDYWGQGTLVTVSS (SEQ ID NO: 135)

QMQLVQSGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYFWSGFSAFDIWGKGTLVTVS (SEQ ID NO: 136)

VL sequences:

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLVWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKVEIK (SEQ ID NO: 137)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK (SEQ ID NO: 138)

DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO: 139)

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 140)

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPFGGGTKVEIK (SEQ ID NO: 141)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTRLEIK (SEQ ID NO: 142)

AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK (SEQ ID NO: 143)

DIVMTQSPSTLSASVGDRVTITCRASQGISSWLAWYQQKPGRAPKVLIYKASTLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPWTFGQGTKLEIK (SEQ ID NO: 144)

[00191] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS (SEQ ID NO: 145)

VL sequences:

EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO: 146)

[00192] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 147)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSGSWIHWVRQAPGKGLEWVAWILPYGGSSYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 148)

VL sequences:

(SEQ ID NO: 149).

(SEQ ID NO: 150).

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAPPWTFGQGTKVEIKR (SEQ ID NO: 151)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTVPWTFGQGTKVEIKR (SEQ ID NO: 152)

(SEQ ID NO: 153).

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGTDFTLTISSLQPEDFATYYCQQGYGVPRTFGQGTKVEIKR (SEQ ID NO: 154)

(SEQ ID NO: 155)

(SEQ ID NO: 156)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYYTPPTFGQGTKVEIKR (SEQ ID NO: 157)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFFYTPPTFGQGTKVEIKR (SEQ ID NO: 158)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLFTPPTFGQGTKVEIKR (SEQ ID NO: 159)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLYTPPTFGQGTKVEIKR (SEQ ID NO: 160)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSWYHPPTFGQGTKVEIKR (SEQ ID NO: 161)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYFYIPPTFGQGTKVEIKR (SEQ ID NO: 162)

(SEQ ID NO: 163).

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYFIPPTFGQGTKVEIKR (SEQ ID NO: 164)

[00193] In some embodiments of the present invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

METGLRWLLLVAVLKGVQCLSVEESGGRLVTPGTPLTLTCTASGFTITNYHMFWVRQAPGKGLEWIGVITSSGIGSSSTTYYATWAKGRFTISKTSTTVNLRITSPTTEDTATYFCARDYFTNTYYALDIWGPGTLVTVSS (SEQ ID NO: 165)

QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 166)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDVHWVRQAPGQRLEWMGWLHADTGITKFSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARERIQLWFDYWGQGTLVTVSS (SEQ ID NO: 167)

QVQLVQSGAEVKKPGSSVKVSCKVSGGIFSTYAINWVRQAPGQGLEWMGGIIPIFGTANHAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDQGIAAALFDYWGQGTLVTVSS (SEQ ID NO: 168)

EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYVVHWVRQAPGKGLEWVSGISGNSGNIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAVPFDYWGQGTLVTVSS (SEQ ID NO: 169)

QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSSYAISWVRQAPGQGLEWMGGIIPIFGRAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 170)

QVQLVQSGAEVKKPGSSVKVSCKTSGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTTTAYMELSSLRSEDTAVYYCARKYDYVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 171)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGLEWMGGIIPIFGSANYAQKFQDRVTITADESTSAAYMELSSLRSEDTAVYYCARDSSGWSRYYMDVWGQGTTVTVSS (SEQ ID NO: 172)

QVQLVQSGAEVKEPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGGIIPLFGIAHYAQKFQGRVTITADESTNTAYMDLSSLRSEDTAVYYCARKYSYVSGSPFGMDVWGQGTTVTVSS (SEQ ID NO: 173)

EVQLVESGGGLVQPGRSLRLSCAASGITFDDYGMHWVRQAPGKGLEWVSGISWNRGRIEYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGRFRYFDWFLDYWGQGTLVTVSS (SEQ ID NO: 174)

VL sequences:

(SEQ ID NO: 175)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLVWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKVEIK (SEQ ID NO: 176)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK (SEQ ID NO: 177)

DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO: 178)

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 179)

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPFGGGTKVEIK (SEQ ID NO: 180)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTRLEIK (SEQ ID NO: 181)

AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK (SEQ ID NO: 182)

[00194] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS (SEQ ID NO: 183)

VL sequences:

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL (SEQ ID NO: 184)

[00195] In some embodiments of this invention, the PDL1-binding domain contains or is a derivative of an antibody sequence or its antigen-binding fragment, which includes a combination of the VH sequence and the VL sequence, consisting of: consisting of:

VH sequences:

EVKLQESGPSLVKPSQTLSLTCSVTGYSITSDYWNWIRKFPGNKLEYVGYISYTGSTYYNPSLKSRISITRDTSKNQYYLQLNSVTSEDTATYYCARYGGWLSPFDYWGQGTTLTVSS (SEQ ID NO: 185)

EVQLQESGPGLVAPSQSLSITCTVSGFSLTTYSINWIRQPPGKGLEWLGVMWAGGGTNSNSVLKSRLIISKDNSKSQVFLKMNSLQTDDTARYYCARYYGNSPYYAIDYWGQGTSVTVSS (SEQ ID NO: 186)

EVKLQESGPSLVKPSQTLSLTCSVTGYSIISDYWNWIRKFPGNKLEYLGYISYTGSTYYNPSLKSRISITRDTSKNQYYLQLNSVTTEDTATYYCARRGGWLLPFDYWGQGTTLTVSS (SEQ ID NO: 187)

EVKLQESGPSLVKPGASVKLSCKASGYTFTSYDINWVKQRPGQGLEWIGWIFPRDNNTKYNENFKGKATLTVDTSSTTAYMELHSLTSEDSAVYFCTKENWVGDFDYWGQGTTLTLSS (SEQ ID NO: 188)

EVQLQQSGPDLVTPGASVRISCQASGYTFPDYYMNWVKQSHGKSLEWIGDIDPNYGGTTYNQKFKGKAILTVDRSSSTAYMELRSLTSEDSAVYYCARGALTDWGQGTSLTVSS (SEQ ID NO: 189)

EIVLTQSPATLSLSPGERATLSCRASSSVSYIYWFQQKPGQSPRPLIYAAFNRATGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQWSNNPLTFGQGTKVEIK (SEQ ID NO: 190)

QVQLVQSGAEVKKPGASVKVSCKASGYTFPDYYMNWVRQAPGQGLEWMGDIDPNYGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGALTDWGQGTMVTVSS (SEQ ID NO: 191

QVQLVQSGAEVKKPGASVKVSCKASGYTFPDYYMNWVRQAPGQSLEWMGDIDPNYGGTNYNQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGALTDWGQGTMVTVSS (SEQ ID NO: 192)

EVQLVQSGAEVKKPGASVKVSCKASGYTFPDYYMNWVRQAPGQSLEWMGDIDPNYGGTNYNQKFQGRVTMTVDRSSSTAYMELSRLRSDDTAVYYCARGALTDWGQGTMVTVSS (SEQ ID NO: 193)

EVQLVESGGGLVQPGRSLRLSCTASGYTFPDYYMNWVRQAPGKGLEWVGDIDPNYGGTTYAASVKGRFTISVDRSKSIAYLQMSSLKTEDTAVYYCTRGALTDWGQGTMVTVSS (SEQ ID NO: 194)

EVQLVESGGGLVQPGRSLRLSCTASGYTFPDYYMNWVRQAPGKGLEWVGDIDPNYGGTTYNASVKGRFTISVDRSKSIAYLQMSSLKTEDTAVYYCARGALTDWGQGTMVTVSS (SEQ ID NO: 195)

VL sequences:

DIVMTQSHKLMTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQDSSYPLTFGAGTKVELK (SEQ ID NO: 196)

DIVTTQSHKLMTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQDSSYPLTFGAGTKVELK (SEQ ID NO: 197)

DIVMTQSPSSLAVSVGEKVSMGCKSSQSLLYSSNQKNSLAWYQQKPGQSPKLLIDWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYGYPLTFGAGTKLELK (SEQ ID NO: 198)

DIVMTQSPAIMSASPGEKVTMTCSASSSIRYMHWYQQKPGTSPKRWISDTSKLTSGVPARFSGSGSGTSYALTISSMEAEDAATYYCHQRSSYPWTFGGGTKLEIK (SEQ ID NO: 199)

QIVLSQSPAILSASPGEKVTMTCRASSSVSYIYWFQQKPGSSPKPWIYATFNLASGVPARFSGSGSGTSYSLTISRVETEDAATYYCQQWSNNPLTFGAGTKLELK (SEQ ID NO: 200)

EIVLTQSPATLSLSPGERATLSCRASSSVSYIYWFQQKPGQAPRLLIYAAFNRATGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQWSNNPLTFGQGTKVEIK (SEQ ID NO: 201)

QIVLTQSPATLSLSPGERATLSCRASSSVSYIYWFQQKPGQSPRPLIYATFNLASGIPARFSGSGSGTSYTLTISRLEPEDFAVYYCQQWSNNPLTFGQGTKVEIK (SEQ ID NO: 202)

DIQLTQSPSSLSASVGDRVTITCRASSGVSYIYWFQQKPGKAPKLLIYAAFNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWSNNPLTFGQGTKVEIK (SEQ ID NO: 203)

DIQLTQSPSSLSASVGDRVTITCRASSGVSYIYWFQQKPGKAPKPLIYAAFNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWSNNPLTFGQGTKVEIK (SEQ ID NO: 204)

DIQLTQSPSILSASVGDRVTITCRASSSVSYIYWFQQKPGKAPKPLIYATFNLASGVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQWSNNPLTFGQGTKVEIK (SEQ ID NO: 205)

[00196] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARALPSGTILVGGWFDPWGQGTLVTVSS (SEQ ID NO: 206)

EVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYALSWVRQAPGKGLEWVSAISGGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDVFPETFSMNYGMDVWGQGTLVTVSS (SEQ ID NO: 207)

QVQLVQSGGGVVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNSLYLQMNSLRTEDTALYYCAKVLLPCSTSTSCYGSVGAFDIWGQGTTVTVSS (SEQ ID NO: 208)

QVQLVQSGGSVVRPGESLRLSCVASGFIFDNYDMSWVRQVPGKGLEWVSRVNWNGGSTTYADAVKGRFTISRDNTKNSLYLQMNNLRAEDTAVYYCVREFVGAYDLWGQGTTVTVSS (SEQ ID NO: 209)

QVQLVQSGAEVKKPGATVKVSCKVFGDTFRGLYIHWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITTDESTSTAYMELSSLRSEDTAVYYCASGLRWGWFDPWGQGTLVTVSS (SEQ ID NO: 210)

EVQLVQSGAELKKPGSSVKVSCKAFGGTFSDNAISWVRQAPGQGPEWMGGIIPIFGKPNYAQKFQGRVTITADESTSTAYMVLSSLRSEDTAVYYCARTMVRGFLGVMDVWGQGTTVTVSS (SEQ ID NO: 211)

QVQLVQSGGGGGLVQPGSLRLSCASSYASSYAMSWVRQASASASGSASGSASGSGSTYADSVKGRFTISKNTLYLRADEDTAVTIFGVPRYGMDVWGTVTVTVSS (SEQ ID NO: 212)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGRQMFGAGIDFWGPGTLVTVSS (SEQ ID NO: 213)

EVQLVESGAEVKKPGSSVKVSCKVSGGTFGTYALNWVRQAPGQGLEWMGRIVPLIGLVNYAHNFEGRISITADKSTGTAYMELSNLRSDDTAVYYCAREVYGGNSDYWGQGTLVTVSS (SEQ ID NO: 214)

QVQLVQSGGEVKKPGASVKVSCKASGYTLSSHGITWVRQAPGQGLEWMGWISAHNGHASNAQKVEDRVTMTTDTSTNTAYMELRSLTADDTAVYYCARVHAALYYGMDVWGQGTLVTVSS (SEQ ID NO: 215)

QVQLQLQSGGGGGGVVQpgrslrlssssssrhgwvrqapglewvavvavvavvydgsvkyyadsmkgrfsirdnsnsnSnSnSNTSLRADDTAVSYQVSGLSYKVSGFDPWGQGTLVTVSS (SEQ ID NO: 216)

NFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYEDNQRPSGVPDRFSGSIDTSSNSASLTISGLKTKDEADYYCQSYDGITVIFGGGTKLTVL (SEQ ID NO: 217)

NFMLTQPHSVSGSPGKTVTLPCTRSSGSIASHYVQWYQQRPGSAPTTVIYEDNKRPSGVPDRFSGSIDSSSSNSASLSISGLKTEDEADYYCQSYDSSNRWVFGGGTKLTVL (SEQ ID NO: 218)

LPVLTQPASLSASPGASASLTCTLRSGLNVGSYRIYWYQQKPGSRPQYLLNYKSDSDSNKQQASGVPSRFSGSKDASANAGILLISGLQSEDEADYYCMIWYSSAVVFGGGTKLTVL (SEQ ID NO: 219)

VL sequences:

NFMLTQPHSVSESPGKTVTISCTRSSGNIASNYVQWYQQRPGSAPTTVIYEDNQRPSGVPDRFSGSIDSSSSNSASLTISGLKTEDEADYYCQSYDSSNLWVFGGGTKLTVL (SEQ ID NO: 220)

SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHYVFGTGTKVTVL (SEQ ID NO: 221)

LPVLTQAPSVAPGKTARITCGSDIGRKSVHWYQKPGQAPAPAPAPAPAPRPRPSGISGSNSNSNTATAGDEAGDNNNSDNSDHYVFGAGATELIVL (Seq ID No: 222)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSTLPFGGGTKLTVL (SEQ ID NO: 223)

EIVLTQSPATLSLSPGERATLSCRASQSIGNSLAWYQQKPGQAPRLLMYGASSRATGIPDRFSGSGAGTDFTLTISSLEPEDFATYYCQQHTIPTFSFGPGTKVEVK (SEQ ID NO: 224)

DIVMTQTPSFLSASIGDRVTITCRASQGIGSYLAWYQQRPGEAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISNLQPEDFATYYCQQLNNYPITFGQGTRLEIK (SEQ ID NO: 225)

QSALTQPPSVSVSPGQTANIPCSGDKLGNKYAYWYQQKPGQSPVLLIYQDIKRPSRIPERFSGSNSADTATLTISGTQAMDEADYYCQTWDNSVVFGGGTKLTVL (SEQ ID NO: 226)

NFMLTQPHSVSESPGKTVTISCTRSSGSIDSNYVQWYQQRPGSAPTTVIYEDNQRPSGVPDRFSGSIDSSSSNSASLTISGLKTEDEADYYCQSYDSNNRHVIFGGGTKLTVL (SEQ ID NO: 227)

NFMLTQPHSVSESPGKTVTISSTRSSGNIGTNYVQRPGSAPVADYDYDYRPSGVPDRFSIDSSSNSSSNSAGLKPEDEADYCQIHSSYHSSYHSGGTKLTVL (Seq ID No: 228)

(SEQ ID NO: 229)

NFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTTVIYEDNQRPSGVPDRFSGSIDSSSSNSASLTISGLKTEDEADYYCQSYDSTTPSVFGGGTKLTVL (SEQ ID NO: 230)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWTSPHNGLTAFAQILEGRVTMTTDTSTNTAYMELRNLTFDDTAVYFCAKVHPVFSYALDVWGQGTLVTVSS (SEQ ID NO: 231)

EVQLVESGAEVMNPGSSVRVSCRGSGSGDFSWVRQAPGLEWMGRIAPILGIANYAQKKFQRVTIDAYMELSSLRSLRSDTAVYGSDPVLWGQGTLVTVSS (SEQ ID NO: 232)

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKVQGRVTMTTDTSTSTGYMELRSLRSDDTAVYYCARGDFRKPFDYWGQGTLVTVSS (SEQ ID NO: 233)

[00197] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EvqlvqsgpelkpgasvkmSkaskasgwvkqapgqrlewigyvnpfndgtkynemfkgratlsslrsavypwgypwgqawgqgtlvtvs (SEQ ID NO: 234)

EVQLVQSGAEVKKPGASVKMSCKASGYTFTSYVMHWVKQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS (SEQ ID NO: 235)

EVQLVQSGAEVKKPGASVKMSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS (SEQ ID NO: 236)

EVQLVQSGAEVKKPGASVKVSKKASGYTSYTFTSYVRQAPGQREWIGYVNPNPNPNEMFKGRATSDKSTAYMELSLRSLRSLRSLRSLRCAWYPWGQGTLVTVSS (SEQ ID NO: 237)

EVQLVQSGAEVKKPGASVKVSKKAGYTSYTFTSYVRQAPGQREWIGYVNPNPNEMFKYNEMFKGRATSDAYMELSLRSEDTAVYYPWGYPWGQGTLVTVSS (SEQ ID NO: 238)

VL sequences:

DIVLTQSPASLALSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEEEDAAMYFCQQSRRVPYTFGQGTKLEIK (SEQ ID NO: 239)

DIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEAEDAAMYFCQQSRRVPYTFGQGTKLEIK (SEQ ID NO: 240)

EIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEAEDAAMYFCQQSRRVPYTFGQGTKLEIK (SEQ ID NO: 241)

DIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEAEDAATYFCQQSRRVPYTFGQGTKLEIK (SEQ ID NO: 242)

[00198] In some embodiments of the present invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLVQSGAEVKKPGSSVKVSKASSYASSYAISSYAISWVRQAPGIPGIIPIPIPIPHTANYAQKFQRVTAYMELSSLRSEGYSSHYDSFDYWGQGTLVTVSS (SEQ ID NO: 243)

EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVSMTRDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNYYGMDIWGQGTTVTVSS (SEQ ID NO: 244)

QvqlvqsgaevkkpgssvkvskskassyaiswvrqapgqpgiiPiipiPigtanyaqkfqrvtitadkstaymelsselsselsslavphawgqgqgtmvtvss (SEQ ID NO: 245)

EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGQWLVTELDYWGQGTLVTVSS (SEQ ID NO: 246)

EVQLVESGSEVEKPGSSVKVSKASGTFSGISWVRQAPGIPGIIPGIIPMFATPYAQKFQDRVTITIDESGLRSDTAVFYFDLWGRGTLVTVSS (SEQ ID NO: 247)

EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARAPYYYYYMDVWGQGTTVTVSS (SEQ ID NO: 248)

Evqllesgaevkpgssvkvskskaskgtlsryqapgpagpagpagpyphyphyskfqfqdtststhrfedtalyfrldywgqgtlvtvss (SEQ ID NO: 249)

QVQLVQSGSELKKPGSSVKVSCKASGYSFSGYYIHWVRQAPGQGLEWMGWIDPNSGVTNYVRRFQGRVTMTRDTSLSTAYMELSGLTADDTAVYYCARDENLWQFGYLDYWGQGTLVTVSS (SEQ ID NO: 250)

Qvqlvqsgaevkkpgssvkvskskasrygvrqpgqgliprlipivsmtnyaqkfqdrvsittdktymelrslpwvfwfwgqgqgtlvtvss (SEQ ID NO: 251)

QVQLVESGGGGGGVVQpgrsLrlscaASSYASSYAMHWVRQAPGLAVAVAVAVAVAVAVAVAVKYADSVRFTISRDNSLALRTAVYYWLDIWGQGTLVTVSS (SEQ ID NO: 252)

EVQLVESGGGGGGVVQpgrslslscaASSYASSYAMHWVRQAPGLAVAVAVAVAVAVAVAVKYADSVRFTISRDNSLALRTAVYYWLDIVGQGTLVTVSS (SEQ ID NO: 253)

EVQLVQSGGGLVQPGGSLRLSCAASGFTFSDYGMHWVRQPPGKGLEWLAVISYDGSYKIHADSVQGRFTISRDNAKNSVFLQMNSLKTEDTAVYYCTTDRKWLAWHGMDVWGQGTTVTVSS (SEQ ID NO: 254)

EVQLVQSGAEVKKPGSSVKVSKASSYASSYAISSYAISWVRQAPGIPGIIPIPIPIPHTANYAQKFQRVTISSLSSLRSLRSEDTAVYYYYDFQHWGQGTLVTVSS (SEQ ID NO: 255)

EVQLVESGAEVKKPGASVKVSCKASGDTFSRYGITWVRQAPGRGLEWMGNIVPFFGATNYAQKFQGRLTITADKSSYTSYMDLSSLRSDDTAVYYCARDHFYGSGGYFDYWGQGTLVTVSS (SEQ ID NO: 256)

Evqllesgaevkpgasvkvskaskasgytfnsydinwvrqpgiipgiipvfgtanyaesfqrvtmtamelrsedtavyesrpmdvwgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgqgtvtvs

EVQLVESGGGLVRPGGSLRLACAASGFSFSDYYMTWIRQAPGRGLEWIAYISDSGQTVHYADSVKGRFTISRDNTKNSLFLQVNTLRAEDTAVYYCAREDLLGYYLQSWGQGTLVTVSS (SEQ ID NO: 258)

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDEPRAVAGSQAYYYYGMDVWGQGTTVTVSS (SEQ ID NO: 259)

EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSDGSTSYAQKFQGRVTMTRDTSTSTVHMELSSLRSEDTAVYYCARDLFPHIYGNYYGMDIWGQGTTVTVSS (SEQ ID NO: 260)

QMQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 261)

QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 262)

VL sequences:

QSVLTQPPSVSAAPGQKVTISSGNSNYANNYNYNYNYVSWYQLPGTAPKLLIIDNNYRPSGIPSGSGTSATLDEACHTGGGGTKLTVL (SEQ ID NO: 263)

AIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLESGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQLHTFPLTFGGGTKVEIK (SEQ ID NO: 264)

QPVLTQPPSASGSPGQSVTISCTGTSSDVGAYNFVSWYRQHPGKAPKLMIYEVNKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGTNSLGIFGTGTKLTVL (SEQ ID NO: 265)

QSSVTQPPSVSAAPGQKVTISSSDIGNHYVSWYVSWYQLPGTAPGTAPKLLIYDNNQRPSGSGSGTSATLAITGLSPHLFGGGTKLTVL (SEQ ID NO: 266)

QSVLTQPPSVSAAPGQKVTISCSGSSNMGNNYVSWYKQVPGTAPKLLIYENDKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDNSLSGFVFASGTKVTVL (SEQ ID NO: 267)

QSALTQPASVSGSLGQSVTISCTGSSSDVGSYNLVSWYQQHPGKAPNLMIYDVSKRSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTGISTVVFGGGTKLTVL (SEQ ID NO: 268)

QSVLTQPASVSGSPGQISTGTSSDVGSYNLVSWYQHPGKAPKLMIYEVSKRPSNRFSGSGNTASGNTASGLTASHECSYGGGGGGGGGGGGGGGGGGGGGGGGGGGGGTKLTVL (SEQ ID NO: 269)

DIVMTQSPSSLSASIGDRVTITCRASQRISAYVNWYQQKPGKAPKVLIYAASSLRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTYSSPWTFGQGTKVEIK (SEQ ID NO: 270)

QSVLTQPPSASSPGSVTISTSSDIGGYDSVSWYQHPGKAPKLMIYDVSKRPSNRFSGNTASGNTASGLTISSISSITSSYTSSYTSSYTSSYTSSYTSSYTSSYTSSYTSSYTGTGTKVTVL (SEQ ID NO: 271)

LPVLTQPASVSGSPGQISTSDIGGYDYVSWYQHPGKAPKLMIYDVSKRPSNRFSGSGSGNTASGNTASGLTISGLTISSYCSSSTSSSTHFGTKLTVL (SEQ ID NO: 272)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYRSSTLGPVFGGGTKLTVL (SEQ ID NO: 273)

QAGLTQPPSVSEAPRQRVTISSGSSSNAVNAVNAVYVYQLPAPKAPKAPKLLIYYDLPSGVSGSGTSASSELASSEDYYVFGTGTGTKLTVL (SEQ ID NO: 274)

QSaltQPrsvsvspgspgsvtissdvggynyqqhpgkpgkpsklmiDvpsgvpsgsgntasglqaededycsSSSTHFTHFTHFTHFTKVTKVTVL (SEQ ID NO: 275)

QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSVWVFGGGTQLTVL (SEQ ID NO: 276)

QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGRAPRLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEGDYYCSSYTSGGTLGPVFGGTKLTVL (SEQ ID NO: 277)

QAGLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVL (SEQ ID NO: 278)

AIRMTQSPSSPSSLSASVGDRVTITCRASSYLNYLNYLNYLNYLIYASSLIASLIKSGSGSGSGSGSGSGSGSGSGTSSLQTYCQTYSTPYTPYTPYTKGTKLAK (Seq ID NO: 279)

QSVLTQPASVSGSPGQISTGTSSDVGGYNYNYVSWYRQHPGKAPKLMIDVSYRPSNRFSGSGNTASGNTASGLTASGLTISSSTRYVFGTDDDDDDDDDDDDDDDDDDDDDDDDKLTVL (SEQ ID NO: 280)

QpvltqPsASSSASGQRVAISSGSRSNEINSVNICHNEICKLPGTAPKLIYDNNKRPRPRFSGSGTSATGLQTGSWDSADSADVFGTGTKLTVL (SEQ ID NO: 281)

QSVLTQPPSVSAPGKKVTISSGSSNIGNYVSWYVSWYQLPGTAPGTAPKLLIYRNNNNNNENPSGSGTSASSEDEACEDSEDSLNGGGGGGTKLTVL (SEQ ID NO: 282)

QSSVTQPPSVSGAPGAPGAPRVTISTGSSNIGAGYDVHWYQLPGTAPGNNNNNNNRHSGVPRFSGSSASASLAITGLAITYEDSRLTTYVFGSGTKLTVL (SEQ ID NO: 283)

QSSVTQPPSVSAAPGQKVTISSGSSNIGNYVSWYVSWYQLPGTAPKLLIYDNNKRPRPSGSGTSATLGITGLSAVFGGGTKLTVL (SEQ ID NO: 284)

VIWMTQSPSSLSASVGDRVTITCAASSLQSWYQQKPGKAPKLLIYEASTLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEIK (SEQ ID NO: 285)

QSSVTQPPSVSAPGQKVTISSGSSNIGNYVSWYVSWYQVPGTAPKLIYDNNNKRPRPRFSGSNSTSATLGITGLSAWVFGGGTKLTVL (SEQ ID NO: 286)

QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAGSVVFGGGTKLTVL (SEQ ID NO: 287)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCLVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 288)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 289)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 290)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 291)

[00199] In some embodiments of the present invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a heavy chain (HC) sequence and a light chain (LC) sequence selected from the group consisting of:

HC sequences:

QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 292)

QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 293)

LC sequences:

EIVLTQSPATLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKSSVYACESFQ4

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSQTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS(ID)

[00200] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO: 296)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 297)

HC sequences:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 298)

VL sequences:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 299)

LC sequences:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEQ0 (NORGECHKVYACEQ0)

[00201] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRFWMSWVRQAPGKGLEWVANINQDGTEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAGDTAVYYCANTYYDFWSGHFDYWGQGTLVTVSS (SEQ ID NO: 301)

QEHLVESGGGVVQPGRSLRLSCEASGFTFSNFGMHWVRQAPGKGLEWVAALWSDGSNKYYADSVKGRVTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRGAPGIPIFGYWGQGTLVTVSS (SEQ ID NO: 302)

EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKRKTDGGTTDYAAPVKGRFTISRDDSKNTLHLQMNSLKTEDTAVYYCTTDDIVVVPAVMREYYFGMDVWGQGTTVTVSS (SEQ ID NO: 303)

QVQLVQSGAEVKKPGASVQVSCKASGYSFTGYYIHWVRQAPGQGLEWMGWINPNSGTKKYAHKFQGRVTMTRDTSIDTAYMILSSLISDDTAVYYCARDEDWNFGSWFDSWGQGTLVTVSS (SEQ ID NO: 304)

QVHLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPGHGLEWMGWLNPNTGTTKYIQNFQGRVTMTRDTSSSTAYMELTRLRSDDTAVYYCARDEDWNYGSWFDTWGQGTLVTVSS (SEQ ID NO: 305)

EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMTWVRQAPGRGLEWVSGIHWHGKRTGYADSVKGRFTISRDNAKKSLYLQMNSLKGEDTALYHCVRGGMSTGDWFDPWGQGTLVIVSS (SEQ ID NO: 306)

EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMTWVRQVPGKGLEWVSGIHWSGRSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARGGMSTGDWFDPWGQGTLVTVSS (SEQ ID NO: 307)

EVQLVESGGGLVQPGGSLRLSCAASGFTVGSNYMNWVRQAPGKGLEWVSVIYSGGSTYYADSVKGRFTISRLTSKNTLYLQMSSLRPEDTAVYYCARGIRGLDVWGQGTTVTVSS (SEQ ID NO: 308)

EERLVESGGDLVQPGGSLRLSCAASGITVGTNYMNWVRQAPGKGLEWVSVISSGGNTHYADSVKGRFIMSRQTSKNTLYLQMNSLETEDTAVYYCARGIRGLDVWGQGTMVTVSS (SEQ ID NO: 309)

QVQLVQSGAEVKMPGSSVRVSCKASGGIFSSSTISWVRQAPGQGLEWMGEIIPVFGTVNYAQKFQDRVIFTADESTTTAYMELSSLKSGDTAVYFCARNWGLSFYIWGQGTMVTVSS (SEQ ID NO: 310)

EVQLVESGGDLVHPGRSLRLSCAASGFPFDEYAMHWVRQVPGKGLEWVSGISWSNNNIGYADSVKGRFTISRDNAKNSLYLQMNSLRPEDTAFYYCAKSGIFDSWGQGTLVTVSS (SEQ ID NO: 311)

EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVTLISYEGRNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRTLYGMDVWGQGTTVTVSS (SEQ ID NO: 312)

QVTLRESGPALVKTTQTLTLTCTFSGFSLSTNRMCVTWIRQPPGKALEWLARIDWDGVKYYNTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATFYCARSTSLTFYYFDYWGQGTLVTVSS (SEQ ID NO: 313)

EVQLVESGGGLVQPGGSLRLSCAASEFTVGTNHMNWVRQAPGKGLEWVSVIYSGGNTFYADSVKGRFTISRHTSKNTLYLQMNSLTAEDTAVYYCARGLGGMDVWGQGTTVTVSS (SEQ ID NO: 314)

EVQLVESGGGLVQRGESLRLYCAASGFTFSKYWMNWVRQAPGKGLEWVANIKGDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYWGSGYYFDFWGQGTLVTVSS (SEQ ID NO: 315)

EVQLVESGGGLVQSGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRADDTAVYYCARDDIVVVPAPMGYYYYYFGMDVWGQGTTVTVSS (SEQ ID NO: 316)

EVQLVESGGGLVQPGRSLRLSCAASGFTFDDFAMHWVRQAPGKGLEWVSGISWTGGNMDYANSVKGRFTISREDAKNSLYLQMNSLRAADTALYYCVKDIRGIVATGGAFDIWGRGTMVTVSS (SEQ ID NO: 317)

EVQLVESGGGLVQPGGSLRLSCAASGFTVGTNYMNWVRQAPGKGLEWISVIYSGGSTFYADSVKGRFTISRQTSQNTLYLQMNSLRPEDTAVYYCARGIRGFDIWGQGTMVTVSS (SEQ ID NO: 318)

EVQLVESGGGLVQPGGSLRLSCAASGFTISTNYMNWVRQAPGKGLEWVAVIYSSGSTYYIDSVKGRFTISRLTSKNTVYLQMSSLNSEDTAVYYCARGIRGFDIWGQGTMVTVSS (SEQ ID NO: 319)

EVQLVESGGGLVQPGRSLRLSCAASGFTIDDSAMHWVRQTPGKGLEWVSGISWKSGSIGYADSVRGRFTISRDNAKNSLYLQMNSLRVEDTALYYCVKDIRGNWNYGGNWFDPWGQGTLVTVSS (SEQ ID NO: 320)

EVQLVESGGGLVQPGGSLRLSCEASGFTVGVNHMNWVRQAPGKGLEWVSVIFSSGRTFYGDYVKGRLTIFRQTSQNTVYLQMNSLRSEDTAIYYCARGIGGLDIWGRGTMVTVSS (SEQ ID NO: 321)

EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYALHWVRQAPGKGLEWVSGISWTGGTIDYADSVKGRFTISRDNAKNSLYLQMSSLRTEDTAIYYCTRDIRGNWKYGGWFDPWGQGTLVTVSS (SEQ ID NO: 322)

QVQLVQSGTEVKKPGASVKVSCKASGYTFTAYYMHWVRQAPGQGLDWMGWISPNSGFTNYAQKFQGRVTMTRDTSINTFYMELSGLRSDDTAVYYCAREGSTHHNSFDPWGQGTLVTVSS (SEQ ID NO: 323)

EVQLVESGGGLVQPGGSLRLSCAASGFTVGTNFMNWVRQAPGKGLEWVSAIYSGGTANYADSVKGRFTISRDTSRNTLYLQMNSLRTEDTAVYYCARGGGMDVWGQGTTVTVSS (SEQ ID NO: 324)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFNTYVLSWVRQAPGQGLEWMGEIIPILGAANYAQNFQGRVTFTTDESTNTAYMDLSSLRSEDTAVYYCARDRTSGGFDPWGQGTLVTVSS (SEQ ID NO: 325)

QVQLVQSGAEVEKPGASVKVSCKASGYIFTHYGISWVRQAPGQGLEWVGWISPYNGYTDYAQKLQGRVTLTTDTSTTAYMELRNLRSDDTAMYYCSRGRGPYWSFDLWGRGTLVTVSS (SEQ ID NO: 326)

VL sequences:

DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYHSYSYTFGQGTKEIK (SEQ ID NO: 327)

DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYTASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPLTFGGGTKVAIK (SEQ ID NO: 328)

DIQMTQSPSSLSASVGDRVTITCRTSQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNNYPYTFGQGTKLEIK (SEQ ID NO: 329)

DIVMTQTPLSSPVTLGQPASISCRSSQTLVHGDGNTYLSWIQQRPGQPPRLLIYKVSNQFSGVPDRFSGSGAGTDFTLKISRVEAEDVGLYFCMQATHFPITFGQGTRLEIK (SEQ ID NO: 330)

DIVMTQTPLSSPVTLGQPASISCRSSPSLVHSDGNTYLSWLQQRPGQPPRLLIYKISNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCMQATHFPITFGQGTRLEIR (SEQ ID NO: 331)

DIQMTQSPSSLSASLGDRVTITCRASQSINSYLNWYQQKPGKAPKLLIYVASSLQSGVPSRFSGSGSGTEFTLTISNLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 332)

(SEQ ID NO: 333)

DIQMTQSPSSPSSLSASSVGDRVTITCRASKTINILNWYQKKPRAPRASSLIASGSGSGSGSGSGSGSGSGSGTSSLQPEDYCHQSYSTRLEIK (Seq ID NO: 334)

DIQMTQSPSSLSASVGDRVTITCRASQSMSSYLNWYQQKPGRAPKLLIFAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 335)

EIVLTQSPGTLSLSPGERATLSCRASQSFNFNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTINRLEPEDFGVFYCQQYESAPWTFGQGTKVEIK (SEQ ID NO: 336)

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKLLIYAASSLQSGVPSRFSGGGSGTDFTLTISSLRPEDFATYYCQQSYCTPPITFGQGTRLEIK (SEQ ID NO: 337)

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 338)

DRVTITCRASQVISNYLAWYQQKPGKVPRLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPRTFGQGTKVEIK (SEQ ID NO: 339)

DIQMTQSPSSPSSLSASSVGDRVTITCRASKNYLNNYLNNYLNYNYLNYNYLIYAASSFQNAVPSRFSGSGSGSGSGSGSGTSSLQSYNTPLTFGGGGGGGGGGTKVEIK

DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPYTFGQGTKLEIK (SEQ ID NO: 341)

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 342)

[00202] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

QSLEESGGRLVKPDETLTITCTVSGIDLSSNGLTWVRQAPGEGLEWIGTINKDASAYYASWAKGRLTISKPSSTKVDLKITSPTTEDTATYFCGRIAFKTGTSIWGPGTLVTVSS (SEQ ID NO: 343)

VL sequences:

AIVMTQTPSPVSAAVGGTVTINCQASESVYSNNYLSWFQQKPGQPPKLLIYLASTLASGVPSRFKGSGSGTQFTLTISGVQCDDAATYYCIGGKSSSTDGNAFGGGTEVVVR (SEQ ID NO: 344)

[00203] In some options for the implementation of this invention, the PDL1-binding domain contains or is a derivative of an antibody sequence or its antigen-binding fragment, which includes a combination of the VH sequence and the VL sequence, consisting of: consisting of:

VH sequences:

QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGNIVATITPLDYWGQGTLVTVSS (SEQ ID NO: 345)

QpvltqPpsvsaapgqkvtisssssssssnianvswyqlpgtapgtapgtapsgipsgsgsgtsglqtggvfggvfggggggtkltkltkltvl (SEQ ID NO: 346)

EVQLVQSGAEVKKPGSSVKVSKASSYASSYAISSYAISWVRQAPGIPGIIPIPIPIPHTANYAQKFQRVTAYMELSSLSSHYSFDYWGQGTLVTVSS (SEQ ID NO: 347)

QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 348)

EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 349)

QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 350)

EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 351)

EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 352)

QVQLVESGGGGGGVVQpgrsLrlscaASSYASSYAMHWVRQAPGLAVAVAVAVAVAVAVAVAVKYADSVRFTISRDNSLALRTAVYYWLDIWGQGTLVTVSS (SEQ ID NO: 353)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHWVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFFAWGQGTLVTVSS (SEQ ID NO: 354)

QMQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 355)

QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYWGQGTLVTVSS (SEQ ID NO: 356)

QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYSWVRQAPGQGLEWMGGIIPSFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGPIVATITPLDYWGQGTLVTVSS (SEQ ID NO: 357)

QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYSWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGPIVATITPLDYWGQGTLVTVSS (SEQ ID NO: 358)

QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYSWVRQAPGQGLEWMGGIIPSFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGPIVATITPLDYWGQGTLVTVSS (SEQ ID NO: 359)

QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPAFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGPIVATITPLDYWGQGTLVTVSS (SEQ ID NO: 360)

VL sequences:

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 361)

AIRMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYTTSSLKSGVPSRFSGSGSGTDFTLTISRLQPEDFATYYCQQSYSSTWTFGRGTKVEIK (SEQ ID NO: 362)

QSVLTQPPSVSAAPGQKVTISCSGNNSNIANNYVSWYQQLPGTAPKLLIYDNNYRPSGIPDRFSSGSKSGTSATLDITGLQTGDEADYYCGVWDGSLTTGVFGGGTKLTVL (SEQ ID NO: 363)

LPVLTQPASVSGSPGQSITISCTGTTSDIGGYDYVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTHVFGTGTKLTVL (SEQ ID NO: 364)

QSaltQpasvsgspgqspistgtsdvggynyqqhpgkpksnrpsnrpsnrfsnrfsgsgntasltisglqaededycsStlgpvfggtkgtkltvl (SEQ ID NO: 365)

(SEQ ID NO: 366)

QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSTTHVFGTGTKVTVL (SEQ ID NO: 367)

QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSVWVFGGGTQLTVL (SEQ ID NO: 368)

QSVLTQPASVSGSPGQISTGTSSDVGGYNYVSWYVSWYVSWYQHPRAPRAPRPRPSNRPSNRFSGSNTASGLTISGDYEDYDSYTSSYTSSYTSSYTSSYTSSYTSGGGGTKLTVL (SEQ ID NO: 369)

QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAVVFGGGTKLTVL (SEQ ID NO: 370)

QSSVTQPPSVSAPGQKVTISSGSSNIGNYVSWYVSWYQVPGTAPKLIYDNNNKRPRPRFSGSNSTSATLGITGLSAWVFGGGTKLTVL (SEQ ID NO: 371))

QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAGSVVFGGGTKLTVL (SEQ ID NO: 372)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCLVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 373)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 374)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 375)

SYELMQPPSVSVAPGKTATIACGGENIGRKTVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHRIFGGGTKLTVL (SEQ ID NO: 376)

[00204] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

QVQLVQSGSEVKKSGSSVKVSCKTSGGTFSITNYAINWVRQAPGQGLEWMGGILPIFGAAKYAQKFQDRVTITADESTNTAYLELSSLTSEDTAMYYCARGKRWLQSDLQYWGQGTLVTVSS (SEQ ID NO: 377)

VL sequences:

QPVLTQPASVSGSPGQSITISCTGSSSDVGSYDLVSWYQQSPGKVPKLLIYEGVKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGTRNFVFGGGTQLTVL (SEQ ID NO: 378)

[00205] In some embodiments of this invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a combination of a VH sequence and a VL sequence selected from the group consisting of:

VH sequences:

EVQLLESGGGGGLVQPGSLRLSCASSYASSYAMSYAMSWVRQAPGLVSSIYSSISSISSVKGRFTISKNSLRADVYYCSRPGFDYWGQGTLVTVSS (SEQ ID NO: 379)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIYSTGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGQSWPGFDYWGQGTLVTVSS (SEQ ID NO: 380)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIYSTGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGQSFPGFDYWGQGTLVTVSS (SEQ ID NO: 381)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIYSTGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWSAAFDYWGQGTLVTVSS (SEQ ID NO: 382)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIYSTGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWSAGYDYWGQGTLVTVSS (SEQ ID NO: 383)

EvqllesgggglvqpgslscaassyasSyamssyamswvrqpglewvssiystgatyadsvkgrftisrdnskmnslqmnslraedtavycgfdywgqgtlvtvs (SEQ ID NO: 384)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWKQGIVTVYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTV (SEQ ID NO: 385)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWRNGIVTVYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSS (SEQ ID NO: 386)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSDIWKQGMVTVYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSS (SEQ ID NO: 387)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWRQGLATAYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSS (SEQ ID NO: 388)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSEIVATGILTSYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSS (SEQ ID NO: 389)

EVQLLESGGGGGLVQPGSLRLSCASSYASSYAMSWVRQAPGLWVSSIGRQGLITVYDSVKRFTISKNSLRADVYYCSAGQGTLVTVSS (SEQ ID NO: 390)

EvqllesgggglvqpgslsCaSSYASSYAMSSYAMSWVRQAPGLVSSIWYQGLVTVYDSVKGRFTISRDNSKNSLRADVYYCSAGQGQGTLVTVSS (SEQ ID NO: 391)

EVQLLESGGGGGLVQPGSLRLSCASSYASSYAMSWVRQAPGLVSDIWKQGFATASVKGRFTISKNSLALRADADYDYWGQGTLVTVSS (SEQ ID NO: 392)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWKQGIVTVYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSS (SEQ ID NO: 393)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWRQGLATAYDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSS (SEQ ID NO: 394)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWRNGIVTVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWSAAFDYWGQGTLVTVSS (SEQ ID NO: 395)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWRNGIVTVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWSAGYDYWGQGTLVTVSS (SEQ ID NO: 396)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWRNGIVTVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWSKGFDYWGQGTLVTVSS (SEQ ID NO: 397)

EvqllesgggglvqpgslscaassyassyametswvrqpglewvssiwywywywywtvyadsvkrftisrdnSkMetnslraedtavycakwsawgqgtlvtvss (SEQ ID 398)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIWYQGLVTVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWSAGYDYWGQGTLVTVSS (SEQ ID NO: 399)

EvqllesggggglvqpgslsCaSSYASSYAMSSYAMSWVRQAPGLVSSIWYQGLVTVYADSVKRFTISRDNSKMNSLRAEDVYCHFDYWGQGTLVTVSS (SEQ ID NO: 400)

VL sequences:

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDNGYPSTFGQGTKVEIKR (SEQ ID NO: 401)

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDNGYPSTFGQGTKVEIKR (SEQ ID NO: 402)

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDNGYPSTFGGGTKVEIKR (SEQ ID NO: 403)

[00206] In some embodiments of the invention, the PDL1 binding domain comprises or is derived from an antibody sequence or an antigen-binding fragment thereof, which includes a single chain Fv (scFv) sequence selected from the group consisting of:

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSDITASGQRTTYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSKIAFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYKASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQRALKPVTFGQGTKVEIKR (SEQ ID NO: 404)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSINKDGHYTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKNLDEFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPNTFGQGTKVEIKR (SEQ ID NO: 405)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIMATGAGTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDGAGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYSASQLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSRPSTFGQGTKVEIKR (SEQ ID NO: 406)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLQWVSTITSSGAATYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKNYTGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYNASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYTYGPGTFGQGTKVEIKR (SEQ ID NO: 407)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIYSTGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSSAGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDNGYPSTFGQGTKVEIKR (SEQ ID NO: 408)

Dual targeting PDL1 and 41BB

[00207] In some embodiments of this invention, the fusion proteins are bispecific molecules that include TBD, which binds 41BB and a binding domain directed to PDL1. In these embodiments of the present invention, PDL1 binding is able to provide an additional crosslinking function, and TNFRSF activation can be achieved with only one or two anti-41BB TBDs. In these embodiments of the present invention, TNFRSF signaling is enhanced and focused by the presence of a PDL1-expressing cell.

Tetravalent 41BB agonist: hzRH3v5-1

EVQLLESGGGEVQPGGSLRLSCAASGFSFSINAMGWYRQAPGKRREFVAAIESGRNTVYAESVKGRFTISRDNAKNTVYLQMSSLRAEDTAVYYCGLLKGNRVVSPSVAYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGS EVQLLESGGGEVQPGGSLRLSCAASGFSFSINAMGWYRQAPGKRREFVAAIESGRNTVYAESVKGRFTISRDNAKNTVYLQMSSLRAEDTAVYYCGLLKGNRVVSPSVAYWGQGTLVTVKPGG (SEQ ID NO: 448)

Bispecific PDL1 and 41BB: hz28A2v5 x hzRH3v5-1

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGS EVQLLESGGGEVQPGGSLRLSCAASGFSFSINAMGWYRQAPGKRREFVAAIESGRNTVYAESVKGRFTISRDNAKNTVYLQMSSLRAEDTAVYYCGLLKGNRVVSPSVAYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 449)

Bispecific PDL1 and 41BB: hz28A2v5 x hzRH3v5-2

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGS EVQLLESGGGEVQPGGSLRLSCAASGFSFSINAMGWYRQAPGKRREFVAAIYSGRNTVYAESVKGRFTISRDNAKNTVYLQMSSLRAEDTAVYYCGLLKGNRVVSPSVAYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 450)

Bispecific PDL1 and 41BB: hz28A2v5 x hzRH3v5-16

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGS EVQLLESGGGEVQPGGSLRLSCAASGFSFSINAMGWYRQAPGKRREFVAAIYSGSSTVYAESVKGRFTISRDNAKNTVYLQMSSLRAEDTAVYYCGLLKGNRVVSPSVAYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 451)

Bispecific PDL1 and 41BB: hz28A2v5 x hz4E01v16

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGSEVQLLESGGG EVQLLESGGGEVQPGGSLRLSCAASGWAFGNYGMAWFRQAPGKEREFVSRLAWQGGSTDYVESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCARQRSYSRYDIRTPQTYDYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 452)

Bispecific PDL1 and 41BB: hz28A2v5 x hz4E01v18

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGSEVQLLESGGG EVQLLESGGGEVQPGGSLRLSCAASGWAFGNYGMAWFRQAPGKEREFVSRLAWGGGSTDYVESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCARQRSYSRYDIRTPQTYDYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 453)

Bispecific PDL1 and 41BB: hz28A2v5 x hz4E01v21

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGSEVQLLESGGG EVQLLESGGGEVQPGGSLRLSCAASGWAFSNYGMAWFRQAPGKEREFVSRLAWGGGSTDYVESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCARQRSYSRYDIRTPQTYDYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 454)

Bispecific PDL1 and 41BB: hz28A2v5 x hz4E01v22

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGSEVQLLESGGG EVQLLESGGGEVQPGGSLRLSCAASGWAFGNYGMAWFRQAPGKEREFVSRLAWSGGSTDYVESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCARQRSYSRYDIRTPQTYDYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 455)

Bispecific PDL1 and 41BB: hz28A2v5 x hz4E01v23

EVQLLESGGGEVQPGGSLRLSCAASGGIFAIKPISWYRQAPGKQREWVSTTTSSGATNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCNVFEYWGQGTLVTVKPGGSGGSEVQLLESGGG EVQLLESGGGEVQPGGSLRLSCAASGWAFSNYGMAWFRQAPGKEREFVSRLAWSGGSTDYVESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCARQRSYSRYDIRTPQTYDYWGQGTLVTVKP GGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 456)

Targeting folic acid receptor alpha (FRα)

[00208] In some embodiments of the present invention, the fusion proteins are multispecific, containing TBD and a binding domain directed to the folic acid receptor alpha (FRα). In these embodiments of the present invention, FRα binding is able to provide an additional crosslinking function, and TNFRSF activation can be achieved with only one or two TBDs. In these embodiments of the present invention, TNFRSF signaling is enhanced and focused by the presence of an FRα-expressing cell.

[00209] Exemplary FRα-targeted single domain sequences are shown below:

CDR1: GSIFSIDA (SEQ ID NO: 429)

CDR2: ITSSGST (SEQ ID NO: 430)

CDR3: NAITRMGGSTYDF (SEQ ID NO: 431)

[00210] This invention will be additionally described in the following examples that do not limit the volume of the invention described in the invention formula.

EXAMPLES

Example 1 Binding of 41BB via 41BB-targeted single domain antibodies

[00211] 41BB-targeted single-domain antibodies (sdAbs) referred to herein as 1G3 (SEQ ID NO: 432), 1H4 (SEQ ID NO: 436), 1H1 (SEQ ID NO: 440), 4H4 (SEQ ID NO: 16), 1H8 (SEQ ID NO: 444), 4F5 (SEQ ID NO: 23), and 4E1 (SEQ ID NO: 20) bind recombinant human 41BB (Figure 2A) and cynomolgus monkey 41BB (Figure 2B). 41BB-targeted single domain antibodies (sdAbs) referred to herein as 4F5 (SEQ ID NO: 23), 4H04 (SEQ ID NO: 16), 4E01 (SEQ ID NO: 20), RH03 (SEQ ID NO: 25), and D1 (SEQ ID NO: 29) bind human 41BB expressed on the surface of CHO cells (Figure 3). 41BB-targeted sdAbs are referred to herein as 4H04, RH03 and bind to 41BB of the cynomolgus monkey. Figure 2A, Figure 2B and Figure 4 illustrate the results of binding assessed by ELISA, wherein the recombinant 41BB-mFc fusion protein (fusion protein containing 41BB operably linked to the mouse Fc region) was immobilized on a 96-well Medisorp plate. Figure 3 illustrates the results of binding assessed by flow cytometry using CHO cells expressing 41BB, with data presented as median fluorescence intensity.

Example 2 Blocking 41BB with 41BB-targeted single domain antibodies

[00212] 41BB-targeted single domain antibodies (sdAb) referred to herein as 4F05 (SEQ ID NO: 23), 4H04 (SEQ ID NO: 16), 4E01 (SEQ ID NO: 20), RH03 (SEQ ID NO: 25), and D1 (SEQ ID NO: 29) blocked the interaction between 41BB and its 41BBL ligand. All analyzed single-domain antibodies, with the exception of RH3, block the interaction between 41BB and 41BBL. Blocking was assessed by flow cytometry using recombinant 41BB fusion protein and CHO cells expressing 41BB, with data presented as median fluorescence intensity.

[00213] In contrast to the 41BB sdAbs of the present invention, conventional anti-41BB bivalent antibodies did not induce 41BB signalling, except when additional clustering was performed with an exogenous anti-human IgG crosslinker. Figure 6 demonstrates the inability of the conventional divalent anti-41BB antibody PF-05082566, as described in US Pat. No. 8,337,850, to induce 41BB signalling, except when additional clustering was performed with an exogenous anti-human IgG crosslinker. 41BB signaling depicted in Figure 6 was monitored using the NFkB reporter cell line 293 expressing 41BB.

Example 3 Binding of PDL1 and blocking the interaction between PLD1 and PD1 by PDL1-targeted single domain antibodies

[00214] The studies presented herein use a generic PDL1 single domain antibody (sdAb) referred to herein as 28A10 (SEQ ID NO: 100) to demonstrate that the PDL1-targeted sdAbs of this invention bind PDL1 on the cell surface (Figure 7A) and block the interaction of PDL1 with PD1 (Figure 7B). Binding was assessed by flow cytometry on PDL1-expressing CHO cells, and blocking was assessed by flow cytometry using recombinant PD1 fusion protein and PDL1-expressing CHO cells. The data shown in Figures 7A and 7B are presented as median fluorescence intensity.

Example 4 Fusion Proteins Targeting PDL1-41BB

[00215] The present invention provides fusion proteins that target at least PDL1 and 41BB. These bispecific fusion proteins targeting PDL1-41BB are agonists of PDL1-dependent 41BB-mediated signaling. Figures 8A and 8B are conceptual diagrams in which the bispecific fusion proteins have minimal 41BB agonist properties (Figure 8A), except when they are associated with a PD-L1 expressing cell (Figure 8B). Figure 8C demonstrates the ability of a PDL1 positive cell, in this case a population of PDL1 transfected CHO cells, to mediate 41BB signaling and the inability of a PDL1 negative cell, in this case non-transfected CHO cells, to mediate 41BB signaling. This figure illustrates two separate bispecific fusion proteins, each containing a separate 41BB-binding VHH (eg, 4E01 or RH3) and PD-L1-binding VHH, 28A10. 41BB signaling was monitored using the NFkB reporter cell line 293 expressing 41BB. This reporter cell line employs NF-kB-induced secreted alkaline phosphatase to monitor NF-kB signaling.

[00216] The fusion proteins of this invention targeting PDL1-41BB include a humanized anti-41BB sequence. In the assays presented herein, fusion proteins of the invention targeting PDL1-41BB include a humanized anti-41BB sequence such as hzRH3v5-1 (SEQ ID NO: 30) and/or hzRH3v9 (SEQ ID NO: 82) and bind both human and cynomolgus 41BB (Figures 9A, 9B), including human 41BB and cynomolgus 41BB expressed on the surface of CHO cells (Figures 9C, 9D). Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB.

[00217] The hzRH3v5-1 and hzRH3v9 humanized variants do not block 41BBL binding to 41BB on the cell surface, as illustrated in Figure 9E. In these studies, a recombinant 41BBL-mFc fusion protein containing a mouse Fc region was used, and 41BBL binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00218] The hzRH3v5-1 humanized variant specifically binds 41BB compared to other members of the TNFRSF family: OX40 and GITR (Figure 10). Binding was assessed by flow cytometry using CHO cells expressing this member of the TNFRSF family.

[00219] Analyzed additional humanized variants of 41BB. Figures 11A, 11B, 11C and 11D demonstrate binding of humanized 4E01 variants to human 41BB (Figure 11A and Figure 11C) or cynomolgus monkey (Figure 11B). Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB. Figure 11D demonstrates that the humanized variants hz4E01v16, hz4E01v18, hz4E01v21, hz4E01v22 and hz4E01v23 block the binding of 41BBL to 41BB on the cell surface. In these studies, a recombinant 41BBL-mFc fusion protein containing a mouse Fc region was used, and 41BBL binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00220] The fusion proteins of this invention targeting PDL1-41BB also include a humanized anti-PDL1 sequence. In the assays presented herein, fusion proteins of the invention targeting PDL1-41BB include a humanized anti-PDL1 sequence such as hz28A2v1 (SEQ ID NO: 120), hz28A2v2 (SEQ ID NO: 121), hz28A2v3 (SEQ ID NO: 122) and hz28A2v4-1 (SEQ ID NO: 123). Figure 12 shows binding of humanized single domain antibodies targeting PDL1. Binding was assessed by flow cytometry on CHO cells expressing PDL1.

[00221] Figure 13 is a schematic representation of two exemplary formats of the PDL1x41BB bispecific fusion protein of the invention, referred to herein as INBRX-105-1. INBRX-105-1-A (left) has PDL1 and 41BB binding domains located at opposite end positions from the central Fc region, while INBRX-105-1-B (right) has PDL1 and 41BB binding domains, located in tandem, at the N-terminus relative to the Fc region.

[00222] These two formats were further evaluated for their ability to bind human or cynomolgus 41BB, block the interaction between 41BB and 41BBL, bind PDL1, and block the interaction between PDL1 and PD1.

[00223] In particular, Figures 14A, 14B and 14C demonstrate equivalent binding to human (Figure 14A) or cynomolgus monkey (Figure 14B) 41BB by two different formats of a bispecific fusion protein targeting PDL1 and 41BB, referred to herein as INBRX -105-1-A and INBRX-105-1-B and illustrated in Figure 13. Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB. In the studies presented herein, hzRH3v5-1 (SEQ ID NO: 124) is the 41BB binding domain used in both formats. As illustrated in Figure 14C, the hzRh3v5-1 bispecific fusion protein does not block 41BBL binding to 41BB on the cell surface. In these studies, a recombinant 41BBL fusion protein and mouse Fc region was used, and 41BBL binding was detected using a specific anti-mouse IgG-Fc secondary antibody.

[00224] Moreover, Figures 15A, 15B, 15C and 15D demonstrate equivalent binding (Figure 15A and Figure 15C) and blocking of PD1 (Figure 15B and Figure 15D) by two different formats of the bispecific fusion protein targeting PDL1 and 41BB, and referred to in this document as INBRX-105-1-A and INBRX-105-1-B. Binding was assessed by flow cytometry on human 293freestyle cells (Figure 15A) or cynomolgus monkey (Figure 15C) expressing PDL1. Blocking was assessed by flow cytometry on human 293freestyle cells (Figure 15B) or cynomolgus monkey (Figure 15D) expressing PDL1 with either recombinant human PD1-mFc fusion protein (Figure 15B) or cynomolgus monkey (Figure 15D). PD1 binding was detected using a specific anti-mouse IgG-Fc secondary antibody. In the studies presented in this document, hz28A2v5 is the PDL1 binding domain used in both formats.

[00225] PDL1x41BB bispecific fusion proteins were evaluated for their ability to induce PDL1-dependent 41BB agonism. Figure 16 demonstrates the ability of humanized versions of the PDL1x41BB bispecific fusion protein (INBRX-105-1) to induce PDL1-dependent 41BB agonism. This document provides two different formats: INBRX-105-1-A and INBRX-105-1-B, having PDL1 and 41BB binding domains located at opposite ends or in tandem in the fusion protein, respectively. Notably, INBRX-105-1-A compared to INBRX-105-1-B shows equivalent PDL1-dependent agonist activity. The 41BB-expressing NFkB reporter cell line 293 was used to evaluate 41BB signaling, and the PDL1-expressing CHO cell line was used as the PDL1 source. This reporter cell line employs NF-kB-induced secreted alkaline phosphatase to monitor NF-kB signaling.

[00226] The ability of 41BB-specific binding and PDL1-specific binding through binding domains in PDL1x41BB bispecific fusion proteins was assessed. Figures 17A and 17B demonstrate 41BB-specific binding via the 41BB-binding portion of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention. Binding was assessed by flow cytometry on 293freestyle cells expressing 41BB (Figure 17A) or the closest homologue, TNFRSF21/DR6 (Figure 17B). An anti-DR6 antibody (Invitrogen) was used as a positive control for DR6 expression. In addition, Figures 18A, 18B and 18C demonstrate PDL1-specific binding via the PDL1-binding portion of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention. Binding was assessed by flow cytometry on 293freestyle cells expressing PDL1 (Figure 18A) or its closest homologue PDL2 (Figure 18B) or VISTA/PDL3 (Figure 18C) An anti-PDL2 antibody and an anti-VISTA antibody known as VSTB174, which is described in PCT Publication No. WO 2015/097536 were used as positive controls for the expression of PDL2 and PDL3, respectively.

[00227] The ability of the PDL1x41BB bispecific fusion protein to simultaneously bind PDL1 and 41BB was evaluated. Figures 19A and 19B demonstrate the ability of the PDL1x41BB bispecific fusion protein to simultaneously bind PDL1 and 41BB. INBRX-105-1 was titrated on K562 cells expressing PDL1 and 25 nM of 41BB-mFc recombinant proteins were added. 41BB binding was detected using a specific anti-mouse IgG-Fc secondary antibody. Figure 19A is a graph showing the binding of INBRX-105-1 to K562 cells expressing PDL1. Figure 19B is a graph showing the binding of recombinant 41BB to INBRX-105-1 on cells expressing PDL1.

[00228] Figure 20 demonstrates the ability of the PDL1x41BB bispecific fusion protein to simultaneously bind recombinant PDL1 and recombinant 41BB in an ELISA assay. INBRX-105-1 was titrated against immobilized (Medicorp plate) recombinant PDL1, then either 2 or 10μg/ml biotinylated recombinant 41BB (His-labeled) was added. Bound recombinant 41BB was detected using streptavidin-HRP.

[00229] The effect of PDL1x41BB bispecific fusion proteins on T cell activation and proliferation was evaluated. Figures 21A, 21B and 21C show the effect of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention on T cell activation and proliferation. In this study, autologous in vitro co-culture was performed for 7 days using immature DC (iDC) and donor matched T cells. PDL1 ⁺ iDC was generated by enriching a monocyte population (EasySep™ Human Monocyte Enrichment Kit, STEMCELL Technologies Inc.) from human donor PBMCs and culturing them in 500 U/mL GM-CSF, and 250 U/mL IL-4, for 7 days. Simultaneously, autologous T cells were enriched (EasySep™ human T cell enrichment kit, STEMCELL Technologies Inc.) and cryopreserved until completion of iDC formation. Enriched T cells were added to iDC at an approximate ratio of 20:1 (T cell:iDC) and co-cultured for at least 7 days in the presence of IL-7. The bispecific PDL1x41BB fusion protein, INBRX-105-1, is superior to the monospecific PDL1 sdAb-Fc fusion protein (hz28A2v5-Fc), the sdAb-Fc 41BB fusion protein (hzRH3v5-1-Fc), the combination of hz28A2v5-Fc and hzRH3v5-1-Fc, anti-PDL1 antibody atezolizumab, anti-41BB antibody, utomilumab (PF-05082566 described in US8337850) or anti-PD1 antibody prembrolizumab and combinations thereof when inducing INFγ (Figure 21A) or mediating CD8 ⁺ proliferation (Figure 21B) and activation (Figure 21B) 21C) T cells. INFγ production in the cell supernatant was monitored by ELISA and normalized to a standard curve. T cell proliferation was monitored by flow cytometry using CTV labeling of T cells. Activation of T cells was evaluated by the presence of the activation marker CD25, controlled using running citometry. Antibodies were used at a concentration of 10 nM. InBRX-105-1, apparently, increases the low level and/or activates the function of activation/signaling of T cells, which is weakened during the interaction of PDL1: PD1.

[00230] Figures 22A and 22B demonstrate PDL1-dependent 41BB agonism mediated by the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention. In these studies, T cells were cultured alone or with autologous immature DC (iDC, PDL1-expressing), PDL1-expressing K562 cell line, or parental K562 cell line (PDL1-negative) in the presence or absence of 10 nM INBRX-105-1 for 7 days. The proliferation of CD8 ⁺ T cells (Figure 22A) was monitored using CTV-labeling, and the production of INFγ (Figure 22B) in the cell supernatant was monitored by ELISA analysis and normalized to a standard curve.

[00231] Figure 23 demonstrates the ability of the PDL1x41BB bispecific fusion protein (INBRX-105-1) of the invention to enhance the Th1 lineage-defined transcription factor, T-bet, expressed in T cell populations. In these studies, T cells were co-cultured with autologous immature DCs in the presence or absence of INBRX-105-1 for 7 days. T-bet expression was assessed on populations of CD4 ⁺ and CD8 ⁺ T cells by flow cytometry by intracellular staining after fixation and permeabilization. INBRX-105-1 had a stronger effect on T-bet expression in CD8 ⁺ T cells.

[00232] Bisperphytic merged proteins PDL1x41bb in this invention were compared with various well -known monopony antibodies. On the figures of 24A and 24B, the ability of the bispeicentic merged protein PDL1x41bb (INBRX-105-1) is compared at this invention and a combination of mono-specific antibodies atotle atotlezolymab (anti-PDL1) and Tyno-41BB) induce Infγ (Figure 24a) or TNFα (Figure 24b (Figure 24b ) from CD4 ⁺ or CD8 ⁺ T cells. In these studies, the T-cells were jointly cultivated with autological immature DC in the presence or absence of INBRX-105-1 for 7 days, or a combination of monopoly antibodies. InBRX-105-1 was characterized by a significantly greater effect with the joint stimulation of T cells compared to mono-specific antibodies aimed at the same antigens. The expression of cytokines was evaluated at the CD4 ⁺ and CD8 ⁺ T cells using running citometry by intracellular staining after fixation and permeabilization.

Figures 25A and 25B demonstrate the agonistic ability of the tetravalent 41BB binding fusion protein and the PDL1x41BB bispecific fusion proteins of the invention in the presence of an additional PDL1 positive (Figure 25A) or negative (Figure 25B) cell line. Notably, only the tetravalent 41BB binding fusion protein was able to induce 41BB signaling in the absence of a cell line expressing PDL1. The PDL1x41BB bispecific fusion proteins (INBRX-105-1, INBRX-105-2, and INBRX-105-16) induced 41BB signaling only when bound to PDL1 on the cell surface, as illustrated in Figure 25A. This demonstrates that the bivalent interaction of 41BB, as in the case of INBRX-105, is insufficient for efficient clustering and mediation of productive 41BB signaling. The interaction of the second cell surface antigen, PDL1, as in this example, provides additional 41BB clustering and productive signaling. In this study, a 41BB NFkB-expressing HEK293 reporter cell was used and co-incubated with either a PDL1-negative K562 cell line (Figure 25B) or a stably transfected PDL1-expressing K562 cell line (Figure 25A). INBRX-105-1 includes a 41BB-targeted sdAb: hzRH3v5-1, INBRX-105-2 includes a 41BB-targeted sdAb: hzRH3v5-2, and INBRX-105-16 includes a 41BB-targeted sdAb: hzRH3v5- 16 and all include hz28A2v5 PDL1-targeted sdAb. The tetravalent 41BB-targeted fusion protein used in this invention has the following format, containing hzRH3v5-1-Fc-hzRH3v5-1.

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SEQUENCE LIST

<110> INHIBRX LP

<120> MULTIVALENT AND MULTI-SPECIFIC 41BB-BINDING FUNCTION PROTEINS

<130> INHI-027001WO 322124-2114

<140> PCT/US2017/13040

<141> 2017-01-11

<150> US 62/277,028

<151> 2016-01-11

<160> 456

<170> PatentIn version 3.5

<210> 1

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 1

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

35 40 45

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

50 55 60

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

65 70 75 80

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

85 90 95

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

100 105 110

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

115 120 125

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

130 135 140

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

145 150 155 160

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

165 170 175

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

180 185 190

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

195 200 205

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215

<210> 2

<211> 215

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 2

Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

1 5 10 15

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

20 25 30

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

35 40 45

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

50 55 60

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

65 70 75 80

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

85 90 95

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

100 105 110

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

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Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

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Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

145 150 155 160

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

165 170 175

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

180 185 190

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

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Leu Ser Leu Ser Pro Gly Lys

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<210> 3

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<212> PRT

<213> Artificial sequence

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<223> chemically synthesized

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Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

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Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

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Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr

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Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

50 55 60

Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His

65 70 75 80

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

85 90 95

Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln

100 105 110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met

115 120 125

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135 140

Ser Asp Ile Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

145 150 155 160

Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu

165 170 175

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

180 185 190

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215

<210> 4

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 4

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp

35 40 45

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

50 55 60

Glu Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu

65 70 75 80

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

85 90 95

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly

100 105 110

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

115 120 125

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

130 135 140

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn

145 150 155 160

Asn Tyr Asn Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe

165 170 175

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

180 185 190

Ile Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr

195 200 205

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215

<210> 5

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 5

Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp

35 40 45

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

50 55 60

Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

65 70 75 80

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

85 90 95

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

100 105 110

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu

115 120 125

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

130 135 140

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

145 150 155 160

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

165 170 175

Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

180 185 190

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

195 200 205

Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

210 215

<210> 6

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 6

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

1 5 10 15

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

20 25 30

Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp

35 40 45

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

50 55 60

Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

65 70 75 80

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

85 90 95

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

100 105 110

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu

115 120 125

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

130 135 140

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

145 150 155 160

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

165 170 175

Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

180 185 190

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

195 200 205

Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

210 215

<210> 7

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 7

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys

1 5 10

<210> 8

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 8

Asp Lys Thr His Thr Cys Pro Pro Cys

15

<210> 9

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 9

Glu Ser Lys Tyr Gly Pro Cys Pro Cys

1 5 10

<210> 10

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 10

Gly Gly Ser Gly Gly Ser

15

<210> 11

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 11

Gly Gly Ser Gly Gly Ser Gly Gly Ser

15

<210> 12

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 12

Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser

1 5 10

<210> 13

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 13

Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser

1 5 10 15

<210> 14

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 14

Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly

1 5 10

<210> 15

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 15

Gly Gln Gly Thr Leu Val Thr Val Glu Pro Gly Gly

1 5 10

<210> 16

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 16

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Asp

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Asp Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Gly Tyr Gly Ile Arg Thr Pro Gln Thr

100 105 110

Tyr ASP Tyr Trp Gly Gln Gly Thr Gln Val Thr

115 120

<210> 17

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 17

Gly Trp Ala Phe ASP ASN TYR GLY

15

<210> 18

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 18

Leu Ala Trp Asn Gly Gly Ser Thr

15

<120> 19

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 19

Ala Arg Gln Arg Ser Tyr Ser Gly Tyr Gly Ile Arg Thr Pro Gln Thr

1 5 10 15

TYR ASP TYR

<210> 20

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 20

Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Ala Gly Asp

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Asn Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr

115 120

<210> 21

<211> 8

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 21

Gly Trp Ala Phe Gly Asn Tyr Gly

15

<210> 22

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 22

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

1 5 10 15

TYR ASP TYR

<210> 23

<211> 123

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 23

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Asp Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Gly Ile Arg Ala Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr

115 120

<210> 24

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 24

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Gly Ile Arg Ala Pro Gln Thr

1 5 10 15

Tyr Asp Tyr

<210> 25

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 25

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Leu

35 40 45

Ala Ala Ile Asp Ser Gly Arg Asn Thr Val Tyr Ala Val Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Gln Val Thr

115

<210> 26

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 26

Gly Phe Ser Phe Ser Ile Asn Ala

15

<210> 27

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 27

Ile Asp Ser Gly Arg Asn Thr

15

<210> 28

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 28

Gly Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr

1 5 10 15

<210> 29

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 29

Glu Val Gln Pro Val Gln Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Thr Ile Phe Ser Asn Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Thr Gly Gly Phe Thr Asn Tyr Arg Asp Ser Val Lys

50 55 60

Gly Arg Phe Asp Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Val Leu Arg Tyr Ser Arg Asp Tyr Ser Tyr Thr Thr Val Lys Glu

100 105 110

Tyr Trp Gly Gln Gly Thr Gln Val

115 120

<210> 30

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 30

Ala Thr Ile Phe Ser Asn Asn Ala

15

<210> 31

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 31

Ile Thr Thr Gly Gly Phe Thr

15

<210> 32

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 32

Asn Val Val Leu Arg Tyr Ser Arg Asp Tyr Ser Tyr Thr Thr Val Lys

1 5 10 15

Glu Tyr

<210> 33

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 33

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Ala Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 34

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 34

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Ala Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 35

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 35

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Ala Glu Ser

50 55 60

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu

65 70 75 80

Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln

100 105 110

Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys

115 120 125

<210> 36

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 36

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 37

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 37

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 38

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 38

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 39

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 39

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 40

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 40

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 41

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 41

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Gln Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 42

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 42

Leu Ala Trp Gly Gly Ser Thr

15

<210> 43

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 43

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile

35 40 45

Gly Arg Leu Ala Trp Asn Ala Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 44

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 44

Leu Ala Trp Asn Ala Gly Ser Thr

15

<210> 45

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 45

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 46

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 46

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Asn Ala Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 47

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 47

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 48

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 48

Leu Ala Trp Gly Gly Gly Ser Thr

15

<210> 49

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 49

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Ser Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 50

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 50

Gly Trp Ala Phe Ser Asn Tyr Gly

15

<210> 51

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 51

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Ser Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 52

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 52

Leu Ala Trp Ser Gly Gly Ser Thr

15

<210> 53

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 53

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Ser Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Ser Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 54

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 54

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Gly Tyr Asp Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 55

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 55

Ala Arg Gln Arg Ser Tyr Ser Gly Tyr Asp Ile Arg Thr Pro Gln Thr

1 5 10 15

Tyr Asp Tyr

<210> 56

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 56

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Gly Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 57

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 57

Ala Arg Gln Arg Ser Tyr Ser Arg Tyr Gly Ile Arg Thr Pro Gln Thr

1 5 10 15

Tyr Asp Tyr

<210> 58

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 58

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr

20 25 30

Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Arg Ser Tyr Ser Gly Tyr Gly Ile Arg Thr Pro Gln Thr

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

115 120 125

<210> 59

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 59

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ala Ile Asp Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 60

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 60

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 61

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 61

Ile Glu Ser Gly Arg Asn Thr

15

<210> 62

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 62

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Tyr Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 63

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 63

Ile Tyr Ser Gly Arg Asn Thr

15

<210> 64

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 64

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 65

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 65

Gly Phe Thr Phe Ser Ile Asn Ala

15

<210> 66

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 66

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 67

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 67

Gly Phe Ser Phe Ser Ile Asn Ala

15

<210> 68

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 68

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 69

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 69

Gly Phe Thr Phe Ser Ser Asn Ala

15

<210> 70

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 70

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Ser Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 71

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 71

Ile Glu Ser Ser Arg Asn Thr

15

<210> 72

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 72

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Ser Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 73

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 73

Ile Glu Ser Gly Ser Asn Thr

15

<210> 74

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 74

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Ser Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 75

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 75

Ile Glu Ser Gly Arg Ser Thr

15

<210> 76

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 76

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Tyr Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 77

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 77

Ile Glu Ser Gly Arg Asn Thr

15

<210> 78

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 78

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Tyr Ser Gly Ser Ser Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 79

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 79

Ile Tyr Ser Gly Ser Ser Thr

15

<210> 80

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 80

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

ALA ALA ILU GLU SERG ARG ASN THR VAL TYR ALA GLU SER VAL LYS

50 55 60

Gly Arg Phe Thr Ile Serg ASP ALA LYS ASN Thr Val Tyr Leu

65 70 75 80

GLN MET Ser LEU ARG ALA GLU ASP Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 81

<211> 121

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 81

GLU VAL GLN LEU LEU GLU SER GLY GLY GLU Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Val Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

GLN MET Ser LEU ARG ALA GLU ASP Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 82

<211> 121

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 82

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 83

<211> 121

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 83

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Leu

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro

115 120

<210> 84

<211> 119

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 84

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Gly Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Lys Asn Glu Glu Asp Gly Gly Phe Asp His Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<120> 85

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 85

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Gly Ser Gly Ser Asn Thr 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 Arg Leu Tyr Ala Gln Phe Glu Gly Asp Phe Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 86

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 86

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Thr Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Lys Ile Tyr Pro Gly Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gly Tyr Gly Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 87

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 87

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Thr Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Lys Ile Tyr Pro Gly Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gly Tyr Gly Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 88

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 88

Asp Ile Glu Leu Thr Gln Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Leu Gly Asp Tyr Tyr Ala

20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Ser Asn 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 Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Gly Thr Leu His Phe

85 90 95

Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 89

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 89

Asp Ile Glu Leu Thr Gln Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly Ser Lys Tyr Val

20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Ser Asp Ser Glu 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 Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Gly Ser Ile Ser Arg

85 90 95

Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 90

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 90

Asp Ile Glu Leu Thr Gln Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr

35 40 45

Gln Asp Lys Asn 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 Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Tyr Thr Gly Phe Gly Ser Leu

85 90 95

Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 91

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 91

Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr

35 40 45

Gln Asp Lys Asn 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 Ala Thr Tyr Thr Gly Phe Gly Ser Leu

85 90 95

Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 92

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 92

Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Val Val Ile Tyr

35 40 45

Gln Asp Lys Asn 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 Ala Thr Tyr Thr Gly Phe Gly Ser Leu

85 90 95

Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 93

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 93

Asp Ile Glu Leu Thr Gln Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr

35 40 45

Gln Asp Lys Asn 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 Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Ser Thr Tyr Thr Phe Val Gly Phe Thr

85 90 95

Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 94

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 94

Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr

35 40 45

Gln Asp Lys Asn 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 Ser Thr Tyr Thr Phe Val Gly Phe Thr

85 90 95

Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 95

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 95

Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Val Val Ile Tyr

35 40 45

Gln Asp Lys Asn 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 Ser Thr Tyr Thr Phe Val Gly Phe Thr

85 90 95

Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 96

<211> 448

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 96

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Gly Gly Tyr Val Thr Tyr Asn Pro Ser Leu Glu

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Tyr Gly Pro Gly Asn Tyr Asp Trp Tyr Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 97

<211> 451

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 97

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Gly Gly Tyr Val Thr Tyr Asn Pro Ser Leu Glu

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Tyr Gly Pro Gly Asn Tyr Asp Trp Tyr Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 20 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<120> 98

<211> 216

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 98

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro

85 90 95

Ala Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val

100 105 110

Ala Ala Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys

115 120 125

Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg

130 135 140

Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn

145 150 155 160

Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser

165 170 175

Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys

180 185 190

Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr

195 200 205

Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<120> 99

<211> 178

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 99

Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val

1 5 10 15

Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr

20 25 30

Val Val Gly Gln Ala Gly Asn Ile Arg Leu Arg Glu Asp Lys Asp Pro

35 40 45

Ile Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr

50 55 60

Asp Val Thr Met Val Lys Phe Asp Asp Lys Lys Cys Met Tyr Asp Ile

65 70 75 80

Trp Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys

85 90 95

Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser

100 105 110

Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln

115 120 125

Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu

130 135 140

Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly

145 150 155 160

Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile

165 170 175

ASP Gly

<120> 100

<211> 109

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 100

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ala Cys Thr Thr Ser Gly Gly Ile Phe Asn Ile Arg

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Pro Pro Gly Met Gln Arg Glu Trp Val

35 40 45

Ala Thr Ile Ala Phe Gly Gly Ala Thr Asn Tyr Ala Asn Ser Ile Lys

50 55 60

Gly Arg Phe Thr Ala Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ala Phe Glu Ile Trp Gly Gln Gly Thr Gln Val Thr Val

100 105

<210> 101

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 101

Gly Gly Ile Phe Asn Ile Arg Pro

15

<210> 102

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 102

Ile Ala Phe Gly Gly Ala Thr

15

<210> 103

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 103

Asn Ala Phe Glu Ile

15

<210> 104

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 104

Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Arg Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ala Cys Thr Thr Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Pro Pro Gly Gln Glu Arg Glu Trp Val

35 40 45

Thr Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Asn Ser Ile Lys

50 55 60

Gly Arg Phe Thr Val Ala Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Asp Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val

100 105

<210> 105

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 105

Gly Gly Ile Phe Ala Ile Lys Pro

15

<210> 106

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 106

Thr Thr Ser Ser Gly Ala Thr

15

<210> 107

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 107

Asn Val Phe Glu Tyr

15

<210> 108

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 108

Gln Val Gln Leu Gln Glu Ser Gly Gly Asp Leu Val Gln Ala Gly Ser

1 5 10 15

Ser Leu Arg Leu Ala Cys Ala Thr Ser Gly Gly Val Phe Asn Ile Arg

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Pro Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ala Thr Ile Ala Ser Gly Gly Ala Thr Asn Tyr Ala Asn Ser Ile Lys

50 55 60

Gly Arg Phe Thr Ala Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ala Phe Glu Val Trp Gly Gln Gly Thr Gln Val Thr Val

100 105

<210> 109

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 109

Gly Gly Val Phe Asn Ile Arg Pro

15

<210> 110

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 110

Ile Ala Ser Gly Gly Ala Thr

15

<210> 111

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 111

Asn Ala Phe Glu Val

15

<210> 112

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 112

Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ala Cys Thr Thr Ser Gly Gly Ile Phe Asn Ile Arg

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Pro Pro Gly Met Gln Arg Glu Trp Val

35 40 45

Ala Thr Ile Ala Ser Gly Gly Ala Thr Asn Tyr Ala Asn Ser Ile Lys

50 55 60

Gly Arg Phe Thr Ala Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Thr Leu Asn Phe Trp Gly Arg Gly Thr Gln Val Thr Val

100 105

<210> 113

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 113

Asn Thr Leu Asn Phe

15

<210> 114

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 114

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ala Cys Thr Thr Ser Gly Gly Ile Phe Asn Ile Arg

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Pro Pro Gly Met Gln Arg Glu Trp Val

35 40 45

Ala Thr Ile Ala Ser Gly Gly Ala Thr Asn Tyr Ala Asn Ser Ile Lys

50 55 60

Gly Arg Phe Thr Ala Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Ile Trp Gly Gln Gly Thr Gln Val Thr Val

100 105

<210> 115

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 115

Asn Val Phe Glu Ile

15

<210> 116

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 116

Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ala Cys Ile Thr Ser Gly Gly Ile Phe Asn Ile Arg

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Pro Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ala Thr Ile Ala Ser Gly Gly Ala Ala Asn Tyr Ala Asn Ser Ile Lys

50 55 60

Gly Arg Phe Thr Ala Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ala Phe Glu Asn Trp Gly Gln Gly Thr Gln Val Thr Val

100 105

<210> 117

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 117

Ile Ala Ser Gly Gly Ala Ala

15

<210> 118

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 118

Asn Ala Phe Glu Asn

15

<210> 119

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 119

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

100 105 110

<210> 120

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 120

Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

100 105 110

<210> 121

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 121

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

100 105 110

<210> 122

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 122

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

100 105 110

<210> 123

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 123

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Thr Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

100 105 110

<210> 124

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 124

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

100 105 110

<210> 125

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 125

Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala

1 5 10 15

Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn

20 25 30

Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe

35 40 45

Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr

50 55 60

Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg

65 70 75 80

Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro

85 90 95

Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr

100 105 110

<210> 126

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 126

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Thr Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Phe Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 127

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 127

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Thr Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 128

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 128

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Leu His Ala Asp Thr Gly Ile Thr Lys Phe Ser Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Arg Ile Gln Leu Trp Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

<210> 129

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 129

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Gly Ile Phe Ser Thr Tyr

20 25 30

Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn His Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gln Gly Ile Ala Ala Ala Leu Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 130

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 130

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Val Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Gly Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Val Pro

85 90 95

Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

100 105 110

<210> 131

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 131

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Arg Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 132

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 132

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Lys Tyr Asp Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 133

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 133

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Ser Ser Gly Trp Ser Arg Tyr Tyr Met Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 134

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 134

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Leu Phe Gly Ile Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Lys Tyr Ser Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 135

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 135

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Asp Asp Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Asn Arg Gly Arg Ile Glu Tyr Ala 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 Leu Tyr Tyr Cys

85 90 95

Ala Lys Gly Arg Phe Arg Tyr Phe Asp Trp Phe Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 136

<211> 120

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 136

GLN MET GLN LEU Val Gln Ser Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

ALA ASN Ile Lys Gln 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 Asp Tyr Phe Trp Ser Gly Phe Ser Ala Phe Asp Ile Trp Gly

100 105 110

Lys Gly Thr Leu Val Thr Val Ser

115 120

<210> 137

<211> 107

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 137

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Val Trp Tyr Gln Lys Pro GLY GLN ALA Pro Arg Leu Leu Ile

35 40 45

Tyr ASP ALA Ser asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Leu Glu Pro

65 70 75 80

GLU ASP PHE ALA VAL TYR TYR CYS GLN ARG SER ASN TRP Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 138

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 138

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr

85 90 95

PHE GLY GLN Thr Lys Val Glu Ile Lys

100 105

<210> 139

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 139

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Leu Glu Ile Lys

100 105

<210> 140

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 140

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 141

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 141

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

PHE Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 142

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 142

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr

85 90 95

Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 143

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 143

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 144

<211> 107

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 144

Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<120> 145

<211> 121

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 145

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Asn Ile Lys Gln 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 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 146

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 146

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<120> 147

<211> 118

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 147

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ala

115

<210> 148

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 148

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Leu Pro Tyr Gly Gly Ser Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ala

115

<210> 149

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 149

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 150

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 150

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Val Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 151

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 151

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 152

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 152

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Val Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 153

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 153

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Thr Phe

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Val Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 154

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 154

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Val Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 155

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 155

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Phe Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 156

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 156

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Phe Ile Thr Pro Thr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 157

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 157

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 158

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 158

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Phe Tyr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 159

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 159

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Phe Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 160

<211> 108

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 160

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

GLU ASP PHE ALA ThR TYR TYR CYS GLN GLN Ser LEU TYR THR PRO PRO PRO PRO

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 161

<211> 108

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 161

ASP Ile Gln Met Thr Gln Ser Pro Ser Leu Ser Ala Ser Val Gly

1 5 10 15

ASP Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser thr Ala

20 25 30

VAL ALA TRP TYR GLN LYS Pro Gly Lys Ala Pro Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Leu Gln Pro

65 70 75 80

GLU ASP PHE ALA ThR TYR TYR CYS GLN GLN SER TRP Tyr HIS Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 162

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 162

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Phe Tyr Ile Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 163

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 163

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Tyr Thr Pro Thr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 164

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 164

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Phe Ile Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 165

<211> 141

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 165

Met Glu Thr Gly Leu Arg Trp Leu Leu Leu Val Ala Val Leu Lys Gly

1 5 10 15

Val Gln Cys Leu Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro

20 25 30

Gly Thr Pro Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Thr Ile Thr

35 40 45

Asn Tyr His Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

50 55 60

Trp Ile Gly Val Ile Thr Ser Ser Gly Ile Gly Ser Ser Ser Thr Thr

65 70 75 80

Tyr Tyr Ala Thr Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser

85 90 95

Thr Thr Val Asn Leu Arg Ile Thr Ser Pro Thr Thr Glu Asp Thr Ala

100 105 110

Thr Tyr Phe Cys Ala Arg Asp Tyr Phe Thr Asn Thr Tyr Tyr Ala Leu

115 120 125

Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

130 135 140

<210> 166

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 166

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Thr Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 167

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 167

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Leu His Ala Asp Thr Gly Ile Thr Lys Phe Ser Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Arg Ile Gln Leu Trp Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 168

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 168

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Gly Ile Phe Ser Thr Tyr

20 25 30

Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn His Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gln Gly Ile Ala Ala Ala Leu Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 169

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 169

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Val Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Asn Ser Gly Asn Ile Gly Tyr Ala 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 Leu Tyr Tyr Cys

85 90 95

Ala Val Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 170

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 170

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Arg Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 171

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 171

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Lys Tyr Asp Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 172

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 172

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Ser Ser Gly Trp Ser Arg Tyr Tyr Met Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 173

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 173

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Leu Phe Gly Ile Ala His Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Lys Tyr Ser Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 174

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 174

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Asp Asp Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Asn Arg Gly Arg Ile Glu Tyr Ala 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 Leu Tyr Tyr Cys

85 90 95

Ala Lys Gly Arg Phe Arg Tyr Phe Asp Trp Phe Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 175

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 175

Met Asp Thr Arg Ala Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Pro Gly Ala Arg Cys Ala Leu Val Met Thr Gln Thr Pro Ser Ser

20 25 30

Thr Ser Thr Ala Val Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser

35 40 45

Gln Ser Ile Ser Val Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

50 55 60

Pro Pro Lys Leu Leu Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val

65 70 75 80

Pro Ser Arg Phe Lys Gly Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr

85 90 95

Ile Ser Gly Val Gln Arg Glu Asp Ala Ala Thr Tyr Tyr Cys Leu Gly

100 105 110

Ser Ala Gly Ser

115

<210> 176

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 176

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 177

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 177

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 178

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 178

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 179

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 179

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 180

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 180

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 181

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 181

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr

85 90 95

Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 182

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 182

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 183

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 183

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr 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 Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 184

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 184

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 185

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 185

Glu 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 Tyr Ser Ile Thr Ser Asp

20 25 30

Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Val

35 40 45

Gly Tyr Ile Ser Tyr Thr Gly Ser 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 Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Tyr Gly Gly Trp Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Leu Thr Val Ser Ser

115

<210> 186

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 186

Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr

20 25 30

Ser Ile Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Met Trp Ala Gly Gly Gly Thr Asn Ser Asn Ser Val Leu Lys

50 55 60

Ser Arg Leu Ile Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala

85 90 95

Arg Tyr Tyr Gly Asn Ser Pro Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 187

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 187

Glu 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 Tyr Ser Ile Ile Ser Asp

20 25 30

Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Leu

35 40 45

Gly Tyr Ile Ser Tyr Thr Gly Ser 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 Arg Gly Gly Trp Leu Leu Pro Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Leu Thr Val Ser Ser

115

<210> 188

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 188

Glu Val Lys Leu Gln Glu Ser Gly Pro Ser Leu Val Lys 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

Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Phe Pro Arg Asp Asn Asn Thr Lys Tyr Asn Glu Asn Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Lys Glu Asn Trp Val Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Leu Thr Leu Ser Ser

115

<210> 189

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 189

Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Thr Pro Gly Ala

1 5 10 15

Ser Val Arg Ile Ser Cys Gln Ala Ser Gly Tyr Thr Phe Pro Asp Tyr

20 25 30

Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asp Ile Asp Pro Asn Tyr Gly Gly Thr Thr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Ile Leu Thr Val Asp Arg Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ala Leu Thr Asp Trp Gly Gln Gly Thr Ser Leu Thr Val

100 105 110

Ser Ser

<210> 190

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 190

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr

35 40 45

Ala Ala Phe Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu

65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 191

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 191

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Asp Pro Asn Tyr Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ala Leu Thr Asp Trp Gly Gln Gly Thr Met Val Thr Val

100 105 110

Ser Ser

<210> 192

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 192

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met

35 40 45

Gly Asp Ile Asp Pro Asn Tyr Gly Gly Thr Asn Tyr Asn Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ala Leu Thr Asp Trp Gly Gln Gly Thr Met Val Thr Val

100 105 110

Ser Ser

<210> 193

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 193

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met

35 40 45

Gly Asp Ile Asp Pro Asn Tyr Gly Gly Thr Asn Tyr Asn Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Val Asp Arg Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ala Leu Thr Asp Trp Gly Gln Gly Thr Met Val Thr Val

100 105 110

Ser Ser

<210> 194

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 194

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Phe Pro Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Asp Ile Asp Pro Asn Tyr Gly Gly Thr Thr Tyr Ala Ala Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Val Asp Arg Ser Lys Ser Ile Ala Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Gly Ala Leu Thr Asp Trp Gly Gln Gly Thr Met Val Thr Val

100 105 110

Ser Ser

<210> 195

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 195

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Phe Pro Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Asp Ile Asp Pro Asn Tyr Gly Gly Thr Thr Tyr Asn Ala Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Val Asp Arg Ser Lys Ser Ile Ala Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ala Leu Thr Asp Trp Gly Gln Gly Thr Met Val Thr Val

100 105 110

Ser Ser

<210> 196

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 196

Asp Ile Val Met Thr Gln Ser His Lys Leu Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Asp Ser Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Val Glu Leu Lys

100 105

<210> 197

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 197

Asp Ile Val Thr Thr Gln Ser His Lys Leu Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Asp Ser Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Val Glu Leu Lys

100 105

<210> 198

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 198

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Glu Lys Val Ser Met Gly Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Asp Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 199

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 199

Asp Ile Val Met Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Ile Arg Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Lys Arg Trp Ile Ser

35 40 45

Asp Thr Ser Lys Leu Thr Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ala Leu Thr Ile Ser Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Ser Ser Tyr Pro Trp Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 200

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 200

Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr

35 40 45

Ala Thr Phe Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Thr Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 201

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 201

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr

35 40 45

Ala Ala Phe Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu

65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 202

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 202

Gln Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr

35 40 45

Ala Thr Phe Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu

65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 203

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 203

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Gly Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr

35 40 45

Ala Ala Phe Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 204

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 204

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Gly Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Leu Ile Tyr

35 40 45

Ala Ala Phe Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 205

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 205

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Leu Ile Tyr

35 40 45

Ala Thr Phe Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Asn Asn Pro Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 206

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 206

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Leu Pro Ser Gly Thr Ile Leu Val Gly Gly Trp Phe Asp

100 105 110

Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 207

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 207

Glu Val Gln Leu Val Gln 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 Ser Tyr

20 25 30

Ala Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr 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 Val Phe Pro Glu Thr Phe Ser Met Asn Tyr Gly Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 208

<211> 128

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 208

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Leu Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Val Leu Leu Pro Cys Ser Ser Thr Ser Cys Tyr Gly Ser Val

100 105 110

Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 209

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 209

Gln Val Gln Leu Val Gln Ser Gly Gly Ser Val Val Arg Pro Gly Glu

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Asp Asn Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Arg Val Asn Trp Asn Gly Gly Ser Thr Thr Tyr Ala Asp Ala Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Arg Glu Phe Val Gly Ala Tyr Asp Leu Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 210

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 210

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Thr Val Lys Val Ser Cys Lys Val Phe Gly Asp Thr Phe Arg Gly Leu

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Thr Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Gly Leu Arg Trp Gly Ile Trp Gly Trp Phe Asp Pro Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 211

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 211

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Phe Gly Gly Thr Phe Ser Asp Asn

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Lys Pro Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Val Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Thr Met Val Arg Gly Phe Leu Gly Val Met Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 212

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 212

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Gln Phe Val Thr Ile Phe Gly Val Pro Arg Tyr Gly Met

100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 213

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 213

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Arg Gln Met Phe Gly Ala Gly Ile Asp Phe Trp Gly Pro

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 214

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 214

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Gly Thr Phe Gly Thr Tyr

20 25 30

Ala Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Val Pro Leu Ile Gly Leu Val Asn Tyr Ala His Asn Phe

50 55 60

Glu Gly Arg Ile Ser Ile Thr Ala Asp Lys Ser Thr Gly Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Asn Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Val Tyr Gly Gly Asn Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 215

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 215

Gln Val Gln Leu Val Gln Ser Gly Gly Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Ser Ser His

20 25 30

Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala His Asn Gly His Ala Ser Asn Ala Gln Lys Val

50 55 60

Glu Asp Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val His Ala Ala Leu Tyr Tyr Gly Met Asp Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 216

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 216

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Arg His

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Ser His Asp Gly Ser Val Lys Tyr Tyr Ala Asp Ser Met

50 55 60

Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Asn Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asp Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Leu Ser Tyr Gln Val Ser Gly Trp Phe Asp Pro Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 217

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 217

Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys

1 5 10 15

Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn

20 25 30

Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val

35 40 45

Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ile Asp Thr Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly

65 70 75 80

Leu Lys Thr Lys Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Gly

85 90 95

Ile Thr Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 218

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 218

Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Gly Ser Pro Gly Lys

1 5 10 15

Thr Val Thr Leu Pro Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser His

20 25 30

Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val

35 40 45

Ile Tyr Glu Asp Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Ser Ile Ser Gly

65 70 75 80

Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser

85 90 95

Ser asn Arg Trp Val Phe Gly Gly Thr Lys Leu Val Leu

100 105 110

<210> 219

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 219

Leu Pro Val Leu Thr Gln Pro Ala Ser Leu Ser Ala Ser Pro Gly Ala

1 5 10 15

Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Leu Asn Val Gly Ser

20 25 30

Tyr Arg Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Arg Pro Gln Tyr

35 40 45

Leu Leu Asn Tyr Lys Ser Asp Ser Asn Lys Gln Gln Ala Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly Ile

65 70 75 80

Leu Leu Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys

85 90 95

Met Ile TRP TYR Ser Ser Ala Val Val Phe Gly Gly Thr Lys Leu

100 105 110

Thr Val Leu

115

<210> 220

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 220

Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys

1 5 10 15

Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Asn Ile Ala Ser Asn

20 25 30

Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val

35 40 45

Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly

65 70 75 80

Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser

85 90 95

Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 221

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 221

Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala

20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser

50 55 60

Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105

<210> 222

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 222

Leu Pro Val Leu Thr Gln Ala Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Ser Asp Ile Gly Arg Lys Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ala Leu Val Ile Tyr

35 40 45

Ser Asp Arg Asp Arg Pro Ser Gly Ile Ser Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Asn Asn Ser Asp His

85 90 95

Tyr Val Phe Gly Ala Gly Thr Glu Leu Ile Val Leu

100 105

<210> 223

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 223

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Thr Leu Pro Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 224

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 224

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Gly Asn Ser

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met

35 40 45

Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly

50 55 60

Ser Gly Ala Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Thr Ile Pro Thr Phe

85 90 95

Ser Phe Gly Pro Gly Thr Lys Val Glu Val Lys

100 105

<210> 225

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 225

Asp Ile Val Met Thr Gln Thr Pro Ser Phe Leu Ser Ala Ser Ile Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Arg Pro Gly Glu Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Asn Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 226

<211> 105

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 226

Gln Ser Ala Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Asn Ile Pro Cys Ser Gly Asp Lys Leu Gly Asn Lys Tyr Ala

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Leu Ile Tyr

35 40 45

Gln Asp Ile Lys Arg Pro Ser Arg Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Ala Asp Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Asn Ser Val Val Phe

85 90 95

Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 227

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 227

Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys

1 5 10 15

Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Asp Ser Asn

20 25 30

Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val

35 40 45

Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly

65 70 75 80

Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser

85 90 95

Asn Asn Arg His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 228

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 228

Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys

1 5 10 15

Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Asn Ile Gly Thr Asn

20 25 30

Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Val Ala Leu

35 40 45

Ile Tyr Glu Asp Tyr Arg Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Ile Ile Ser Gly

65 70 75 80

Leu Lys Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr His Ser

85 90 95

Ser Gly Trp Glu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 229

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 229

Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Gly Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 230

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 230

Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys

1 5 10 15

Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn

20 25 30

Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val

35 40 45

Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly

65 70 75 80

Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser

85 90 95

Thr Thr Pro Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 231

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 231

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Thr Ser Pro His Asn Gly Leu Thr Ala Phe Ala Gln Ile Leu

50 55 60

Glu Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Asn Leu Thr Phe Asp Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Lys Val His Pro Val Phe Ser Tyr Ala Leu Asp Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 232

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 232

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Met Asn Pro Gly Ser

1 5 10 15

Ser Val Arg Val Ser Cys Arg Gly Ser Gly Gly Asp Phe Ser Thr Tyr

20 25 30

Ala Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Tyr Gly Ser Asp Pro Val Leu Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 233

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 233

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Val

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Gly Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Phe Arg Lys Pro Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 234

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 234

Glu Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Phe Asn Asp Gly Thr Lys Tyr Asn Glu Met Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Ala Trp Gly Tyr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 235

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 235

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Phe Asn Asp Gly Thr Lys Tyr Asn Glu Met Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Ala Trp Gly Tyr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 236

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 236

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Phe Asn Asp Gly Thr Lys Tyr Asn Glu Met Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Ala Trp Gly Tyr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 237

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 237

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Phe Asn Asp Gly Thr Lys Tyr Asn Glu Met Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Ala Trp Gly Tyr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 238

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 238

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Phe Asn Asp Gly Thr Lys Tyr Asn Glu Met Phe

50 55 60

Lys Gly Arg Ala Thr Ile Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Ala Trp Gly Tyr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 239

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 239

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Val Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Ser Val Asp Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Ser Leu Glu Glu Glu Asp Ala Ala Met Tyr Phe Cys Gln Gln Ser Arg

85 90 95

Arg Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 240

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 240

Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Val Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Ser Val Asp Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Ser Leu Glu Ala Glu Asp Ala Ala Met Tyr Phe Cys Gln Gln Ser Arg

85 90 95

Arg Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 241

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 241

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Val Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Ser Val Asp Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Ser Leu Glu Ala Glu Asp Ala Ala Met Tyr Phe Cys Gln Gln Ser Arg

85 90 95

Arg Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 242

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 242

Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Val Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Ser Val Asp Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Phe Cys Gln Gln Ser Arg

85 90 95

Arg Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 243

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 243

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Thr Ile Tyr Asp Ser Ser Gly Tyr Ser Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 244

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 244

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Gly Ser Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Ser Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Leu Phe Pro His Ile Tyr Gly Asn Tyr Tyr Gly Met Asp

100 105 110

Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 245

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 245

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Val Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 246

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 246

Glu Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Ala Val Ile

35 40 45

Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly

85 90 95

Gln Trp Leu Val Thr Glu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 247

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 247

Glu Val Gln Leu Val Glu Ser Gly Ser Glu Val Glu Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Ser

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Met Phe Ala Thr Pro Tyr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Gly Leu Arg Ser Asp Asp Thr Ala Val Phe Tyr Cys

85 90 95

Ala Arg Asp Arg Gly Arg Gly His Leu Pro Trp Tyr Phe Asp Leu Trp

100 105 110

Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 248

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 248

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Pro Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 249

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 249

Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Arg Tyr

20 25 30

Ala Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Val

35 40 45

Gly Ala Ile Ile Pro Ile Phe Gly Thr Pro His Tyr Ser Lys Lys Phe

50 55 60

Gln Asp Arg Val Ile Ile Thr Val Asp Thr Ser Thr Asn Thr Ala Phe

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Phe Glu Asp Thr Ala Leu Tyr Phe Cys

85 90 95

Ala Arg Gly His Asp Glu Tyr Asp Ile Ser Gly Tyr His Arg Leu Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 250

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 250

Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Gly Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asp Pro Asn Ser Gly Val Thr Asn Tyr Val Arg Arg Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Leu Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Gly Leu Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Asn Leu Trp Gln Phe Gly Tyr Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 251

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 251

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Leu Ile Pro Ile Val Ser Met Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Ser Ile Thr Thr Asp Lys Ser Thr Gly Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ser Val Gly Gln Gln Leu Pro Trp Val Phe Phe Ala Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 252

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 252

Gln Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 253

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 253

Glu Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 254

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 254

Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Gly Met His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Ile His Ala Asp Ser Val

50 55 60

Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Thr Asp Arg Lys Trp Leu Ala Trp His Gly Met Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 255

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 255

GLU VAL GLN LEU VAL GLN SER GLA GLU VAL LYS LYS PRO GLY SER

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Ile Val Ala Asp Phe Gln His Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 256

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 256

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Ser Arg Tyr

20 25 30

Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Val Pro Phe Phe Gly Ala Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Leu Thr Ile Ala Asp Lys Ser ser thr Ser Tyr

65 70 75 80

Met Asp Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp His Phe Tyr Gly Ser Gly Gly Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 257

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 257

Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Sers Lys Ala Ser Gly Tyr Phe asn Ser Tyr

20 25 30

Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Val Phe Gly Thr Ala Asn Tyr Ala Glu Ser Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Ala Asp His Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Asn Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

ALA Arg ASP Arg Trp HIS TYR GLU SERG PRO MET ASP Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 258

<211> 119

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 258

GLU VAL GLN LEU VALU SER GLY GLY LEU VAL Arg Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ala Cys Ala Ser Gly Phe Ser Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Arg Gly Leu Glu Glu Trp Ile

35 40 45

Ala Tyr Ile Ser Asp Ser Gly Gln Thr Val His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Ile Serg ASP ASN Thr Lys Asn Ser Leu Phe

65 70 75 80

Leu Gln Val Asn Thr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Asp Leu Leu Gly Tyr Tyr Leu Gln Ser Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 259

<211> 131

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 259

Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn

20 25 30

Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu

35 40 45

Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala

50 55 60

Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn

65 70 75 80

Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val

85 90 95

Tyr Tyr Cys Ala Arg Asp Glu Pro Arg Ala Val Ala Gly Ser Gln Ala

100 105 110

Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr

115 120 125

Val Ser Ser

130

<210> 260

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 260

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Asp Gly Ser Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val His

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Leu Phe Pro His Ile Tyr Gly Asn Tyr Tyr Gly Met Asp

100 105 110

Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 261

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 261

Gln Met Gln Leu Val Gln 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 262

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 262

Gln Val Gln Leu Val Gln 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 263

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 263

Gln Ser Val Leu Thr Gln Pro Ser Val Ser Ala Ala Pro Gly Gln

1 5 10 15

Lys Val Thr Ile Ser Cys Ser Gly Asn Asn Ser Asn Ile Ala 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 Tyr Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Asp Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Val Trp Asp Gly Ser Leu

85 90 95

Thr Thr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 264

<211> 107

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 264

ALA ILE GLN MET ThR Gln Ser Pro Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Lys Pro Gly Lys Val Pro Leu Leu Ile

35 40 45

Tyr ALA ALA SER LEU GLU SER GLY VAL PRO SERG PHE SER GLY

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Leu Gln Pro

65 70 75 80

Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Leu His Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 265

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 265

Gln Pro Val Leu Thr Gln Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr

20 25 30

ASN PHE VAL SER TRP TYR Arg Gln HIS Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Asn Lys Arg Pro Gly Val Pro ASP Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

GLN ALA GLU ASP GLU ALA ASP TYR TYR CYS Ser Ser Tyr Ala Gly Thr

85 90 95

Asn Ser Leu Gly Ile Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 266

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 266

Gln Ser Val Val Thr Gln Pro Ser Val Ser Ala Ala Pro Gly Gln

1 5 10 15

Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asp Ile Gly Asn His

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 Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Ala Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asn Ser Leu

85 90 95

Ser Pro His Leu Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 267

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 267

Gln Ser Val Leu Thr Gln 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 Met Gly Asn Asn

20 25 30

Tyr Val Ser Trp Tyr Lys Gln Val Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Glu Asn Asp 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 Gly Thr Trp Asp Asn Ser Leu

85 90 95

Ser Gly Phe Val Phe Ala Ser Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 268

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 268

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Leu Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asp Val Gly Ser Tyr

20 25 30

Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Asn Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Ser Gly Val Ser Asn Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln

65 70 75 80

Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Gly Ile Ser

85 90 95

Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 269

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 269

Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr

20 25 30

Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Gly Phe

85 90 95

Asn Asn Leu Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 270

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 270

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ala Tyr

20 25 30

Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Arg Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Ser Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 271

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 271

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr

20 25 30

Asp Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Ile Phe Phe Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 272

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 272

Leu Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Thr Ser Asp Ile Gly Gly Tyr

20 25 30

ASP Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

GLN ALA GLU ASP GLU ALA ASP TYR TYR CYS Ser Ser Thr Ser Ser

85 90 95

Ser thr his her val phe gly thr leu thr val leu

100 105 110

<210> 273

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 273

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

ASN TYR VAL SER TRP TYR GLN HIS PRO GLY LYS ALA Pro LEU

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

GLN ALA GLU ASP GLU ALA ASP TYR TYR CYS Ser Ser Tyr Arg Ser Ser

85 90 95

Thr Leu Gly Pro Val Phe Gly Gly Thr Leu Thr Val Leu

100 105 110

<210> 274

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 274

Gln Ala Gly Leu Thr Gln Pro Ser Val Ser Glu Ala Pro Arg Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn

20 25 30

Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 275

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 275

Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

GLN ALA GLU ASP GLU ALA ASP TYR TYR CYS Ser Ser Thr Ser Ser

85 90 95

Thr Thr His Val Phe Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 276

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 276

Gln Ser Val Val Thr Gln 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 Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Val Trp Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu

100 105 110

<210> 277

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 277

Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Arg Ala Pro Arg Leu

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Gly Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Gly

85 90 95

Gly Thr Leu Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 278

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 278

Gln Ala Gly Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 279

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 279

Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Thr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 280

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 280

Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Arg Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Tyr Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Asp Ser

85 90 95

Ser Thr Arg Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 281

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 281

Gln Pro Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Ala Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Glu Ile Asn

20 25 30

Ser Val Asn 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 Gly Ser Trp Asp Ser Ser Leu

85 90 95

Ser Ala Asp Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 282

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 282

Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Lys

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 Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu

85 90 95

Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<120> 283

<211> 111

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 283

Gln Ser Val Val Thr Gln Pro Ser Val Ser Gly Ala Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly

20 25 30

Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu

35 40 45

Leu Ile Tyr Gly Asn Asn Asn Arg His Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Glu Phe Phe Cys Gly Thr Trp Asp Ser Arg

85 90 95

Leu Thr Thr Tyr Val Phe Gly Ser Gly Thr Lys Leu Thr Val Leu

100 105 110

<120> 284

<211> 110

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 284

Gln Ser Val Val Thr Gln 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 Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 285

<211> 103

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 285

Val Ile Trp Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ala Ala Ser Ser Leu Gln Ser Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser

35 40 45

Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

50 55 60

Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

65 70 75 80

Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln

85 90 95

Gly Thr Lys Leu Glu Ile Lys

100

<210> 286

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 286

Gln Ser Val Val Thr Gln 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 Val 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 Asn Ser Asp Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 287

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 287

Gln Ser Val Val Thr Gln 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 Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Ala Gly Ser Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 288

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 288

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 289

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 289

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 290

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 290

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 291

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 291

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 292

<211> 447

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 292

Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 293

<211> 440

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 293

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser

115 120 125

Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr

145 150 155 160

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Ser Gly Leu Tyr

165 170 175

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys

180 185 190

Thr Tyr Thr Cys ASN Val Asp His Lys Pro ASN Thr Lys Val Asp

195 200 205

Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

210 215 220

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

225 230 235 240

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

245 250 255

Val ASP Val Ser Gln Asp Pro Glu Val Gln Phe ASN TRP TYR VAL

260 265 270

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

275 280 285

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

290 295 300

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

305 310 315 320

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

325 330 335

Arg Glu Pro Gln Val Thr Leu Pro Ser Gln Glu Glu Met Thr

340 345 350

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

355 360 365

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

370 375 380

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

385 390 395 400

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

405 410 415

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

420 425 430

Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 294

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 294

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Leu His Trp Tyr Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val ASP Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 295

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 295

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 296

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 296

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys

115 120

<210> 297

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 297

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 298

<211> 447

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 298

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

<210> 299

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 299

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 300

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 300

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val PHE ILE PRE PRO SER ASP GLU GLN LEU LYS SER GLY

115 120 125

Thr Ala Ser Val Cys Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

GLU Ser Val Thr Glu Gln Asp Ser Lys Asp Ser thr Tyr Ser Leu Ser

165 170 175

Ser thr Leu Thr Leu Ser Lys Ala ASP TYR GLU LYS HIS LYS VAL TYR

180 185 190

ALA CYS GLU VAL THR HIS GLN GLY LEU SER SER PRO VAL THR LYS SER

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 301

<211> 121

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 301

GLU VAL GLN LEU Val GLU SER GLY GLY LEU VAL GLN Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe Thr Phe Ser Arg Phe

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

ALA ASN Ile ASN GLN ASP Gly Thr 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 Gly Asp Thr Ala Val Tyr Tyr Cys

85 90 95

ALA asn Thr Tyr Tyr Asp Phe Trp Ser Gly His Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 302

<211> 121

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 302

GLN GLU HIS LEU Val Glu Ser Gly Gly Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe THR PHE SER asn PHE

20 25 30

Gly MET HIS TRP Val Arg Gln Ala Pro Lys Gly Leu Glu Trp Val

35 40 45

Ala Ala Leu Trp Ser Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Val 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 Arg Gly Arg Gly Ala Pro Ile Pro Ile Phe Gly Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 303

<211> 130

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 303

GLU VAL GLN LEU VALU SER GLY GLY LEU VAL LYS Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe THR PHE SER asn Ala

20 25 30

TRP MET SER TRP Val Arg Gln Ala Pro Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Arg Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu His Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Ty

85 90 95

Tyr Cys Thr ASP Asp Ile Val Val Val Val Met Arg Glu

100 105 110

Tyr Tyr PHE Gly Met Asp Val Trp Gly Gln Gly Thr Val Thr Val

115 120 125

Ser Ser

130

<210> 304

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 304

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Thr Lys Lys Tyr Ala His Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asp Thr Ala Tyr

65 70 75 80

Met Ile Leu Ser Ser Leu Ile Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Asp Trp Asn Phe Gly Ser Trp Phe Asp Ser Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 305

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 305

Gln Val His Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly His Gly Leu Glu Trp Met

35 40 45

Gly Trp Leu Asn Pro Asn Thr Gly Thr Thr Lys Tyr Ile Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Thr Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Asp Trp Asn Tyr Gly Ser Trp Phe Asp Thr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 306

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 306

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Gly Met Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile His Trp His Gly Lys Arg Thr Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Leu Tyr His Cys

85 90 95

Val Arg Gly Gly Met Ser Thr Gly Asp Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val ile Val Ser.

115 120

<210> 307

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 307

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Gly Met Thr Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile His Trp Ser Gly Arg Ser Thr Gly Tyr Ala 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 Leu Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Met Ser Thr Gly Asp Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 308

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 308

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Gly Ser Asn

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Leu Thr Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Ile Arg Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr

100 105 110

Val Ser Ser

115

<210> 309

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 309

Glu Glu Arg Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Gly Thr Asn

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Gly Gly Asn Thr His Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Ile Met Ser Arg Gln Thr Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Glu Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Ile Arg Gly Leu Asp Val Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 310

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 310

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Met Pro Gly Ser

1 5 10 15

Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Ser Ser Ser

20 25 30

Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Glu Ile Ile Pro Val Phe Gly Thr Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Ile Phe Thr Ala Asp Glu Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Lys Ser Gly Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Asn Trp Gly Leu Gly Ser Phe Tyr Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 311

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 311

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val His Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Asp Glu Tyr

20 25 30

Ala Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Ser Asn Asn Asn Ile Gly Tyr Ala 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 Pro Glu Asp Thr Ala Phe Tyr Tyr Cys

85 90 95

Ala Lys Ser Gly Ile Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 312

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 312

Glu Val Gln Leu Val 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 Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Thr Leu Ile Ser Tyr Glu Gly Arg 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 Thr Leu Tyr Gly Met Asp Val Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 313

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 313

Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Thr Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Asn

20 25 30

Arg Met Cys Val Thr Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu

35 40 45

Trp Leu Ala Arg Ile Asp Trp Asp Gly Val Lys Tyr Tyr Asn Thr Ser

50 55 60

Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Phe Tyr

85 90 95

Cys Ala Arg Ser Thr Ser Leu Thr Phe Tyr Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 314

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 314

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Val Gly Thr Asn

20 25 30

His Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Tyr Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg His Thr Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Thr Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Leu Gly Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr

100 105 110

Val Ser Ser

115

<210> 315

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 315

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Arg Gly Glu

1 5 10 15

Ser Leu Arg Leu Tyr Cys Ala Ser Gly Phe Thr Phe Ser Lys Tyr

20 25 30

TRP MET ASN TRP VAL Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

ALA ASN Ile Lys Gly Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Ile Serg 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 ASP Tyr Trp Gly Ser Gly Tyr Tyr Phe Asp Phe Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 316

<211> 130

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 316

GLU VAL GLN LEU Val Glu Ser Gly Gly Leu Val Gln Ser Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

TRP MET SER TRP Val Arg Gln Ala Pro Lys Gly Leu Glu Trp Val

35 40 45

ALA ASN Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Ile Serg ASP ASN ALA LYS ASN Ser LEU TYR

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

ALA Arg ASP ASP Ile Val Val Pro Ala Pro Gly Tyr Tyr Tyr

100 105 110

Tyr Tyr PHE Gly Met Asp Val Trp Gly Gln Gly Thr Val Thr Val

115 120 125

Ser Ser

130

<210> 317

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 317

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Phe

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Thr Gly Gly Asn Met Asp Tyr Ala Asn Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Glu Asp Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Ala Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Val Lys Asp Ile Arg Gly Ile Val Ala Thr Gly Gly Ala Phe Asp Ile

100 105 110

Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 318

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 318

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Gly Thr Asn

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Gln Thr Ser Gln Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Ile Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 319

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 319

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Tyr Ser Ser Gly Ser Thr Tyr Tyr Ile Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Leu Thr Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Asn Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Ile Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 320

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 320

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asp Asp Ser

20 25 30

Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Lys Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val

50 55 60

Arg 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 Val Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Val Lys Asp Ile Arg Gly Asn Trp Asn Tyr Gly Gly Asn Trp Phe Asp

100 105 110

Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser

115 120

<210> 321

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 321

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Val Gly Val Asn

20 25 30

His Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Phe Ser Ser Gly Arg Thr Phe Tyr Gly Asp Tyr Val Lys

50 55 60

Gly Arg Leu Thr Ile Phe Arg Gln Thr Ser Gln Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Arg Gly Ile Gly Gly Leu Asp Ile Trp Gly Arg Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 322

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 322

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Ala Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Thr Gly Gly Thr Ile Asp Tyr Ala 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 Ser Ser Leu Arg Thr Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Thr Arg Asp Ile Arg Gly Asn Trp Lys Tyr Gly Gly Trp Phe Asp Pro

100 105 110

TRP Gly Gln Gly Thr Leu Val Thr Val Ser

115 120

<210> 323

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 323

Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Asp Trp Met

35 40 45

Gly Trp Ile Ser Pro Asn Ser Gly Phe Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Phe Tyr

65 70 75 80

Met Glu Leu Ser Gly Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Ser Thr His His Asn Ser Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 324

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 324

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Gly Thr Asn

20 25 30

Phe Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Tyr Ser Gly Gly Thr Ala Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Arg Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Gly Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

100 105 110

Ser Ser

<210> 325

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 325

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Thr Tyr

20 25 30

Val Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Glu Ile Ile Pro Ile Leu Gly Ala Ala Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Phe Thr Thr Asp Glu Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Thr Ser Gly Gly Phe Asp Pro Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 326

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 326

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Glu Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr His Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val

35 40 45

Gly Trp Ile Ser Pro Tyr Asn Gly Tyr Thr Asp Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Leu Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Asn Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ser Arg Gly Arg Gly Pro Tyr Trp Ser Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 327

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 327

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Ser Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Glu Ile Lys

100 105

<210> 328

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 328

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Ala Ile Lys

100 105

<210> 329

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 329

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Asn Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 330

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 330

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Leu Val His Gly

20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Ile Gln Gln Arg Pro Gly Gln Pro

35 40 45

Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Gln Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Leu Tyr Phe Cys Met Gln Ala

85 90 95

Thr His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105 110

<210> 331

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 331

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Pro Ser Leu Val His Ser

20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro

35 40 45

Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Thr His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Arg

100 105 110

<210> 332

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 332

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 333

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 333

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 334

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 334

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Asn Ile Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Ser Tyr Ser Thr Pro Pro

85 90 95

Ile Thr Phe Gly Glyn Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 335

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 335

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Met Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Ile

35 40 45

Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro

85 90 95

Ile Thr Phe Gly Glyn Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 336

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 336

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Asn Phe Asn

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Gly Val Phe Tyr Cys Gln Gln Tyr Glu Ser Ala Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 337

<211> 105

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 337

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Leu Leu Ile Tyr Ala Ala

35 40 45

Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Ser

50 55 60

Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Arg Pro Glu Asp Phe

65 70 75 80

Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Cys Thr Pro Pro Ile Thr Phe

85 90 95

Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 338

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 338

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro

85 90 95

Ile Thr Phe Gly Glyn Gly Thr Arg Leu Glu Ile Lys

100 105

<120> 339

<211> 91

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 339

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Ser Asn Tyr

1 5 10 15

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Arg Leu Leu Ile

20 25 30

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

35 40 45

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

50 55 60

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Arg

65 70 75 80

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

85 90

<120> 340

<211> 107

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 340

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Asn Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Phe Gln Asn Ala Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Thr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 341

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 341

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 342

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 342

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro

85 90 95

Ile Thr Phe Gly Glyn Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 343

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 343

Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Lys Pro Asp Glu Thr

1 5 10 15

Leu Thr Ile Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Gly

20 25 30

Leu Thr Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Ile Gly

35 40 45

Thr Ile Asn Lys Asp Ala Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Gly

50 55 60

Arg Leu Thr Ile Ser Lys Pro Ser Ser Thr Lys Val Asp Leu Lys Ile

65 70 75 80

Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Gly Arg Ile

85 90 95

Ala Phe Lys Thr Gly Thr Ser Ile Trp Gly Pro Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 344

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 344

Ala Ile Val Met Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Val Tyr Ser Asn

20 25 30

Asn Tyr Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

35 40 45

Leu Ile Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val

65 70 75 80

Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ile Gly Gly Lys Ser Ser

85 90 95

Ser Thr Asp Gly Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Arg

100 105 110

<210> 345

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 345

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asn Ile Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 346

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 346

Gln Pro Val Leu Thr Gln 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 Ala 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 PHE ALA ASN LYS Arg Pro Gly Ile Pro ASP Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Leu Asp Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Asp Leu

85 90 95

Arg Ala Gly Val Phe Gly Gly Thr Leu Thr Val Leu

100 105 110

<210> 347

<211> 123

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 347

GLU VAL GLN LEU VAL GLN SER GLA GLU VAL LYS LYS PRO GLY SER

1 5 10 15

Ser Val Lys Val Sers Lys Ala Ser Gly Thr Phe Ser Ser Tyr

20 25 30

ALA ILE SER TRP VAL Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Gly Thr Ala asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Ala Asp Lys Ser thr Thr Ala Tyr

65 70 75 80

MET GLU LEU Ser LeU Arg Serg Asp Thr Ala Val Tyr Tyr Cys

85 90 95

ALA Arg Glu Gly Thr Ile Tyr Asp Ser Ser Gly Tyr Ser Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 348

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 348

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

ALA VAL ILE SER PHE ASP Gly Ser asn Lys Tyr Tyr Ala ASP Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 349

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 349

Glu Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

ALA VAL ILE SER PHE ASP Gly Ser asn Lys Tyr Tyr Ala ASP Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 350

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 350

Gln Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 351

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 351

Glu Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 352

<211> 118

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 352

Glu Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 353

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 353

Gln Val Gln Leu Val 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val ser

115

<210> 354

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 354

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Leu Ile Pro Ile Val Ser Met Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Ser Ile Thr Thr Asp Lys Ser Thr Gly Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ser Val Gly Gln Gln Leu Pro Trp Val Phe Phe Ala Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val ser

115 120

<210> 355

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 355

Gln Met Gln Leu Val Gln 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val ser

115

<210> 356

<211> 118

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 356

Gln Val Gln Leu Val Gln 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 Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Arg 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 Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val ser

115

<210> 357

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 357

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Tyr Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ser Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro Ile Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 358

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 358

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Tyr Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro Ile Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 359

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 359

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Tyr Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ser Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro Ile Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 360

<211> 121

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 360

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ala Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro Ile Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 361

<211> 108

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 361

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<120> 362

<211> 107

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 362

Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Thr Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ser Thr Trp

85 90 95

Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys

100 105

<210> 363

<211> 110

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 363

Gln Ser Val Leu Thr Gln Pro Ser Val Ser Ala Pro Gly Gln

1 5 10 15

LYS VAL THR ILE SER CYS SER ASN ASN SER ASN ILA ALA ASN

20 25 30

Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Leu Leu

35 40 45

Ile Tyr Asp Asn Asn Tyr Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Asp Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala ASP Tyr Tyr Cys Gly Val Trp Asp Gly Ser Leu

85 90 95

Thr Thr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 364

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 364

Leu Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Thr Ser Asp Ile Gly Gly Tyr

20 25 30

Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr His Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 365

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 365

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

ASN TYR VAL SER TRP TYR GLN HIS PRO GLY LYS ALA Pro LEU

35 40 45

Met Ile Tyr ASP Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Arg Ser Ser

85 90 95

Thr Leu Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 366

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 366

Gln Ala Gly Leu Thr Gln Pro Ser Val Ser Glu Ala Pro Arg Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser asn Ile Gly ASN

20 25 30

Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala TRP ASP ASP Ser Leu

85 90 95

Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 367

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 367

Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Thr Thr His Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 368

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 368

Gln Ser Val Val Thr Gln 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 Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Val Trp Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu

100 105 110

<210> 369

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 369

Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Arg Ala Pro Arg Leu

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Gly Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Gly

85 90 95

Gly Thr Leu Gly Pro Gly Gly Gly Thr Leu Thr Val Leu

100 105 110

<210> 370

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 370

GLN SER VAL THR GLN PRO SER VAL SERA ALA PRO GLY GLN

1 5 10 15

LYS VAL THR ILE SER CYS SER Gly Ser Ser asn Ile Gly 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 Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 371

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 371

GLN SER VAL THR GLN PRO SER VAL SERA ALA PRO GLY GLN

1 5 10 15

LYS VAL THR ILE SER CYS SER Gly Ser Ser asn Ile Gly ASN

20 25 30

Tyr Val Ser Trp Tyr Gln Gln Val 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 Asn Ser Asp Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 372

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 372

Gln Ser Val Val Thr Gln 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 Leu Leu

35 40 45

Ile Tyr ASP ASN LYS Arg Pro Ser Gly Ile Pro 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 Gly Thr Trp Asp Ser Leu

85 90 95

Ser Ala Gly Ser Val Val Phe Gly Gly Thr Leu Thr Val Leu

100 105 110

<210> 373

<211> 108

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 373

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr ASP Ser ASP Arg Pro Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 374

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 374

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 375

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 375

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 376

<211> 108

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 376

Ser Tyr Glu Leu Met Gln Pro Ser Val Ser Val Ala Pro Gly Lys

1 5 10 15

Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Tyr Asp Ser Asp 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 Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<120> 377

<211> 122

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 377

Gln Val Gln Leu Val Gln Ser Gly Ser Glu Val Lys Lys Ser Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Gly Thr Phe Ser Ile Thr

20 25 30

Asn Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu

35 40 45

Trp Met Gly Gly Ile Leu Pro Ile Phe Gly Ala Ala Lys Tyr Ala Gln

50 55 60

Lys Phe Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr

65 70 75 80

Ala Tyr Leu Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Met Tyr

85 90 95

Tyr Cys Ala Arg Gly Lys Arg Trp Leu Gln Ser Asp Leu Gln Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 378

<211> 110

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 378

Gln Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Ser Ser Ser Asp Val Gly Ser Tyr

20 25 30

Asp Leu Val Ser Trp Tyr Gln Gln Ser Pro Gly Lys Val Pro Lys Leu

35 40 45

Leu Ile Tyr Glu Gly Val Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Thr

85 90 95

Arg Asn Phe Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu

100 105 110

<210> 379

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 379

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Ile Serg 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 SER SER GLY GLN SERG PRO GLY PHE ASP TYR TRP Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 380

<211> 121

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 380

GLU VAL GLN LEU LEU GLU SER GLY GLY LEU Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

ALA MET SER TRP Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala 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 SER SER GLY GLN SER TRP PRE GLY PHE ASP Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 381

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 381

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala 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 Ser Ser Ala Gly Gln Ser Phe Pro Gly Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 382

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 382

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala 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 Trp Ser Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 383

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 383

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala 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 Trp Ser Ala Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 384

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 384

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala 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 Trp Ser Lys Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 385

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 385

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

ALA MET SER TRP Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser ser Ile TRP Lys Gln Gly Ile Val Thr Val Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

GLN MET ASN SER LEU ARG ALU ASP Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val

<210> 386

<211> 115

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 386

GLU VAL GLN LEU LEU GLU SER GLY GLY LEU Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

ALA MET SER TRP Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser ser Ile TRP Arg Asn Gly Ile Val Thr Val Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Serg ASP ASN Ser Lys ASN Thr Leu Tyr Leu

65 70 75 80

GLN MET ASN SER LEU ARG ALU ASP Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 387

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 387

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Asp Ile Trp Lys Gln Gly Met Val Thr Val Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 388

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 388

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Arg Gln Gly Leu Ala Thr Ala Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 389

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 389

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Val Ala Thr Gly Ile Leu Thr Ser Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 390

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 390

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Gly Arg Gln Gly Leu Ile Thr Val Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 391

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 391

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Tyr Gln Gly Leu Val Thr Val Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 392

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 392

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Asp Ile Trp Lys Gln Gly Phe Ala Thr Ala Asp Ser Val Lys Gly

50 55 60

Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln

65 70 75 80

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys

85 90 95

Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 393

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 393

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Lys Gln Gly Ile Val Thr Val Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 394

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 394

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Arg Gln Gly Leu Ala Thr Ala Tyr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Lys Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 395

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 395

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Arg Asn Gly Ile Val Thr Val 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 Trp Ser Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 396

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 396

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Arg Asn Gly Ile Val Thr Val 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 Trp Ser Ala Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 397

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 397

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Arg Asn Gly Ile Val Thr Val 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 Trp Ser Lys Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 398

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 398

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Glu Thr Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

35 40 45

Trp Val Ser Ser Ile Trp Tyr Gln Gly Leu Val Thr Val Tyr Ala Asp

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Glu Thr Asn Ser Leu Arg Ala Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Lys Trp Ser Ala Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 399

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 399

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Tyr Gln Gly Leu Val Thr Val 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 Trp Ser Ala Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 400

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 400

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Trp Tyr Gln Gly Leu Val Thr Val 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 Trp Ser Lys Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 401

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 401

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Asn Gly Tyr Pro Ser

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 402

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 402

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Asn Gly Tyr Pro Ser

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 403

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 403

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Asn Gly Tyr Pro Ser

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105

<210> 404

<211> 240

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 404

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Asp Ile Thr Ala Ser Gly Gln Arg Thr Thr 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 Arg Ser Lys Ile Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser

145 150 155 160

Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Lys Ala Ser Arg Leu Gln Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ala

210 215 220

Leu Lys Pro Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

225 230 235 240

<210> 405

<211> 240

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 405

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Asn Lys Asp Gly His Tyr Thr Ser 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 Asn Leu Asp Glu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser

145 150 155 160

Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr

210 215 220

Ser Thr Pro Asn Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

225 230 235 240

<210> 406

<211> 240

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 406

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Met Ala Thr Gly Ala Gly Thr Leu 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 Gly Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser

145 150 155 160

Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Ser Ala Ser Gln Leu Gln Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn

210 215 220

Ser Arg Pro Ser Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

225 230 235 240

<210> 407

<211> 240

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 407

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val

35 40 45

Ser Thr Ile Thr Ser Ser Gly Ala Ala Thr 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 Asn Tyr Thr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser

145 150 155 160

Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asn Ala Ser Ser Leu Gln Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Thr

210 215 220

Tyr Gly Pro Gly Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

225 230 235 240

<210> 408

<211> 240

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 408

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Tyr Ser Thr Gly Gly Ala Thr Ala 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 Ser Ser Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser

145 150 155 160

Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Asn

210 215 220

Gly Tyr Pro Ser Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

225 230 235 240

<210> 409

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 409

Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Met Phe Tyr Ile Ser

20 25 30

Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Thr Ile Thr Ser Gly Gly Thr Thr Asn Tyr Ala Asp Ser Val Glu

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

85 90 95

Ala His Gly Pro Thr Tyr Gly Ser Thr Trp Asp Asp Leu Trp Gly Gln

100 105 110

Gly Thr Gln Val Thr Val Lys Pro Gly Gly

115 120

<210> 410

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 410

Gly Ile Met Phe Tyr Ile Ser Asp

15

<210> 411

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 411

Thr Ile Thr Ser Gly Gly Thr Thr Asn Tyr

1 5 10

<210> 412

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 412

Thr Ala His Gly Pro Thr Tyr Gly Ser Thr Trp Asp Asp Leu

1 5 10

<210> 413

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 413

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Thr Phe Gly Val Val Phe

20 25 30

Thr Leu Gly Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Val Thr Gly Thr Asp Thr Val Asp Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ser Asp Phe Ala Arg Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Thr Gly Ala Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Lys Pro Gly

100 105 110

gly

<210> 414

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 414

Thr Phe Gly Val Val Phe Thr

15

<210> 415

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 415

Val Thr Gly Thr Asp Thr Val

15

<210> 416

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 416

Asn Thr Gly Ala Tyr

15

<210> 417

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 417

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Thr Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ala Ser Thr Tyr

20 25 30

Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Gln Phe Val

35 40 45

Ala Arg Ile Ile Trp Ser Thr Gly Ser Thr Tyr Tyr Thr Asn Ser Val

50 55 60

Glu Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ala Arg Glu Pro Thr Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Gln

100 105 110

Val Thr Val Lys Pro Gly Gly

115

<210> 418

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 418

Gly Arg Thr Ala Ser Thr Tyr Ser

15

<210> 419

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 419

Ile Trp Ser Thr Gly Ser Thr

15

<210> 420

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 420

Thr Ala Arg Glu Pro Thr Gly Tyr Asp Tyr

1 5 10

<210> 421

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 421

Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Gly Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Arg Phe Gly

20 25 30

Ala Arg Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Ile Ile Thr Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Gln

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Ser Gly Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Asp Arg Ser Asp Ala Val Gly Val Gly Trp Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Gln Val Thr Val Lys Pro Gly Gly

115 120

<210> 422

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 422

Gly Ser Ile Phe Arg Phe Gly Ala

15

<210> 423

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 423

Ile Thr Ser Gly Gly Ser Thr

15

<210> 424

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 424

Ala Ala Asp Arg Ser Asp Ala Val Gly Val Gly Trp Asp Tyr

1 5 10

<210> 425

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 425

Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Thr Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ala Ser Thr Tyr

20 25 30

Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Gln Phe Val

35 40 45

Ala Arg Ile Ile Trp Ser Thr Gly Ser Thr Tyr Tyr Thr Asn Ser Val

50 55 60

Glu Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ala Arg Asp Pro Thr Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Gln

100 105 110

Val Thr Val Lys Pro Gly Gly

115

<210> 426

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 426

Ile Ile Trp Ser Thr Gly Ser Thr

15

<120> 427

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 427

Thr Ala Arg Asp Pro Thr Gly Tyr Asp Tyr

1 5 10

<120> 428

<211> 121

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 428

Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser Ile Asp

20 25 30

Ala Thr Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Ile Ile Thr Ser Ser Gly Ser Thr Asn Tyr Pro Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Leu Tyr Ser Cys Asn

85 90 95

Ala Ile Thr Arg Met Gly Gly Ser Thr Tyr Asp Phe Trp Gly Gln Gly

100 105 110

Thr Gln Val Thr Val Lys Pro Gly Gly

115 120

<120> 429

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 429

Gly Ser Ile Phe Ser Ile Asp Ala

15

<210> 430

<211> 7

<122> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 430

Ile Thr Ser Ser Gly Ser Thr

15

<120> 431

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 431

Asn Ala Ile Thr Arg Met Gly Gly Ser Thr Tyr Asp Phe

1 5 10

<210> 432

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 432

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Pro Ala Gly Asp Gly Ser Thr Lys Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Lys Ser Arg Gly Trp Ser Thr Val Asp Asp Met Asp Tyr Trp Gly

100 105 110

Lys Gly Thr Gln Val

115

<210> 433

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 433

Gly Phe Thr Phe Ser Ser Tyr Ala

15

<210> 434

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 434

Ile Pro Ala Gly Asp Gly Ser Thr

15

<210> 435

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 435

Ala Lys Ser Arg Gly Trp Ser Thr Val Asp Asp Met Asp Tyr

1 5 10

<210> 436

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 436

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Val Ser Gly Phe Thr Phe Arg Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Thr Ile Asn Ser Gly Glu Ser Ser Thr Lys Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Asp Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Lys His Arg Gly Trp Ser Thr Val Asp Asp Ile Asn Tyr Trp Gly

100 105 110

Lys Gly Thr Gln Val

115

<210> 437

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 437

Gly Phe Thr Phe Arg Ser Tyr Ala

15

<210> 438

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 438

Ile Asn Ser Gly Glu Ser Ser Thr

15

<210> 439

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 439

Ala Lys His Arg Gly Trp Ser Thr Val Asp Asp Ile Asn Tyr

1 5 10

<210> 440

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 440

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp His

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Trp Asn Gly His Tyr Thr Tyr Tyr Ala Glu Ser Met

50 55 60

Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Lys Gly Trp Arg Gly Ser Tyr Thr Arg Asp Arg Pro Phe Ala Ser

100 105 110

Trp Gly Gln Gly Thr Gln Val

115

<210> 441

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 441

Gly Phe Thr Phe Asp Asp His Ala

15

<210> 442

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 442

Ile Ser Trp Asn Gly His Tyr Thr

15

<210> 443

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 443

Val Lys Gly Trp Arg Gly Ser Tyr Thr Arg Asp Arg Pro Phe Ala Ser

1 5 10 15

<210> 444

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 444

Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Thr Ile Ser Thr Asn Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Tyr

50 55 60

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Glu Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

85 90 95

Gln Tyr Tyr Cys Val Arg Thr Arg Trp Glu Gly Val Tyr Asp Tyr Trp

100 105 110

Gly Leu Gly Thr Gln Val

115

<210> 445

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 445

Gly Phe Thr Phe Ser Ser Tyr Tyr

15

<210> 446

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 446

Ile Ser Thr Asn Thr Gly Gly Gly Ser Thr

1 5 10

<210> 447

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 447

Val Arg Thr Arg Trp Glu Gly Val Tyr Asp Tyr

1 5 10

<210> 448

<211> 482

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 448

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ile Asn

20 25 30

Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Arg Arg Glu Phe Val

35 40 45

Ala Ala Ile Glu Ser Gly Arg Asn Thr Val Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly

85 90 95

Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser Val Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly Gly Gly Asp Lys Thr

115 120 125

His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu

130 135 140

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

145 150 155 160

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

165 170 175

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

180 185 190

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

195 200 205

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

210 215 220

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

225 230 235 240

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

245 250 255

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

260 265 270

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

275 280 285

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

290 295 300

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

305 310 315 320

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

325 330 335

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ser Gly Gly Gly

340 345 350

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly

355 360 365

Gly Glu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser

370 375 380

Gly Phe Ser Phe Ser Ile Asn Ala Met Gly Trp Tyr Arg Gln Ala Pro

385 390 395 400

Gly Lys Arg Arg Glu Phe Val Ala Ala Ile Glu Ser Gly Arg Asn Thr

405 410 415

Val Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

420 425 430

Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp

435 440 445

Thr Ala Val Tyr Tyr Cys Gly Leu Leu Lys Gly Asn Arg Val Val Ser

450 455 460

Pro Ser Val Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro

465 470 475 480

Gly Gly

<210> 449

<211> 466

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 449

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe

130 135 140

Ser Phe Ser Ile Asn Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys

145 150 155 160

Arg Arg Glu Phe val Ala Ile Glu Ser Gly Arg Asn Thr Val Ty

165 170 175

ALA GLU SER VAL LYS GLY Arg PHE THR ILE SERG ASP ASN ALA LYS

180 185 190

Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala

195 200 205

Val Tyr Tyr Cys Gly Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser

210 215 220

VAL ALA TYR TRP GLY GLN THR LEU VAL VAL LYS Pro Gly Gly

225 230 235 240

Gly Gly ASP Lys Thr Hi Cys Pro Cys Pro Ala Pro Gly Gly

245 250 255

Pro Ser Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile

260 265 270

Ser Arg Thr Pro Glu Val Thr Cys Val Val Asp Val Ser His Glu

275 280 285

ASP Pro Glu Val Lys Phe ASN TRP Tyr Val Asp Gly Val Glu Val HIS

290 295 300

ASN ALA Lys Thr Lys Pro Arg Glu Glu Gln Tyr asn Ser Thr Tyr Arg

305 310 315 320

Val Val Ser Val Leu Val Leu His Gln Asp Trp Leu Asn Gly Lys

325 330 335

GLU TYR LYS CYS LYS VALSN LYS ALA LEU PRO ALA PRO ILE GLU

340 345 350

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

355 360 365

Thr Leu Pro Ser Arg ASP GLU LeU Thr Lys Asn Gln Val Ser Leu

370 375 380

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

385 390 395 400

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

405 410 415

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

420 425 430

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

435 440 445

GLU ALA LeU HISN HIS TYR ThR GLN LYS SER LEU SER LEU Ser Pro

450 455 460

Gly Lys

465

<210> 450

<211> 466

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 450

GLU VAL GLN LEU LEU GLU SER GLY GLY GLU Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Gly Gly Ile Phe Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val PHE GLU TYR TRP GLY GLN ThR Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe

130 135 140

Ser Phe Ser Ile Asn Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys

145 150 155 160

Arg Arg Glu Phe val Ala Ile Tyr Ser Gly Arg ASN Thr Val Ty

165 170 175

Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

180 185 190

Asn Thr Val Tyr Leu Gln Met Ser Leu Arg Ala Glu Asp Thr Ala

195 200 205

Val Tyr Tyr Cys Gly Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser

210 215 220

VAL ALA TYR TRP GLY GLN THR LEU VAL VAL LYS Pro Gly Gly

225 230 235 240

Gly Gly ASP Lys Thr Hi Cys Pro Cys Pro Ala Pro Gly Gly

245 250 255

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

260 265 270

Ser Arg Thr Pro Glu Val Thr Cys Val Val Asp Val Ser His Glu

275 280 285

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

290 295 300

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

305 310 315 320

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

325 330 335

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

340 345 350

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

355 360 365

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

370 375 380

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

385 390 395 400

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

405 410 415

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

420 425 430

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

435 440 445

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

Gly Lys

465

<210> 451

<211> 466

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 451

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

130 135 140

Ser Phe Ser Ile Asn Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys

145 150 155 160

Arg Arg Glu Phe Val Ala Ala Ile Tyr Ser Gly Ser Ser Thr Val Tyr

165 170 175

Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

180 185 190

Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala

195 200 205

Val Tyr Tyr Cys Gly Leu Leu Lys Gly Asn Arg Val Val Ser Pro Ser

210 215 220

Val Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly

225 230 235 240

Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly

245 250 255

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

260 265 270

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

275 280 285

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

290 295 300

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

305 310 315 320

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

325 330 335

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

340 345 350

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

355 360 365

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

370 375 380

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

385 390 395 400

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

405 410 415

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

420 425 430

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

435 440 445

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

Gly Lys

465

<210> 452

<211> 481

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 452

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr Gly

145 150 155 160

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser

165 170 175

Arg Leu Ala Trp Gln Gly Gly Ser Thr Asp Tyr Val Glu Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

195 200 205

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

210 215 220

Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr Tyr

225 230 235 240

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly Gly

245 250 255

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro

260 265 270

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

275 280 285

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

290 295 300

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

305 310 315 320

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

325 330 335

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

340 345 350

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

355 360 365

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

370 375 380

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

385 390 395 400

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

405 410 415

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

420 425 430

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

435 440 445

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

450 455 460

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

465 470 475 480

Lys

<210> 453

<211> 481

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 453

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr Gly

145 150 155 160

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser

165 170 175

Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

195 200 205

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

210 215 220

Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr Tyr

225 230 235 240

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly Gly

245 250 255

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro

260 265 270

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

275 280 285

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

290 295 300

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

305 310 315 320

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

325 330 335

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

340 345 350

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

355 360 365

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

370 375 380

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

385 390 395 400

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

405 410 415

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

420 425 430

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

435 440 445

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

450 455 460

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

465 470 475 480

Lys

<210> 454

<211> 481

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 454

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Ser Asn Tyr Gly

145 150 155 160

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser

165 170 175

Arg Leu Ala Trp Gly Gly Gly Ser Thr Asp Tyr Val Glu Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

195 200 205

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

210 215 220

Arg Gln Arg Ser Tyr Arg Tyr Asp Ile Arg Thr Pro Gln Thr Tyr

225 230 235 240

ASP Tyr TRP GLY GLN GLY LEU VAL THR VAL LYS Pro Gly Gly Gly

245 250 255

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro

260 265 270

Ser Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

275 280 285

Arg Thr Pro Glu Val Thr Cys Val Val Asp Val Ser His Glu ASP

290 295 300

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

305 310 315 320

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

325 330 335

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

340 345 350

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

355 360 365

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

370 375 380

Leu Pro Pro Serg ASP GLU Leu Lys Asn Gln Val Ser Leu Thr

385 390 395 400

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

405 410 415

Ser asn Gly Gln Pro ASN ASN TYR LYS Thr Pro Pro val Leu

420 425 430

ASP Ser ASP Gly Ser Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

435 440 445

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

450 455 460

ALA LeU HISN HIS TYR THR GLN LYS SER LEU Ser Leu Ser Pro Gly

465 470 475 480

Lys

<210> 455

<211> 481

<212> PRT

<213> Artificial sequence

<220>

<223> chemically synthesized

<400> 455

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser thr thr thr ser Ser gly Ala th Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Val PHE GLU TYR TRP GLY GLN ThR Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Gly Asn Tyr Gly

145 150 155 160

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser

165 170 175

Arg Leu Ala Trp Ser Gly Gly Ser Thr Asp Tyr Val Glu Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

195 200 205

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

210 215 220

Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr Tyr

225 230 235 240

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly Gly

245 250 255

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro

260 265 270

Ser Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

275 280 285

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

290 295 300

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

305 310 315 320

ALA Lys Thr Lys Pro Arg Glu Glu Gln Tyr ASN Ser thr Tyr Arg Val

325 330 335

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

340 345 350

Tyr Lys Cys Lys Val Ser asn Lys Ala Leu Pro Ile Glu Lys

355 360 365

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

370 375 380

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

385 390 395 400

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Glu Trp Glu

405 410 415

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

420 425 430

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

435 440 445

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

450 455 460

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

465 470 475 480

Lys

<210> 456

<211> 481

<212> PRT

<123> Artificial sequence

<220>

<223> chemically synthesized

<400> 456

GLU VAL GLN LEU LEU GLU SER GLY GLY GLU Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Ala Ile Lys

20 25 30

Pro Ile Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val

35 40 45

Ser Thr Thr Thr Ser Ser Gly Ala Thr Asn Tyr Ala Glu Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Serg ASP ALA LYS ASN THR LEU TYR LEU

65 70 75 80

GLN MET Ser LEU ARG ALA GLU ASP Thr Ala Val Tyr Tyr Cys ASN

85 90 95

Val Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly

100 105 110

Gly Ser Gly Gly Ser Glu Val Gln Leu Glu Ser Gly Gly Gly Glu

115 120 125

Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Ala Phe Ser Asn Tyr Gly

145 150 155 160

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser

165 170 175

Arg Leu Ala Trp Ser Gly Gly Ser Thr Asp Tyr Val Glu Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

195 200 205

Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

210 215 220

Arg Gln Arg Ser Tyr Ser Arg Tyr Asp Ile Arg Thr Pro Gln Thr Tyr

225 230 235 240

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly Gly Gly

245 250 255

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro

260 265 270

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

275 280 285

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

290 295 300

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

305 310 315 320

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

325 330 335

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

340 345 350

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

355 360 365

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

370 375 380

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

385 390 395 400

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

405 410 415

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

420 425 430

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

435 440 445

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

450 455 460

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

465 470 475 480

Lys

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Claims (16)

1. An isolated polypeptide that binds PDL1 and 41BB, wherein said polypeptide contains at least one VHH domain that binds 41BB and contains a complementarity determining region 1 (CDR1) containing the amino acid sequence of SEQ ID NO: 26, complementarity determining region 2 (CDR2) containing the amino acid sequence of SEQ ID NO: 61 and complementarity determining region 3 (CDR3) containing the amino acid sequence of SEQ ID NO: 28; and at least one VHH domain that binds PDL1 and contains a CDR1 containing the amino acid sequence of SEQ ID NO: 105, a CDR2 containing the amino acid sequence of SEQ ID NO: 106, and a CDR3 containing the amino acid sequence of SEQ ID NO: 107. 2. The isolated polypeptide of claim 1, wherein at least one 41BB-binding VHH domain contains an amino acid sequence at least 95% identical to SEQ ID NO: 60, and wherein at least one PDL1-binding VHH domain contains an amino acid sequence that is at least 95% identical to SEQ ID NO: 124. 3. The isolated polypeptide of claim 1, wherein at least one 41BB-binding VHH domain contains the amino acid sequence of SEQ ID NO: 60, and wherein at least one PDL1-binding VHH domain contains the amino acid sequence of SEQ ID NO: 124. 4. Selected polypeptide according to any one of paragraphs. 1-3, wherein at least one VHH domain that binds 41BB and at least one VHH domain that binds PDL1 are operably linked via a linker polypeptide. 5. Selected polypeptide according to any one of paragraphs. 1-4, where each VHH domain is a humanized VHH domain. 6. Selected polypeptide according to any one of paragraphs. 1-5, wherein said isolated polypeptide comprises an immunoglobulin Fc region polypeptide. 7. The isolated polypeptide of claim 6, wherein said immunoglobulin Fc region polypeptide comprises an amino acid sequence selected from SEQ ID NOs: 1-6. 8. The isolated polypeptide of claim 7, wherein said immunoglobulin Fc region polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 9. Selected polypeptide according to any one of paragraphs. 6-8, wherein said polypeptide contains the structure: VHH-linker-VHH-linker-hinge-Fc, wherein each VHH is a humanized VHH sequence. 10. An isolated polypeptide that binds PDL1 and 41BB, wherein said polypeptide contains the amino acid sequence of SEQ ID NO: 449. 11. An isolated polynucleotide that encodes a polypeptide according to any one of paragraphs. 1-10. 12. An isolated cell that expresses a polypeptide according to any one of paragraphs. 1-10 containing a polynucleotide according to claim 11 and a control sequence containing at least a promoter and a transcription termination sequence. 13. The method of obtaining a polypeptide according to any one of paragraphs. 1-10, including culturing the isolated cell according to claim 12 under conditions suitable for expressing said polypeptide. 14. The use of a polypeptide according to any one of paragraphs. 1-10 for the treatment of neoplasms. 15. Use according to claim 14, wherein said neoplasm is cancer. 16. The use of a polypeptide according to any one of paragraphs. 1-10 to modulate immune cells to enhance tumor destruction.

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